Thalidomide: Dermatological Indications, Mechanisms of Action and Side-Effects J.J

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. Hsu and S.K. Tyring** *Department of Dermatology, University of California, Irvine, Irvine, CA, U.S.A. Division of Infectious Diseases, Department of Medicine, and Department 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. Center 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, Behçet’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 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 prevention 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 ‘thalidomide 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

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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

Antagonism of acetylcholine, histamine, prostaglandins E2 and F2, and serotonin Stabilization of lysosomal membranes Inhibition of basic ﬁbroblast growth factor-induced angiogenesis Reduction of cellular proliferation, myelin phagocytosis and subperineural oedema. Decrease in the production of hydroxyl and superoxide radicals at sites of inﬂammation Decrease in the capacity to release elastase and lactoferrin by lipopolysaccharide or lipoteichoic acid-stimulated granulocytes

HIV, human immunodeﬁciency virus; IL, interleukin; MHC, major histocompatibility complex.

Although thalidomide is considered first-line for ENL, no at 400 mg daily for the first 5 days, followed by 200 mg daily trials have compared it with corticosteroids or clofazimine. It for the next 15–60 days. Oral and genital lesions healed very has been noted that ENL is not a serious disease and that tha- rapidly, with milder and shorter recurrences. However, there lidomide should not be used because of its well-documented was no effect on ocular lesions or arthritis. These results were risks,13 but most would agree that thalidomide greatly lessens similar to that of another open trial.15 Other trials showed sim- the morbidity of ENL. ilar efficacy (Table 4). A pilot study was conducted from 1993 to 1996 to determine the dosage of thalidomide leading to the best efficacy ⁄toxicity ratio, and it was concluded that an initial Aphthous stomatitis dose of 50 mg daily is efficacious and that 50 mg every 2 or The first report of thalidomide for recurrent aphthous stomati- 3 days is efficacious to maintain remission in more than 60% tis was in 1979.14 Six patients had scrotal and mouth ulcers of patients.17 and were treated with thalidomide 100 mg daily. The lesions Thalidomide may work in Behçet’s syndrome by reducing were painless after 2–3 days and completely resolved after the production of hydroxyl and superoxide radicals that cause 7–10 days. Multiple small clinical studies (Table 3) and case tissue damage at sites of inflammation.18 The pathogenesis of reports have reported similar results. Thalidomide is also bene- Behçet’s syndrome is associated with an increase in chemotac- ficial for human immunodeficiency virus (HIV)-associated tic activity of neutrophils, neutrophil migration, and circula- aphthous ulcers (Table 3). However, it appears that thalido- ting immune complex-mediated vascular damage.18 Although mide in lower intermittent doses is not effective for prevent- thalidomide decreases chemotaxis of neutrophils and cell- ing recurrence of aphthous ulcers in patients with HIV. As mediated immunity, no change in these factors was found aphthous ulcers often heal on their own, thalidomide should when patients with Behçet’s syndrome were successfully trea- be reserved for only the most severe or recalcitrant cases of ted with thalidomide.19 As the lesions of Behçet’s syndrome orogenital ulceration.15 tend to resolve on their own, thalidomide should be used only in severe or unresponsive cases.15 Behçet’s syndrome Lupus erythematosus After reports of the efficacy of thalidomide in treating aphthous ulcers, thalidomide was used for the first time in Behçet’s syn- In 1977, thalidomide was first used successfully for discoid drome in an open trial of 22 patients.16 Thalidomide was given lupus erythematosus in 20 patients.20 Several studies have

2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273 Thalidomide in dermatology, J.J. Wu et al. 257

Table 2 Clinical uses

Strong supporting literature (randomized controlled trials or multiple series) Erythema nodosum leprosum Actinic prurigo Adult Langerhans cell histiocytosis (histiocytosis X) Aphthous stomatitis Aphthous ulceration associated with human immunodeficiency virus Behçet’s syndrome Cutaneous sarcoidosis Erythema multiforme Graft-versus-host disease Jessner–Kanof lymphocytic infiltration of the skin Kaposi sarcoma Lichen planus Lupus erythematosus Melanoma Prurigo nodularis Uraemic pruritus Less supporting literature (single series or case reports) Chronic erythematous oedema Cutaneous benign lymphoid hyperplasia Cutaneous Rosai–Dorfman disease Cutaneous vasculitis Generalized eruptive histiocytosis Immune complex vasculitis Palmoplantar pustulosis Pemphigoid Perforating folliculitis Polymorphic light eruption Porphyria cutanea tarda Fig 2. A patient with erythema nodosum leprosum, with Postherpetic neuralgia Pyoderma gangrenosum erythematous nodules of the skin and subcutaneous tissue leading to Refractory vulval ulcerations associated with Crohn disease scarring and hypopigmentation. Schnitzler syndrome Scleromyxoedema equivalent of a sun protection factor of 1Æ56 to > 4Æ0, which Weber–Christian disease may explain the therapeutic effects of thalidomide in photo- sensitive disorders.24 shown strong efficacy (Table 5). The response rates are lower Prurigo nodularis than the published literature might suggest, as most of these trials consisted of patients who were refractory to other In 1965, Sheskin was also the first to treat prurigo nodularis conventional therapies. Not only is it effective, thalidomide with thalidomide.6 Twelve patients had a decrease in pruritus administration also allowed a reduction in prednisone and after 2–3 weeks of treatment and had a disappearance of azathioprine. In our own clinical experience, thalidomide is lesions after several months.3 After receiving thalidomide very effective for systemic lupus erythematosus (Figs 4 and 5), 100–300 mg daily, four patients had a response after 1 month discoid lupus erythematosus, subacute cutaneous lupus erythe- and resolution within 4–6 months.25 Two to 3 years later, matosus and tumid lupus erythematosus. However, it seems two patients were still in remission. that the skin manifestations recur within days to 1 week after Twenty-two patients with prurigo nodularis were treated stopping the medicine. with thalidomide 50–300 mg daily for an average of The mechanism of thalidomide in lupus erythematosus is 12 months (range 2 weeks)5 years).26 Twenty patients had not known. It may stabilize lysosomal membranes,21 inhibit an immediate relief from pruritus and a significant decrease in hydroxyl and superoxide free radical production by neutroph- size and number of skin lesions after 1–2 months. However, ils,22 inhibit the synthesis of IgM and its subsequent depos- the therapy had to be discontinued in 13 patients (59%) due ition on the basement membrane,23 or suppress neutrophil to side-effects, of which neuropathy occurred in five patients. chemotaxis and macrophage phagocytosis. One study found In an uncontrolled, prospective case series, 10 HIV-positive that thalidomide 100 mg daily for 4 weeks inhibited acute patients with prurigo nodularis were treated with thalido- ultraviolet (UV) B erythema at 24 h after exposure, with the mide.27 Two of the patients were lost to follow-up, but the

