THALIDOMIDE

0733-8635/01 $15.00

SYSTEMIC DERMATOLOGIC THERAPY

+ .OO

THALIDOMIDE Carrie L. Radomsky, PharmD, MD, and Norman Levine, MD

Thalidomide first was produced in Germany in the early 1950s and was marketed under the brand name Contergan in 1957.57 The drug was promoted as a safe sedative and was found to be useful as an antiemetic during pregnancy, resulting in its widespread use throughout Europe. In late 1960, reports of neuropathy associated with long-term use of thalidomide first appeared.96Shortly afterward, the use of thalidomide was associated with the appearance of previously rare birth defects-deformities of the arms and legswhich afflicted approximately 12,000 newborns. This discovery resulted in the withdrawal of thalidomide from world markets in 1961. Thalidomide had not been sold in the United States because of careful scrutiny by the Food and Drug Administration (FDA), which insisted on more data regarding its neuropathic side effects as well as its safety during pregnancy. For years, thalidomide was available only for strictly defined research purposes. In 1997, an FDA advisory committee recommended the approval of thalidomide for the treatment of erythema nodosum leprosum (ENL), which led to its July 1998 final approval for use in this condition in the United States. The FDA approval of thalidomide for ENL allows its use in many currently unapproved circumstances. This article reviews the pharmacology, adverse effects, and regulatory concerns and provides general therapeutic guidelines for the use of thalidomide in various dermatologic conditions.

PHARMACOLOGY

Thalidomide (a-N-phthalimidoglutarimide) is a synthetic derivative of glutamic acid.70It is a 2-ring system consisting of a left phthalimide ring and a right glutarimide ring with a single asymmetric carbon. It exists as optically active R and S forms that interconvert rapidly in vivo. In its clinically useful form, thalidomide is an optically inactive racemic mixture. It contains 4 amide bonds that are susceptible to hydrolytic cleavage, which occurs rapidly at a pH greater than 6.1°1 Thalidomide is a white, crystalline, odorless and tasteless substance with a molecular weight of 258.2 and a melting point of 271°C.55It is insoluble in ether and benzene; sparingly soluble in water, methanol, ethanol, and glacial acetic acid; and readily soluble in dimethyl s ~ l f o x i d e , 'dioxane, ~~ dimethyl formamide, pyridine, and chloroform.101Thalidomide is lipid soluble and crosses placental membranes readily, but its polar metabolites do not. Thalidomide does not appear to have any acute toxicity, making a fatal overdose nearly i m p ~ s s i b l e . ~ ~ PHARMACOKINETICS

Thalidomide shows first-order absorption and elimination kinetics. Its absolute bioavailability has been difficult to elucidate because of its poor water solubility. Thalidomide has an absorption half-life of 1.70 2 1.05 hours.

From the Section of Dermatology, University of Arizona College of Medicine, Tucson, Arizona

DERMATOLOGIC CLINICS VOLUME 19 * NUMBER 1 *JANUARY2001

87

88

RADOMSKY & LEVINE

After a 200-mg oral dose, a peak plasma concentration of 1.15 k 0.20 kg/mL is achieved in 4.39 t 1.27 hours.lO'Administration with a high-fat meal can delay the absorption by approximately 2 hours. The extent of protein binding is unknown, but it does appear to bind a-acid glycoprotein.lo2It has a large volume of d i s t r i b ~ t i o nand ~ ~ may reach slightly higher concentrations in the skin and kidn e y than ~ ~ in ~ other organs. Primary metabolism of thalidomide is by nonenzymatic hydrolytic cleavage, although the cytochrome P-450 enzymes may play a role in metabolizing the parent It does not induce or inhibit its own metabolism. It has an elimination half-life of 8.70 k 4.11 hours and a total body clearance rate of 10.41 t 2.04L/ho~r.'~'Urinary excretion accounts for less than 1% of the total dose over 24 hours.'O' A small portion appears to be excreted through the bile.3z Clearance of thalidomide in patients with renal or hepatic disease has not been determined. MECHANISMS OF ACTION