2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273 258 Thalidomide in dermatology, J.J. Wu et al.

peripheral neuropathy (to lose the sensation to scratch) and the sedation. The sedative properties of thalidomide may dis- rupt the itch–scratch cycle, but this seems unlikely as other sedatives do not control pruritus well.30 With treatment, zinc and iron content in the lesions of prurigo nodularis decreased towards the normal range.31

Moderately effective

Actinic prurigo

The first study of thalidomide in treating actinic prurigo was in the early 1970s.32 Thirty-four patients were given thalidomide 300 mg daily tapered to maintenance doses of 15 mg daily. All but two patients showed clinical improvement within an average of 50 days. However, upon discontinuing treatment, the condition recurred. Another study of 51 patients with actinic prurigo reported similar results.33 An additional 14 patients were treated with thalidomide 50–200 mg daily, with 11 showing prolonged improvement within 1–3 weeks.34 Eight of these patients required a maintenance dose of 50–100 mg weekly, while the other three patients did not need to continue treatment. One group of investigators performed immunohistochemi- cal studies on biopsy specimens from 20 Mexican patients with actinic prurigo.35 It was found that keratinocytes con- tained high amounts of tumour necrosis factor (TNF)-a and calprotectin. They believed that in these genetically predis- posed patients, UV radiation may trigger excessive TNF-a pro- Fig 3. A patient with erythema nodosum leprosum, with violaceous duction by keratinocytes, which could be prevented by plaques and nodules on the legs. treatment with the TNF-a antagonist thalidomide. Another study demonstrated that complete resolution of actinic prurigo cheilitis was more frequently seen with the combination of remaining eight all had a greater than 50% decrease of itch topical steroids, thalidomide and sun-protection measures over a mean of 3Æ4 months. Seven patients had a greater than (42Æ2%) than with topical steroids and sun-protection meas- 50% decrease of skin involvement over a mean of 5 months. ures (16Æ3%).36 However, three patients developed thalidomide-induced peripheral neuropathy. Adult Langerhans cell histiocytosis (histiocytosis X) Phototherapy also has efficacy in prurigo nodularis, and a prospective open trial sought to determine if both thalidomide The first successful treatment of Langerhans cell histiocytosis and phototherapy could effectively treat the disease.28 Thalido- with thalidomide was documented in 1987.37 Another mide administration was followed by narrowband UVB patient with cutaneous histiocytosis treated with thalidomide (TL-01) irradiation until complete or almost complete remis- 300 mg daily had complete remission after 1 month and no sion of the disease occurred. A high rate of response was recurrence after cessation of therapy.38 Eight other patients achieved after an average of 12 weeks of thalidomide therapy with adult Langerhans cell histiocytosis remitted after and 32 UVB courses. 1–3 months of therapy, but they had frequent relapses after In patients with prurigo nodularis treated with thalidomide, cessation of therapy. There was little or no effect on the 70% of patients have been reported to have peripheral neur- visceral features of the condition.39–45 Histopathological opathy.29 In our clinical experience, thalidomide works very examination after treatment in one patient showed no histi- well in prurigo nodularis in terms of alleviating the pruritus. ocytic infiltrate, implying an effect on the proliferative Neuropathy has not been a major problem in our experience Langerhans cell population.41 A patient with both cutaneous in treating these patients. Langerhans cell granulomatosis and systemic lupus erythe- Several theories have been proposed about the mechanism matosus was first successfully treated with the purine ana- of thalidomide in prurigo nodularis. Thalidomide may have logue, 2-chlorodeoxyadenosine (cladribine), and then with a local effect on proliferated neural tissue in prurigo nodular- thalidomide.46 One patient did not respond to 100 mg is.30 A central effect of thalidomide may be the secondary daily, which led to neuropathy.41

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Table 3 Clinical trials of thalidomide for aphthous ulcerations

Publication No. of patients Description of study Clinical response Other comments Torras et al.128 9 100 mg daily for 10 days for Healed ulcers, reduced pain, and aphthous stomatitis lengthened intervals between relapses in 8 of 9 patients Jenkins et al.129 15 400 mg daily for 5 days and then 200 mg Within 5–21 days, 14 patients had Although remission was maintained daily for 28 days for aphthous stomatitis total healing, and 1 had major during therapy, most relapsed within improvement 1 month of treatment cessation.130 Grinspan131 40 If severe aphthous stomatitis, 300 mg Regardless of treatment group, 75% Patients with relapses were successfully

• daily for 7–30 days was given, and of patients responded well treated with 100 mg daily for 12 days rts ora fDermatology of Journal British if less severe, 100 mg daily Ranselaar 67 A large randomized, double-blind, In the group treated with thalidomide, Those treated with thalidomide also et al.132 placebo-controlled, crossover for 48% had a complete remission had fewer ulcers and less impairment aphthous stomatitis: compared with only 9% in the group 100 mg daily or placebo for 2 treated with placebo months each and then switched treatment without a washout period 2005 Revuz et al.133 73 A randomized, placebo-controlled, In the group treated with thalidomide, Thalidomide-induced remission lasted crossover trial for aphthous 32 of 73 patients (44%) had a an average of 20 days before recurrence 153, stomatitis: thalidomide 100 mg complete remission compared with pp254–273 daily vs. placebo each for 2 months only 6 (8%) in the group treated with placebo Paterson et al.134 20 HIV- positive patients A retrospective review from 14 patients had complete healing and There was no change in CD4+ cell 1989 to 1993 for aphthous 6 had clinical improvement counts during or after treatment

ulceration of the oropharynx, Wu J.J. dermatology, in Thalidomide oesophagus and rectum, 200 mg daily for 2 weeks Weidle135 14 HIV- positive men 7-day course of thalidomide 300 Three-quarters of the thalidomide or 600 mg daily was compared group responded to therapy vs. with placebo none of the placebo group Jacobson 57 HIV- positive patients A double-blind, randomized, In the thalidomide group, 16 of 29 Thalidomide also improved the ability to et al.136 placebo-controlled study for oral patients (55%) had complete eat and decreased pain. 7 patients aphthous ulcers, 4-week course healing of the ulcers after 4 weeks complained of both somnolence and rash each, of either thalidomide 200 mg compared with only 2 of 28 and 6 of the 29 patients ceased treatment daily or placebo patients in the placebo group (7%) because of toxicity (P <0Æ001) tal et . 259 260 Thalidomide in dermatology, J.J. Wu et al.

Cutaneous sarcoidosis

The ﬁrst case report of cutaneous sarcoidosis in four patients treated successfully with thalidomide was in 1983.47 Ten patients with chronic cutaneous sarcoidosis resistant to conventional therapy were treated with thalidomide.48 With a daily ) dose of 1Æ84 mg kg 1 for 2Æ8 months there was a complete

, and soluble TNF response in three patients and a partial response in four patients, a and no response in three patients. Thalidomide was gradually reduced in five of seven patients who had clinical improvement. Three of these five patients relapsed and thalidomide was again given, which reduced or resolved the symptoms. In another open study, eight patients with chronic skin sar- Although there was ain significant largest decrease ulcer diametergroup, in 80% the of thalidomide thesea patients thalidomide-induced also rash exhibited There was no differenceof in HIV plasma RNA, levels TNF- receptor II at the time of ulcer recurrence coidosis were treated with thalidomide for 16 weeks.49 All skin biopsies showed reductions in granuloma size and in epidermal thickness after treatment. In another open-label study, 15 patients with cutaneous sarcoidosis were treated with thalidomide.50 Of the 14 patients who completed 4 months of therapy, all showed patient-evaluated improvement, and 10 of 03)

Æ 12 showed improvement based on photography. In a retro- 0

¼ spective study of 12 patients with cutaneous sarcoidosis trea- P ted with thalidomide, four patients achieved complete responses, six had partial responses, and two had no change 51 221)

Æ in their disease status. However, despite these trials, thalido- 0 mide has not been effective for cutaneous sarcoidosis in our ¼ P

After 8 weeks, 9thalidomide patients group (90%) had in complete the healing of their oralwith ulcers, 2 compared of 6placebo patients group (33%) ( in the In the thalidomide group,patients 14 (61%) of had 23 recurrence compared with 11 of(42%) 26 in patients the placebo( group clinical experience. Interleukin (IL)-2, IFN-c and TNF-a are the major cytokines that drive the granulomatous inﬂammation of sarcoidosis.52,53 Thalidomide inhibits both IFN-c and TNF-a as well as IL-12, which stimulates IFN-c production. Thalidomide increases IL-2, which counteracts the effects of IFN-c and TNF-a. After thalidomide treatment, there is an increase in T-cell recruit- ment into granulomas, the appearance of multinucleated giant cells, and increased numbers of dermal Langerhans cells and mature dendritic cells.49 High levels of serum angiotensin- converting enzyme are normalized, suggesting that thalidomide may inhibit macrophages from producing and releasing angiotensin-converting enzyme.54

placebo-controlled clinical trial where 10 participants were given thalidomide and 6The were 8-week given course placebo. startedoral with dosage an of initial 400for mg 1 daily week, followeddaily by for 200 7 mg weeks randomized, placebo-controlled study for oral andaphthous oesophageal ulcers, 100 mgplacebo or 3 times per6 week for months Erythema multiforme

The ﬁrst case report of recurrent erythema multiforme treated with thalidomide was in 1982.55 After receiving thalidomide 200 mg daily for a few days, the lesions on the hands, feet, lips and glans penis had healed. The patient did not have any relapses while on 100 mg daily for 6 months. After thalidomide administration, two patients with recurrent erythema multiforme had fewer and milder episodes.56 A 23-year-old

16 HIV- positive patients A double-blind, randomized, 49 HIV- positive patients A multicentre, double-blind, woman with disseminated skin erythema multiforme eruptions that had started at menarche and spread during two pregnancies responded well to thalidomide treatment.57 Two

138 other patients responded to thalidomide 100 mg daily, but .

et al later relapsed after tapering the drug and eventually discontin- 58

(Continued) ued therapy due to neuropathy. A 73-year-old woman with 137 . recurrent erythema exudativum multiforme associated with Ramirez-Amador et al Jacobson HIV, human immunodeﬁciency virus; TNF, tumour necrosis factor. herpes simplex was treated successfully with thalidomide.59 Table 3

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Table 4 Clinical trials of thalidomide for Behc¸et’s syndrome

Publication No. of patients Description of study Clinical response Other comments Hamza18 30 men Open study, 100–300 mg daily 20 had a complete response, and 6 However, withdrawing for 1–2 months had a partial response thalidomide caused recurrence in 12 of 13 patients, which was controlled in all 12 after restarting thalidomide Gardner- 59 patients with severe Retrospective study There was complete resolution in The incidence of symptomatic Medwin oral or genital ulcerations 81% of patients within 1 neuropathy secondary to et al.139 (23 of whom had Behc¸et’s month of thalidomide therapy thalidomide use was • rts ora fDermatology of Journal British syndrome) at doses of 200 mg daily. determined to be 13Æ5% No further thalidomide was required by 20% of patients responding, and in the remaining 80%, improvement was maintained with smaller doses of 7–200 mg daily Hamuryudan 96 In a randomized, double-blind, In the thalidomide 100 mg daily Within 4 weeks after therapy

2005 et al.140 placebo-controlled trial, group, 2 of 32 patients (6%) had a ended, most patients had a thalidomide 100 or 300 mg or complete response. In the thalidomide recurrence 153, placebo was given daily for 300 mg daily group, 5 of 31 patients 24 weeks (16%) had a complete response. pp254–273 In the placebo group, none had a response (P ¼ 0Æ031) de Wazieres 17 patients with oral and genital A pilot study was conducted 10 patients underwent remission Nerve conduction studies showed et al.17 ulcers, 4 of whom had from 1993 to 1996 to determine within the first month, and 7 other a decrease in sensory nerve action hldmd ndraooy ..Wu J.J. dermatology, in Thalidomide Behçet’s syndrome the dosage leading to the best patients improved. 6 patients had a potentials in 6 patients after efficacy ⁄toxicity ratio, 50 mg complete remission after 2 months of 8.5 months daily for 1 month. If the patient treatment, and 1 patient after 4 months. improved, the dosage was A dosage of 200 mg over 8 days reduced to 50 mg every other induced prolonged remission in day for 1 month and 50 mg 12 patients. A dosage of 100 mg over every 3 days thereafter 8 days induced prolonged remission in 5 of 6 patients Kari et al.141 10 children Retrospective study, 3 children had complete remission, However, neuropathy developed ) 1mg kg 1 weekly to and 2 had less frequent and milder in 2 children and was irreversible ) 1mgkg 1 daily oral ulcers in one of them tal et . 261 262 hldmd ndraooy ..Wu J.J. dermatology, in Thalidomide Table 5 Clinical trials of thalidomide for lupus erythematosus (LE)