The exact mechanism by which thalidomide works is undetermined. Many theories have been proposed to account for its sedative, anti-inflammatory, and immunomodulatory properties: Sedative Activation of the sleep center Anti-inflammatory Inhibition of chemotaxis Inhibition of phagocytosis Stabilization of lysosomal membranes Decreased generation of superoxide and hydroxyl radicals Immunomodulatory Inhibition of tumor necrosis factor (TNF)-a Inhibition of interferon-? Inhibition of interleukin (1L)-12 Enhancement of IL-2, IL-4, and IL-5 Suppression of IgM antibody formation Inhibition of T-lymphocyte proliferation Down-regulation of expression of intercellular adhesion molecule-1 (ICAM-1) and class I1 major histocompatibility complex (MHC) antigens Other Inhibition of angiogenesis Antagonism of prostaglandin E, and F,, histamine, serotonin, and acetylcholine

Increased or decreased expression of human immunodeficiency virus (HIV)-1 The sedative properties of thalidomide are attributed to its glutarimide ring, which makes it similar structurally to other sedativehypnotic drugs. Despite this similarity, thalidomide appears to operate through a different mechanism, possibly involving activation of the sleep center. It does not cause the incoordination or respiratory depression associated with other sedatives.95 Thalidomide has been shown to affect the inflammatory response and immune system at a variety of levels. It has been shown to inhibit chemotaxis of leukocytes95and monoCytes'O in a dose-dependent fashion without cytotoxicity. It has been found to inhibit phagocytosis by polymorphonuclear leukocytes without cytotoxicity.*O Thalidomide exerts its effects on the immune response through modulation of cytokines. It inhibits the production of TNF-a in human monocytesM by enhancing the degradation of its messenger RNA without suppression of protein synthesis, synthesis of IL-1, IL-6, or granulocyte-macrophage colony stimulating facSome data indicate that thalidomide may increase plasma TNF-a levels in HIVinfected patients.39The drug also inhibits production of interferon-? in human peripheral blood mononuclear cell cultures.95Thalidomide inhibits IL-12 production, which may play a role in limiting production of interferon-?. It enhances IL-2 production, which may counteract some of the effects of interferon-? and T N F - c Y although ,~~ in HIV-infected patients IL-2 may be the cause of increased TNF-a levels.62 It also enhances production of IL-4 and IL-5.95 Thalidomide has been shown to suppress the formation of IgM antibodiesfi8 Thalidomide inhibits cellular immunity by blocking lymphocyte proliferation in response to antigenic and mitogenic stimuli.58 It converts lymphocytic responses from Thelper cell type 1 (Thl) to type 2 (Th2) in vitro, which may mediate cytokine regulation of T-cell function Thalidomide also has been shown to decrease the T-helper (CD4)-to-T-suppressor (CD8) cell ratio by decreasing the number of T-helper cells while increasing the number of T-suppressor cells in patients with ENL.lol It appears to block the expression of CD26 on CD4 lymphocytes, which may affect HIV binding to T lymphocyte~.~~

THALIDOMIDE

Thalidomide has multiple other actions, including the ability to down-A-regulate expression of cellular adhesion molecules and class I1 MHC antigens.93It is an antagonist of prostaglandins EZ and FP, histamine, serotonin, and a ~ e t y l c h o l i n eThalidomide .~~ may have a stabilizing effect on lysosomal membranes similar to that of corti~osteroids.~~ It has been shown to decrease the generation of superoxide and hydroxyl radicals that may cause tissue damage at sites of inflammati~n.~O It decreases cellular proliferation, subperineural edema, and myelin phagocytosis.lO1 Thalidomide has been shown to decrease the activation of latent HIV-1 in mononuclear cells in vitro and in viv0,5~although there is new evidence suggesting the 75 It also inhibits the formation of new blood vess e l by ~ inhibiting ~ ~ basic fibroblast growth factor-induced angiogenesis.lo1 THERAPEUTIC USES

Given the extensive list of possible modes of action, thalidomide has been tried in a variety of unrelated dermatologic conditions, of which only ENL is FDA approved. Potential dermatologic uses of thalidomide include the following: Actinic prurigo Adult Langerhans' cell histiocytosis (histiocytosis X) Aphthous stomatitis Behget's syndrome Chronic graft-versus-host disease (GVHD) Cutaneous sarcoidosis Erythema multiforme ENL HIV-associated aphthous ulceration Immune complex vasculitis Jessner's lymphocytic infiltration of the skin Kaposi's sarcoma Lichen planus Lupus erythematosus Pemphigoid Postherpetic neuralgia Prurigo nodularis Pyoderma gangrenosum Uremic pruritus

In most cases, the patients who received thalidomide were treated only after failing trials of conventional therapy. Thalidomide may be beneficial in some of these conditions and could be considered a treatment option when no other satisfactory measures exist.