Publication No. of patients Description of study Clinical response Other comments Housman 23 patients unresponsive Retrospective review, 100 mg 74% demonstrated complete Of the patients experiencing a complete et al.23 to conventional agents, daily resolution of the cutaneous or partial response, 91% saw improvement including antimalarial agents manifestations of LE, 13% within 8 weeks of thalidomide treatment demonstrated 75% or greater initiation improvement, and 13% had less than 75% improvement Kyriakis et al.142 22 patients with chronic discoid LE An open uncontrolled trial, There was a 55% complete response Relapses, which were mild, occurred within 50–200 mg daily rate, 23% partial response rate, and 39Æ4±21Æ4 days after drug discontinuation tal et 14% were withdrawn from the trial due to drug intolerance . 143

05BiihAscaino Dermatologists of Association British 2005 Knop et al. 60 patients with discoid LE 200 mg twice daily, tapered 54 patients (90%) had at least a partial Of the patients treated for more than to 50–100 mg daily after a response, and 39 patients (65%) had 3 months, 11 of 41 patients remained clinical response complete regression of lesions asymptomatic for 2–8 months after therapy. After cessation of therapy, 30 patients relapsed but responded to restarting thalidomide ) Atra and Sato22 23 patients with systemic LE 300 mg daily or 4 mg kg 1 18 of 20 patients (90%) had a 7 of 20 relapsed on withdrawal of therapy daily in children complete response, and 2 had a partial response Sato et al.144 18 patients with systemic Maintained at low dose (25–100 72% complete response rate and LE not responsive to chloroquine mg daily) for a minimum of 28% partial response rate 6 months Ordi-Ros 22 patients with cutaneous A prospective study, 100 mg Complete remission occurred in 12 et al.145 lupus (9with discoid LE, 7 with daily of 16 patients (75%), partial response • rts ora fDermatology of Journal British subacutecutaneous LE, 4 with was achieved in 4 of 16 patients (25%), lupus profunda, 2 with and no response occurred in 3 of nonspeciﬁc rash) 19 patients (16%) Hasper146 11 patients with chronic 100–300 mg daily 7 patients had a complete remission, Of the responding patients, 6 relapsed after cutaneous LE (7 with discoid LE 2 improved signiﬁcantly, and discontinuing therapy, and responded to and 4 with subacute cutaneous LE) 1 had no response after 3 months a maintenance dose of 12Æ5–50 mg daily of treatment Stevens et al.147 11 patients with discoid 50–100 mg daily 7 of 16 patients (44%) had a complete 11 patients were maintained on 25–50 mg

2005 LE, 3 with subacute cutaneous response, 6 of 16 (37%) had a partial daily. All relapses after withdrawal of LE, 1 with subacute cutaneous response, and 3 did not respond thalidomide improved with restarting 153, LE plus malar rash, and 1 with the drug nonspeciﬁc chronic patchy pp254–273 erythema Thalidomide in dermatology, J.J. Wu et al. 263

Fig 5. Malar rash of systemic lupus erythematosus 1 month after Fig 4. Malar rash of systemic lupus erythematosus before thalidomide thalidomide 50 mg nightly. treatment in a 22-year-old Asian woman. She had failed prednisone 40 mg daily and hydroxychloroquine 200 mg twice daily for several months. One prospective randomized trial showed that thalidomide In a retrospective study, 26 patients with chronic erythema may not offer any clinical benefit when incorporated as an ini- 62 multiforme unresponsive to conventional therapies were trea- tial therapy for chronic GVHD. Patients were randomized to ted with thalidomide 100 mg daily.60 On average, the dur- receive either ciclosporin and alternate-day prednisone (n ¼ ation of each episode was reduced by 11 days. Six of the 27) or ciclosporin, prednisone and thalidomide (200–800 mg patients had subacute erythema multiforme, and lesions daily; n ¼ 27). In the thalidomide group and no-thalidomide resolved within 5–8 days. A maintenance dose kept the group, response rates were 83% vs. 89% at 2 months (P ¼ patients in remission. 0Æ7), 88% vs. 84% at 6 months (P >0Æ8) and 85% vs. 73% at 1 year (P ¼ 0Æ5). In the thalidomide group and no-thalidomide group, survival rates were 66% vs. 74% at 1 year, and Graft-versus-host disease 66% vs. 54% at 2 years (P ¼ 0Æ85). The authors concluded The first use of thalidomide in humans for graft-versus-host that despite a high response rate and survival rate, thalidomide disease (GVHD) was in 1988 when a patient with acute cuta- offers no clinical benefit as initial therapy for chronic GVHD. neous GVHD unresponsive to corticosteroids after allogeneic Thalidomide is not useful as prophylaxis of chronic GVHD; it bone marrow transplant improved within 3 days of starting is associated with a higher rate of GVHD and higher mortality 63 thalidomide.61 Several trials have shown moderate efficacy rate. (Table 6) in patients refractory to other therapies. The It is believed that the metabolites of thalidomide act at an response rates are lower than the published literature might early stage in the antigen recognition-activation pathway of imply as most of these studies consisted of patients who were graft T lymphocytes, which downregulates normal lymphocyte 64 refractory to other conventional therapies. Similar to lupus function. This may be achieved by allowing the develop- patients, patients with GVHD may be able to decrease or cease ment of antigen-specific suppressor cells and inhibiting the 65 other immunosuppressive drugs. development of cytotoxic cells.

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Table 6 Clinical trials of thalidomide for graft-versus-host disease (GVHD)

Publication No. of patients Description of study Clinical response Other comments Vogelsang 44 patients refractory 800 mg daily was given for 14 patients had a complete response, In the refractory GVHD group survival was et al.148 with or high-risk chronic 3–6 months 12 had a partial response (deﬁned as 76%, and in the high-risk GVHD group GVHD improvement in more than 50% but survival was 48%

less than 100% of all affected organ al et systems), and 18 had no response 149 . Parker et al. 80 patients with chronic 100 mg four times daily, which 16 patients (20%) had a response, Of those with the standard-risk chronic

05BiihAscaino Dermatologists of Association British 2005 GVHD unresponsive was increased to 200–400 mg with 56% experiencing a complete GVHD, 24% responded, compared with to prednisone with or four times daily depending response and 44% a partial response 16% of the high-risk chronic GVHD group without ciclosporin on the response ) Rovelli et al.150 14 children with refractory 3–9Æ5mgkg 1 daily given After 2 months of treatment, 6 3 with a complete response and 1 with a or high-risk chronic GVHD twice or four times daily patients had a complete response, partial response were able to stop 4 patients had a partial response, thalidomide without any relapses and 4 did not respond Browne et al.151 37 allogeneic bone marrow Single-institution study 14 of 37 patients (38%) had a Overall, the 2-year Kaplan–Meier survival transplantation patients with response after thalidomide was was 41% (95% conﬁdence interval 24–59%) chronic GVHD refractory to started (1 complete, 13 partial). 4 after thalidomide was started standard immunosuppressive of 16 adults (25%) and 10 of 21 therapy children (46%) responded van de Poel 12 patients with GVHD refractory Clinic patients between 4 patients had a complete response, However, of these 5 patients, 3 died 152

• et al. to chronic prednisone and 1991 and 2001 and 5 showed a partial response eventually of ongoing GVHD, pneumonia rts ora fDermatology of Journal British ciclosporin and recurrent leukaemia Arora et al.62 54 patients with chronic GVHD A prospective randomized trial, In the thalidomide group and no- In the thalidomide group and no-thalidomide randomized to receive either thalidomide group, response rates group, survival rates were 66% vs. 74% at ciclosporin and alternate-day were 83% vs. 89% at 2 months 1 year, and 66% vs. 54% at 2 years prednisone (n ¼ 27) or (P ¼ 0Æ7), 88% vs. 84% at 6 months (P ¼ 0Æ85) ciclosporin, prednisone and (P >0Æ8) and 85% vs. 73% at thalidomide (200–800 mg 1 year (P ¼ 0Æ5) daily; n ¼ 27) 2005 153, pp254–273 Thalidomide in dermatology, J.J. Wu et al. 265

administered to debulk disease on her legs. Thalidomide was Jessner–Kanof lymphocytic infiltration of the skin started with alitretinoin 0Æ1% gel applied twice daily to the The first clinical trial of thalidomide for Jessner–Kanof lymph- nonirradiated lesions. Over 7 months, there was a partial ocytic infiltration of the skin was in 1983.66 Three of the five response in both irradiated and nonirradiated lesions. patients had a prior inconsistent or negative response to chlo- A phase II study of thalidomide was performed to evaluate roquine. All five cases had an excellent response with thalido- its efficacy and toxicity for cutaneous AIDS-related Kaposi sar- mide 100 mg daily. However, skin lesions in four patients coma and to determine if the clinical response correlated with reappeared when treatment was stopped. With a maintenance a decrease in titre of human herpesvirus 8 DNA in peripheral dose of 25–50 mg daily for more than 2 years, three of five blood.72 Seventeen men with AIDS-related Kaposi sarcoma patients had normal skin. were given thalidomide 100 mg daily for 8 weeks. Six of 17 In a randomized controlled trial, 28 patients were randomly patients (35%) had a partial response, and eight patients with- assigned to receive thalidomide 100 mg daily or placebo over drew (six due to toxicity, one to noncompliance, and one to a period of 2 months and were then switched to the other early progression of disease). Human herpesvirus 8 DNA load treatment.67 After the first period, 11 of 13 patients treated decreased to undetectable levels in three of the five partial with thalidomide were in complete remission, and the other responders. two patients did not respond. For those who received placebo, In a phase II dose-escalation study, 20 patients with AIDS- there was no complete remission in the patients (P <0Æ0001). related Kaposi sarcoma were treated with an initial dose of After the switch, nine of 14 patients who had received thali- thalidomide 200 mg daily, which was increased to a maxi- domide in the second period were in complete remission, and mum of 1 g daily for up to 1 year.73 The overall response rate 10 of the 13 patients who had received thalidomide during was 40%. The median duration of drug treatment was the first period were in complete remission. Complete remis- 6Æ3 months; the median time to progression was 7Æ3 months. sion occurred in 19 (76%) after thalidomide therapy and in The median thalidomide dose at the time of response was four (16%) after placebo (P <0Æ001). Of the 27 patients who 500 mg daily (range 400–1000). The antiangiogenic proper- received thalidomide, 16 (59%) were in complete remission ties of thalidomide may have possible clinical efficacy in a after 1 month and 20 (74%) were in complete remission after malignancy very dependent on angiogenesis such as Kaposi 2 months. sarcoma.

Uraemic pruritus Lichen planus ⁄lichen planopilaris

One patient with severe pruritus of unknown cause did not A patient with generalized lichen planus refractory to multiple improve with thalidomide.56 In a randomized, double-blind, drugs was given thalidomide 300 mg daily for 2 weeks and crossover trial, 29 patients with refractory uraemic pruritus then 200 mg daily for another 10 weeks, which resulted in were treated with thalidomide 100 mg daily or placebo resolution of all his lesions.74 Four patients with refractory daily for 1 week.68 Two-thirds of patients had an 80% oral lichen planus were successfully treated with thalidomide reduction in pruritus (P <0Æ05). Those with less severe 25–150 mg daily for 15–36 months without recurrence or symptoms seemed more likely to respond. The mechanism adverse effects.56,75,76 A patient with erosive flexural lichen is not known, but it may be related to interference of planus was successfully treated with a combination of thalido- inflammatory mediators. mide and tacrolimus 0Æ1% ointment.77 In a retrospective study of six patients with severe erosive Possibly effective lichen planus treated with thalidomide, four patients had complete healing for 4 months, one had partial healing, and one had no change in the disease. In the five patients with a clin- Kaposi sarcoma ical improvement, oral erosions rapidly relapsed after thalido- A 14-year-old girl with HIV and Kaposi sarcoma was treated mide therapy ended.78 with thalidomide for oral ulcers.69 There was a reduction in A 53-year-old woman with recalcitrant lichen planopilaris the size of existing Kaposi sarcoma lesions, and no new was successfully treated with thalidomide 50 mg twice lesions appeared. Further, there was a decrease in the human daily for 6 months.79 We reported a woman with lichen plan- herpesvirus type 8 DNA level in the peripheral blood. How- opilaris who was started on 150 mg daily for 1 month, which ever, it was also argued that the response was due to the resulted in regrowth of hair.80 One month later, the thalido- withdrawal of corticosteroids rather than treatment with tha- mide was tapered to 50 mg daily, which prevented a recur- lidomide.70 A 46-year-old woman with chronic myelogenous rence of hair loss. Despite the positive results in our case leukaemia who had received an allogeneic haematopoietic report, the use of thalidomide has not consistently yielded stem cell transplantation presented with human herpesvirus good results in other patients.81 Since the publication of our 8-associated Kaposi sarcoma involving her left leg.71 Since her case report, we have treated several more patients with lichen transplant, she had been on continuous immunosuppres- planopilaris with positive results in terms of decreasing any sive therapy because of chronic GVHD. Irradiation was associated erythema.