89

Erythema Nodosum Leprosum

Thalidomide currently is approved in the United States for use only in ENL. This approval is a direct outgrowth of the astute observations of Sheskina7in 1965. He reported on 6 cases in which ENL lesions responded within 24 hours to 300 mg/day of thalidomide. These observations led to further studies of thalidomide in ENL by the U.S. Public Health Service (USPHS) and the World Health Organization (WHO). At the USPHS hospital, 22 patients with active lepromatous leprosy and chronic ENL reactions were enrolled in a crossover study of t h a l i d ~ m i d eIn .~~ the first 21 of 44 cases, the physicians were not blinded, but the last 23 cases were evaluated in a double-blind fashion. Of patients receiving thalidomide, 68% were positive responders based on a temperature of less than 37.6"C (99.6"F) and the prevention of new ENL lesions. None of the patients that received placebo achieved this degree of success. The WHO conducted a short-term, doubleblind trial of thalidomide versus acetysalicylic acid, because of its antipyretic and analgesic effects, instead of After the first course of treatment, 48% of patients receiving thalidomide and 21% of patients receiving acetylsalicylic acid had no further reactions for the duration of the 9-month study. Seventy-five percent of patients receiving thalidomide and 36% of patients receiving acetylsalicylic acid were afebrile within 48 hours. The regression of skin lesions with thalidomide was almost double that of acetylsalicylic acid. Sheskinassubsequently reviewed 4522 patients worldwide treated with thalidomide; 4479 (99%) improved, and only 43 (1%)had no change or worsened ENL lesions. Based on this review, the optimal initial dose appeared to be 400 mg/d with a maintenance dose of 50 to 100 mg/d, if necessary. The duration of therapy varied from occasional use to continuous therapy for greater than 6 years. Most reactional skin lesions responded after 24 to 48 hours of treatment with thalidomide. Other signs and symptoms, including hepatosplenomegaly, orchitis, anorexia, headache, insomnia, arthralgia, myalgia, and vomiting, resolved rapidly. White blood cell counts and erythrocyte sedimentation rates declined. Neural manifestations of ENL appeared to improve rapidly despite known adverse neurologic effects of thalidomide.9aDespite detectable neuropathy in lepromatous leprosy patients, no adverse neurologic ef-