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100 mg daily, leading to complete resolution.88 Another Melanoma patient was successfully treated with thalidomide 100 mg Solid tumours must develop their own blood supply by neo- daily, resulting in complete remission for 2 years, but cessa- angiogenesis to grow and metastasize. As thalidomide inhibits tion of therapy secondary to neuropathy led to immediate the processing of mRNA encoding peptide molecules for the relapse.89 After 6 months of therapy, one patient had healing angiogenic substance, vascular endothelial growth factor, there with scarring and no new lesions.90 One case of pyoderma has been recent research studying its efficacy for tumours such gangrenosum involving the penis refractory to high doses of as melanoma. Thalidomide and pentoxifylline potentiate each prednisolone improved within 5 days of thalidomide 100 mg other’s antiangiogenic effect, as demonstrated in human daily.91 A 47-year-old man with pyoderma gangrenosum malignant melanoma cells in the cornea of Macaca arctoides mon- unresponsive to methylprednisolone had complete healing keys.82 A phase I ⁄II study of thalidomide and temozolomide after 10 weeks of thalidomide.92 Two patients with pyoderma for metastatic melanoma was completed recently.83 Prelimin- gangrenosum in association with Behçet’s syndrome were ary results have shown significant antitumour activity, even in given thalidomide 400 mg daily, later tapered to 50–100 mg brain metastases.84 daily, which resulted in immediate, complete healing of skin The complete results of the above preliminary study showed lesions and prevented the development of new mucocutaneous that thalidomide and temozolomide were well tolerated and lesions.93,94 Despite these case reports, thalidomide has not had significant antitumour activity in patients with advanced been effective in our clinical experience. Most of our patients melanoma.85 Twelve patients with unresectable stage III or IV have discontinued the medication after 3–4 months due to melanoma without brain metastases were entered into four lack of efficacy. ) treatment cohorts: level 1, temozolomide 50 mg m 2 daily for 6 weeks followed by a 4-week break; and levels 2, 3 and ) Contraindicated use 4, temozolomide 75 mg m 2 daily for 6 weeks followed by breaks of 4, 3 and 2 weeks, respectively. Thalidomide was Toxic epidermal necrolysis started at 200 mg daily and increased to a maximum of 400 mg daily. There were one complete response and four The pathogenesis of toxic epidermal necrolysis was believed to partial responses all at dose levels 2–4, and three of these be related to an increased level of TNF-a. Thalidomide was used patients were over 70 years of age. The median duration of in a randomized, double-blind, placebo-controlled trial as tha- response was 6 months (range 4–17+), and the median over- lidomide is known as an inhibitor of TNF-a.95 Ten of 12 all survival was 12Æ3 months (range 4–19+). All regimens patients who received thalidomide 400 mg daily for 5 days were well tolerated. died, compared with only three of 10 who received placebo One study used low-dose thalidomide for several advanced (relative risk 2Æ78, P ¼ 0Æ03). The study was stopped prema- malignancies including melanoma and breast, ovarian and turely because of excess mortality in the thalidomide group. It renal cell cancer.86 Sixty-six patients with advanced measur- was found that there was a paradoxical enhancement of TNF-a able cancer (17 melanoma, 12 breast, 19 ovarian, 18 renal after therapy with thalidomide. In diseases such as toxic epider- cell cancer) received thalidomide 100 mg daily until disease mal necrolysis in which T-cell activation is involved in the path- progression or unacceptable toxicity was encountered. ogenesis, the use of thalidomide, which may stimulate T cells in Although three of 18 patients with renal cell cancer showed vivo, may further worsen the condition.96 Toxic epidermal nec- partial responses, no objective responses were seen in the rolysis was later found not to be related to TNF-a but to the sys- other tumour types. However, there were significant improve- tem of Fas receptors on keratinocytes.97 However, regardless of ments in appetite (P <0Æ05) and sleeping (P <0Æ05). the mechanism, thalidomide should not be used to treat toxic In another study, 20 patients with metastatic melanoma epidermal necrolysis. without symptomatic brain metastases were administered thalidomide 200 mg daily, with increments of 100 mg every Adverse effects 7 days to a maximum dose of 800 mg daily.87 Although none of the patients had an objective response, seven patients Thalidomide is well-known for its side-effects of teratogenicity (35%) experienced stable disease for 12–32 weeks (median and peripheral neuropathy, but it also has endocrine effects 16). The authors believed that the antiangiogenic property of and other more benign adverse effects (Table 7). thalidomide is the basis of cytostatic activity in patients with metastatic melanoma. Considering that metastatic melanoma Teratogenicity has very few therapeutic options, thalidomide seems to be a promising avenue for further research. Birth defects are the most devastating adverse effect of thalidomide, which is classified as pregnancy category X. A single dose of 100 mg within the first 35–50 days of pregnancy can Pyoderma gangrenosum result in deformities.98 It is not known whether it has an A 3-year-old girl with pyoderma gangrenosum refractory to effect on spermatogenesis.21 Of 380 children born to thalido- corticosteroids and clofazimine was given thalidomide mide victims, 11 had congenital limb defects. This occurrence