90

RADOMSKY & LEVINE

fects have been reported in these patients of oral and genital ulcer^.^ A decrease in prewith long-term thalidomide treatment.98Some viously elevated plasma complement degrainvestigators have suggested that neuropathy dation product (C3d) also was noted in these in ENL has not been studied and documented patients. and that it cannot be ruled 0 ~ t . I ~ Fifteen patients with recalcitrant aphthae The exact mechanism of action of thalidowere Thalidomide was given in mide in ENL is unknown.33The histology of doses of 400 mg/d for 5 days, followed by the ENL reaction resembles the Arthus reac200 mg/d for a total of 28 days. All patients t i ~ nNeutrophils .~ are prominent early in the responded to this therapy. Fourteen patients course, followed by lymphocytes and a necrohad total resolution within 5 to 21 days, and tizing vas~ulitis.~ Circulating immune comone had significant improvement. Remission plexes as well as granular deposits of immuwas maintained during treatment, but most noglobulin and complement in dermal lesions relapsed within 1 month of discontinuing have been ob~erved.~ Patients with ENL have the drug4 a reported increase in the ratio of CD4 to Another study evaluated 40 patients with CD88 cells.15 Elevated levels of TNF-a and a ~ h t h a e If. ~the ~ aphthosis was severe, painterferon-y also have been found in ENL tients received 300 mg/d of thalidomide for patients.I0' Treatment of ENL with thalido7 to 30 days, depending on their response. If mide decreases dermal infiltration by polythe condition was less severe, patients were morphonuclear leukocytes and T cells,= detreated with 100 mg daily. Of patients, 75% creases serum IgM levels,'O' and reduces the responded favorably to thalidomide treatCD4-to-CD8 ratio by decreasing CD4 and inment. Relapses were treated with 100 mg/d creasing CD8 cells.15 It also reduces serum for 12 days with a good response. TNF-a and interferon-y levels and downA child with recurrent giant aphthous ulregulates expression of ICAM-1 and MHC cers responded completely to doses of 150 to class I1 antigens on epidermal keratinocyte~.~~300 mg/d of t h a l i d ~ m i d e .Any ~ ~ attempt to Thalidomide is considered a first-line therstop the drug resulted in a relapse. A daily apy for ENL. No trials have been conducted dose of 50 mg, maintained for 6 years, was comparing its efficacy with that of corticostesufficient in controlling these recurrences. The largest randomized, double-blind, plaroids or clofazimine, however. It has been suggested that ENL is not a serious condition cebo-controlled, crossover trial for severe oral and thalidomide should not be used,13 alaphthosis included 67 patients.78 Patients though most investigators would agree that were treated with thalidomide, 10 mg/d, or thalidomide lessens the morbidity of this replacebo for 2 months each, then switched action substantially. without a washout period. Of thalidomidetreated patients, 48% had a complete remission, whereas only 9% of placebo-treated paAphthous Stomatitis tients had a similar result. All patients had fewer aphthae and less functional impairment The first reported use of thalidomide for while on thalidomide. recurrent and necrotic mucocutaneous aphPatients with recurrent mucocutaneous thae was in 1979.54Six patients with mouth aphthae have been shown to have a signifiand scrota1 ulcers, 5 of whom also had pustucantly increased chemotactic response.44Thalar lesions of the body, were treated with thalidomide may be beneficial in this setting by lidomide, 100 mg/d. Within 2 to 3 days, the inhibiting the increased chemotaxis of polylesions were painless, and within 7 to 10 days morphonuclear leukocytes. Aphthous ulcers they had healed completely. Since then, multioften remit spontaneously18; thalidomide ple case reports and a few small studies have should be used only in severe orogenital ulconfirmed these results. ceration unresponsive to other less aggressive Eight of 9 patients with recurrent necrotic approaches.8 giant mucocutaneous aphthae responded with resolution of pain, healing of ulcers, and Human Immunodeficiency longer intervals between recurrences when Virus-Associated Aphthous treated with 100 mg of thalidomide daily for Ulceration 10 days.looTwo women treated with thalidomide at a dose of 200 mg twice daily for 5 Thalidomide is effective in treating aphdays, followed by a slow taper, had resolution thous ulcers associated with HIV infection.

THALIDOMIDE

Numerous case reports describe its benefits in this situation, but until more recently no controlled trials were available to substantiate this anecdotal experience. A number of patients with HIV disease and recurrent oral ulcers were treated with 100 mg/d of thalidomide,23,24, 77, 113 then received maintenance doses of 20 mg/d.23 All healed rapidly. No relapses were observed for 6 months in some 77 although in others, recurrences were common within the first 5 months of discontinuing therapy.l13No relapses were reported while therapy continued.l13No change in CD4 cell count was observed.23,113 One patient with oral and genital ulcers improved within 48 hours of receiving 100 mg of thalidomide twice daily, but therapy was stopped because of peripheral neuropathy and aseptic meningitis, thought to be unrelated to the Twenty additional patients with HIV disease treated with thalidomide for oropharyngeal ulcers as well as esophageal and rectal ulcers were studied. Nineteen responded to 200 mg/d for 14 days.73Rectal ulceration required a longer course of therapy. No change in CD4 count was observed. Two women with HIV-associated orogenital ulcers responded to thalidomide in doses of 100 to 400 mg/d given over 10 days to 5 week^.^,^^^ Thalidomide has been used to treat severe giant aphthous ulcers in children with acquired immunodeficiency syndrome (AIDS) at doses of 3 to 9 mg/kg/d.17,91Symptoms improved within 3 to 7 days, and some had completely resolved within 3 weeks. A preliminary report of a study of 14 HIVpositive men with aphthous ulceration treated with thalidomide (300 or 600 mg/d) or placebo for 7 days confirms prior So far, 75% have responded to thalidomide. None have responded to placebo. Jacobson et a139reported the results of the AIDS Clinical Trial Group protocol 251, in which HIV-positive patients -with oral aphthous ulcers were randomized to receive 200 mg of thalidomide or placebo daily for 4 weeks. If there was not complete resolution by 4 weeks, the dose could be increased to 200 mg twice daily for an additional 4 to 8 weeks. Of patients, 55% (16 of 29) receiving thalidomide had complete resolution by 3.5 weeks versus 7% (2 of 28) receiving placebo ( P < .001). Ninety percent had at least some improvement. Patients also noted an improvement in quality of life as a result of diminished pain while eating ( P < .001), al-

91

though body weight did not change significantly. Seven patients treated with thalidomide and 5 with placebo had new or worsening peripheral neuropathy. More significant was the increase in HIV-1 RNA levels ( P = .04) and the unexpected increase in plasma concentrations of TNF-cc and soluble TNF-a receptors ( P < .005 versus placebo). HIV has been associated with increased circulating concentrations of TNF.17 TNF-a has been shown to induce HIV expression by stimulating nuclear factor-&, a cellular transcription factor used by HIV?5 The study’s findings contradict previous reports of decreases in viral load in vitro with thalidomide treatment.53TNF-a may not be important systemically in the pathogenesis of aphthous ulceration because it increased during treatment with thalidomide despite clinical i m p r ~ v e m e n tThalidomide .~~ probably works in this situation by other immune-modulating mechanisms. Thalidomide should be used cautiously in HIV patients until further studies can determine the effect, if any, this increase in viral load may have on the overall clinical picture. Behqet’s Syndrome

Thalidomide was first used in an open trial of 22 patients with Behqet’s syndrome.86All 22 patients had oral aphthae, and 16 had genital ulcerations as well. Thalidomide, 400 mg/ d was given for 5 days, followed by 200 mg/ d for 15 to 60 days. The oral and genital ulcers healed almost immediately. Recurrences were described as mild and often disappeared spontaneously. Periods between recurrences lengthened. Associated iritis persisted despite treatment with thalidomide. A similar regimen resulted in resolution of orogenital ulcers, but there was no change in arthritis or ~veitis.~ An open study of thalidomide, 100 to 300 mg/d for 1 to 2 months, was conducted in 30 male patients with oral, genital, and cutaneous lesions of Behqet’s Twentyeight of 30 patients responded to treatment. Twenty-six of 27 patients with buccal ulcerations responded within 1 to 2 weeks (20 with a complete response and 6 with a partial response). When thalidomide was withdrawn, 12 of 13 patients had a recurrence after 2 to 6 weeks, which was controlled in all 12 on reintroduction of thalidomide. Twentyfour of 25 patients with genital ulcers re-