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Table 7 Side-effects injury or death, chondrogenesis, DNA synthesis or gene tran- scription, growth factors, or integrins.100 Serious It has been theorized that thalidomide blocks a mesonephric Teratogenicity signal that is essential for normal limb growth.101 Elimination Common of the mesonephros resulted in limb reduction defects similar Sedation to those induced by thalidomide, and upper extremities were Constipation5 more likely to have defects compared with lower extremities, Rash153 Peripheral neuropathy just as observed in thalidomide-induced teratogenicity. The Thromboembolism mesonephros also produces insulin-like growth factor, which Dizziness99 is important in normal limb initiation and development.102 Uncommon Thalidomide-induced teratogenicity may be related to the anti- 116 Amenorrhoea angiogenic properties of thalidomide.103 Oedema5 Neutropenia7 Bradycardia Peripheral neuropathy Dry mouth and skin4 Pruritus6 Peripheral neuropathy is the other well-known side-effect of Headache21 thalidomide. The neuropathy has no relation to the total Hypotension cumulative dose,13 and it can be slow to resolve or may be Increased appetite irreversible.29 A 2-year prospective study monitoring 135 Mood changes patients treated with thalidomide for different dermatological Male sexual dysfunction117 diseases showed that the incidence rate of peripheral neuropa- Nausea5 Tachycardia thy was greatest in the initial year of treatment (20%). The Weight gain risk was related to the daily dose regardless of duration of therapy, with no neuropathy detected in those patients receiving 25 mg or less per day.104 In one study of patients with neuropathy secondary to thalidomide for 4–6 years after end- was five times higher than in the general population. Further, ing therapy, 25% had a full recovery, 25% had some improve- an Australia study by William McBride (who was the first to ment, and 50% had no change.105 The incidence has been report the association between thalidomide and phocomelia in reported to be from 0Æ5% to over 70%, with the elderly and 1961 in The Lancet) claimed that thalidomide altered DNA in women being at a higher risk.106 the sperm and egg cells of rats. In an open letter dated 30 Neuropathy usually first presents as symmetrical painful August 1997 by Randy Warren, Chief Executive Officer, and paraesthesias of the hands and feet with sensory loss in the Giselle Cole, President, of TVAC, which can be found at lower extremities. Muscle weakness or cramps may or may http://www.thalidomide.c./en/information/open_letter_2nd_ not be present, and pyramidal tract signs and carpal tunnel generation.html, it was stressed that these disabled children of syndrome may occur.107 A high incidence of ‘tightness around thalidomide victims were born as a result of some other unre- the feet’ has been reported.108 After discontinuing thalido- lated genetic birth disorder. They mentioned that the media mide, muscle weakness improves rapidly, but sensory deficits falsely reported, for the sake of sensationalism, that thalido- may improve slowly, worsen, or stay the same.109 mide disabilities could be passed to their children or grand- Biopsy findings show loss of large-diameter fibres without children. They also highlighted that William McBride was segmental demyelination and increased numbers of small discredited in 1982 for falsifying the results of his experi- fibres from regeneration.110 Electrophysiological studies show ments regarding the antinausea drug Debendox and was taken axonal neuropathy with reduced sensory nerve action potential off the Australian Medical Register in 1993. The TVAC has amplitude and increased latency in somatosensory-evoked been in communication with the British Thalidomide Society, potentials.111 the FDA, and Celgene Corporation, and the TVAC is confident that thalidomide has not doomed future generations. Miscellaneous side-effects The classification of the teratogenic effects are deformities of the upper and lower extremities such as amelia; absence of The most common side-effect is sedation, which diminishes bones, phocomelia; abnormalities of the external ear such as over time. Other common side-effects are rash, constipation anotia and micro pinna; abnormalities of the eye such as and dizziness. Uncommon side-effects include headache, anophthalmos, with or without association with facial palsy; hypotension, oedema, neutropenia, increased appetite, mood and defects of the internal organs.99 At or shortly after birth, changes, nausea, pruritus and weight gain. the mortality rate is 40%. Another adverse event in patients treated with thalidomide The exact mechanism of action is still not known. It has is thromboembolic complications, such as deep vein thrombo- been proposed that the categories of thalidomide-induced sis and pulmonary embolism.112 A review of data from Med- teratogenicity be divided into those affecting angiogenesis, cell Watch, the FDA’s spontaneous reporting programme, and

2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273 268 Thalidomide in dermatology, J.J. Wu et al. phase II and III clinical trials involving patients with multiple myeloma, renal cell cancer, melanoma and other cancers, revealed that events occurred after a mean of 2 months of thalidomide therapy, at a reported rate of 0–43% of treated patients, with a marked incidence when chemotherapy was given with thalidomide. In a group of 521 patients who received thalidomide and chemotherapy without venous thrombosis prophylaxis, 16% developed thrombotic events; of 60 patients who received thalidomide with dexamethasone, 15% developed thrombotic events; and among 326 patients who received thalidomide monotherapy, 5% developed thrombotic events. It has been suggested that there is a high rate of thromboembolic events in cancer patients treated with thalidomide because thalidomide may alter tumour cell interactions with coagulation factors; generate procoagulant factors; activate platelets or vascular endothelium; increase thrombo- genicity of endothelial cells through increased secretion of IFN by T-helper 1 cells; and induce increases in integrin levels which, combined with chemotherapy-induced endothelial damage, might lead to tumour cell adhesions and platelet clumps that can be thrombogenic. Thrombotic events have also been reported in lupus patients who had antiphospholipid antibodies.113 Some clinicians recommend a coagulation assessment of patients before starting thalidomide, and limited evidence suggests that with the addition of warfarin prophylaxis, patients may be safely continued on thalidomide after having thalidomide-associated thrombotic events.114 Rarely, thalidomide depresses thyroid function, stimulates adrenocorticotrophic hormone and prolactin production, and causes hypoglycaemia.115 Thalidomide has also been reported Fig 6. A human immunodeficiency virus-positive man with total to cause amenorrhoea116 and male sexual dysfunction.117 body erythematous macules following the use of thalidomide to treat Thalidomide may also cause dermatological side-effects. oral aphthous ulcers. Cases of exfoliative118 and erythrodermic119 reactions, allergic vasculitis and thrombocytopenic purpura,120 toxic epidermal should have a negative pregnancy test 2 weeks prior to start- necrolysis121 and psoriasis exacerbation122 have been reported. ing treatment, along with appropriate contraceptive advice. Patients with HIV receiving thalidomide may be more likely Baseline nerve conduction studies (NCS) are recommended to to experience hypersensitivity reactions (Fig. 6).123 In a monitor for the subclinical development of peripheral neuro- open-label clinical trial of 87 patients with multiple myeloma, pathy. Sensory nerve action potential amplitudes should be subjects were treated with thalidomide alone (50 patients) or measured in at least three peripheral nerves, usually the med- thalidomide and dexamethasone (37 patients).124 Skin reac- ian, radial and sural nerves. Falls of 30–40% should lead to a tions occurred in 46% of patients taking thalidomide and in review of thalidomide use, and a fall from baseline values of 43% of those taking thalidomide and dexamethasone. These > 40% on repeat testing should lead to discontinuation of the eruptions included maculopapular, morbilliform, seborrhoeic therapy. After every 10 g cumulative dose or every 6 months, or nonspecific dermatitis. Three patients developed severe skin follow-up testing is recommended. However, NCS every reactions (erythema multiforme, exfoliative erythroderma and 6 months are not practical in the U.K. If any symptoms toxic epidermal necrolysis) that required hospitalization and develop between tests, patients should stop thalidomide termination of thalidomide. immediately and seek medical advice. To prevent teratogenic exposure,125 the manufacturer of thalidomide has created a comprehensive programme to con- Monitoring guidelines trol prescribing, dispensing and use of the drug, known as the Thalidomide should be carefully selected for appropriate System for Thalidomide Education and Prescribing Safety patients, and for those who are of childbearing age both (S.T.E.P.S.TM),126 which is now running in the U.K. Its main counselling and contraceptives should be offered. British goal is to prevent fetal exposure to thalidomide. guidelines for the use of thalidomide include informed con- The three-step approach is to: control access to the drug; sent being obtained in every case and routine dispensing of educate and register prescribers, pharmacists and patients; and information leaflets.125 Women of childbearing potential monitor compliance. Prescribers are sent information about

2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273 Thalidomide in dermatology, J.J. Wu et al. 269 the S.T.E.P.S.TM programme, devised by Celgene Corporation, Drug interactions the manufacturer of thalidomide. If they are interested in par- ticipating, they must agree to: (i) give comprehensive patient Thalidomide enhances the activity of alcohol, barbiturates, counselling on the risks and benefits of thalidomide; (ii) give chlorpromazine and reserpine.106 It raises serum levels of acet- appropriate contraception counselling and pregnancy testing; aminophen and increases its toxicity.29 It antagonizes acetyl- (iii) have patients complete informed consent forms and sub- choline, histamine, prostaglandins and serotonin in vitro. Other mit them to the Slone Epidemiologic Unit; (iv) complete and drugs that cause sedation, neuropathy, or decrease the efficacy submit the prescriber section of the patient-monitoring sur- of oral contraceptives should be used carefully if thalidomide vey; (v) prescribe no greater than 28 days of therapy without is added to the patient’s regimen. refills; and (vi) tell patients to return unused thalidomide to the pharmacy.126 Pharmacies must also register in the TM Conclusions S.T.E.P.S. programme to dispense thalidomide. To receive the medicine, women of childbearing potential Thalidomide is an effective medication for ENL as well as sev- 126 must agree to use two forms of reliable contraception. Only eral other dermatological diseases refractory to conventional women who are postmenopausal, who have undergone a hys- therapies. However, the adverse effects of teratogenicity and terectomy, or who have not had menses for at least 24 con- peripheral neuropathy have to be considered before starting secutive months are considered sterile. Women must use thalidomide. In appropriately selected patients, thalidomide contraception for 4 weeks before the start of therapy and for can be an extremely efficacious medication. 4 weeks after ending therapy. Those who wish to be abstinent must remain so during this same period. References Women must also agree to undergo pregnancy testing before and during treatment.126 This is required every week for the 1 Mellin GW, Katzenstein M. The saga of thalidomide. Neuropathy first month and monthly afterwards in women with regular to embryopathy, with case reports of congenital abnormalities. N menstrual cycles and every 2 weeks in those whose cycles are Engl J Med 1962; 267:1184–93. irregular. Pregnancy testing must also be done if a patient misses 2 Stirling D, Sherman M, Strauss S. Thalidomide. A surprising recovery. J Am Pharm Assoc 1997; NS37:306–13. her cycle or there is any abnormality in menstrual bleeding. To 3 Grosshans E, Illy G. Thalidomide therapy for inflammatory der- encourage compliance with the pregnancy-testing requirement, matoses. Int J Dermatol 1984; 23:598–602. women should receive no more than a 1-week supply for each 4 Mellin GW, Katzenstein M. The saga of thalidomide (concluded): of the first 4 weeks. If pregnancy does occur during therapy, neuropathy to embryopathy, with case reports of congenital thalidomide must be stopped immediately, and the prescriber abnormalities. N Engl J Med 1962; 267:1238–44. and patient must meet to discuss the implications.126 Celgene 5 Neubert R, Neubert D. Pecularities and possible mode of Corporation must be informed immediately. The patient must actions of thalidomide. In: Handbook of Experimental Pharmacology (Kavlock RJ, Daston GP, eds). New York: Springer-Verlag, be referred to a board-certified obstetrician ⁄gynaecologist who 1997: 41–119. has training in reproductive toxicity. 6 Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Male patients must receive oral and written warnings of the Pharmacol Ther 1965; 6:303–6. risk of possible contraception failure and the need to use con- 7 Radomsky CL, Levine N. Thalidomide. Dermatol Clin 2001; doms. All patients must agree not to donate blood or share 19:87–103. thalidomide with others. 8 Sampaio E, Kaplan G, Miranda A et al. The influence of thalido- Patients and prescribers must both sign a four-copy informed mide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis 1993; 168:408–14. consent form. They must also complete frequent follow-up 9 Hastings RC, Trautman JR, Enna CD, Jacobson RR. Thalidomide questionnaires (every month for women and every 3 months in the treatment of erythema nodosum leprosum: with a note on for men). The surveys have questions about demographics, selected laboratory abnormalities in erythema nodosum leprosum. knowledge of the teratogenic risks of thalidomide, sexual activ- Clin Pharmacol Ther 1970; 11:481–7. ity, use of contraception, and not sharing thalidomide. 10 Iyer CG, Languillon J, Ramanujam K et al. WHO co-ordinated A questionnaire was completed by 17 of 19 dermatologists short-term double-blind trial with thalidomide in the treatment concerning thalidomide usage and monitoring practices in of acute lepra reactions in male lepromatous patients. Bull WHO 1971; 45:719–32. Wales.127 Eleven of the 17 respondents had prescribed tha- 11 Sheskin J. The treatment of lepra reaction in lepromatous leprosy: lidomide to a total of 40 patients, but only two dermatologists fifteen years experience with thalidomide. 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