92

RADOMSKY & LEVINE

sponded (20 with a complete response). Other reports have described similar improvements with doses of 200 to 400 mg of thalidomide daily in Behqet’s syndrome with recurrent orogenital aphthous ulcerations and pustular skin lesion^.'^, 48, 78 In a single-case report, a 31-year-old man with Behset’s disease associated with palmoplantar pustulosis responded completely within 2 weeks of starting thalidomide, 200 mg/d.29 This therapy was continued for 2 months, then decreased to 100 mg/d for the following 12 months. The patient relapsed after complete withdrawal but was controlled again with thalidomide. Five patients with Behqet’s diseaseassociated pustular vasculitis, with significant morbidity and refractory to other treatments, were studied to determine if thalidomide therapy was effe~tive.~~ Patients received 200 mg/d of thalidomide for 4 weeks, followed by 4 weeks of therapy, then followed by a second cycle of thalidomide. Two patients had complete resolution of mucocutaneous and arthritic components while on thalidomide, which recurred within 1 to 2 days of stopping therapy. A more recent report of thalidomide’s use in Behqet’s syndrome is a randomized, double-blind, placebo-controlled trial consisting of 96 male patients with primarily mucocutaneous lesions.28They received thalidomide (100 or 300 mg) or placebo daily for 24 weeks. Two of 32 patients (6%) receiving 100 mg/d had a complete response. Five of 31 patients (16%) receiving 300 mg/d responded completely. None of the 32 patients receiving placebo responded ( P = .031). Most patients had a recurrence of mucocutaneous lesions within 4 weeks of the end of therapy. The pathogenesis of Behqet’s syndrome, including palmoplantar pustulosis and pustular vasculitis, has been related to increased neutrophil migration, increased chemotactic activity of polymorphonuclear leukocytes, and circulating immune complex-mediated vascular damage.30Given the ability of thalidomide to decrease cell-mediated immunity and inhibit chemotaxis of neutrophils, it may be useful in Behqet’s syndrome and other pathologically related diseases. Changes in circulating immune complexes, neutrophil migration, and neutrophil adhesion molecules have been studied, however, and no significant changes in these parameters could be attributed to treatment with thalidomide41despite its purported mechanisms of action. Thalidomide

may work in Behqet’s syndrome by decreasing the generation of superoxide and hydroxyl radicals capable of causing tissue damage at sites of i n f l a r n m a t i ~ n .Because ~~ Behqet’s disease-associated aphthae often remit spontaneously, thalidomide should be used only in severe cases and in cases unresponsive to other treatments.18 Thalidomide has been used in the treatment of patients with aphthae associated with other systemic diseases. An 8-year-old child with Crohn’s disease and severe recurrent aphthous ulceration associated with pain and weight loss responded to thalidomide, 50 mg/d.91 Within a few days, the pain decreased, and within 2 weeks the lesions resolved. The resulting long, ulcer-free periods allowed the discontinuation of thalidomide. Patients with Crohn’s disease have been shown to have elevated mucosal TNF-a. Thalidomide may be effective in treating the associated aphthous lesions by reducing TNF-a and the resulting increase in inflammatory cells in Crohn’s disease.71 Chronic Graft-Versus-Host Disease

Thalidomide is effective in the treatment of acute and chronic GVHD in animal models.21,107 The first use in humans was reported in 1988. A 34-year-old man with acute cutaneous GVHD worsening on corticosteroids after allogeneic bone marrow transplant improved within 3 days of starting thalidomide.49Another patient with chronic cutaneous GVHD was treated with thalidomide with progressive improvement over a 6month period.85The patient had no reactivation of disease during the 10 months after discontinuation of the drug. Six other case reports revealed no effect of thalidomide in acute GVHD, whereas 2 of 3 patients with chronic GVHD treated with 200 to 600 mg/d Two children with chronic GVHD unresponsive to increasing doses of corticosteroids, azathioprine, and cyclosporine responded to thalidomide, 100 to 200 mg/d.35 Thalidomide was continued for 24 months, allowing the discontinuation of azathioprine and reduction of steroid dosage in one case. Three adults with chronic cutaneous GVHD responded to the same doses within 6 to 12 weeks.36 Forty-four patients with chronic GVHD were treated with thalidomide in doses to 1600 mg/d to achieve plasma levels of 5 k g /

THALIDOMIDE

mL.lo5Treatment was continued for 3 months after a complete response and 6 months after a partial response. Twenty-three patients had chronic GVHD refractory to conventional treatment, and 21 patients were classified as high-risk GVHD. Overall, 32% had a complete response (7 patients from each group), 27% had a partial response (11 patients with chronic GVHD and 1 with high-risk GVHD), and 41% had no response to therapy (5 patients with chronic GVHD and 13 with highrisk GVHD). The overall survival was 64%. Of patients 76% with chronic GVHD survived, whereas only 48% with high-risk GVHD survived. A group of 80 patients with chronic GVHD who failed to respond to predinisone with or without cyclosporine were treated with thalid~mide.~* Patients were started at 100 mg 4 times daily and increased to 200 to 400 mg 4 times daily, depending on the response observed and the occurence of side effects. Patients were treated for an average of 16 months. Twenty percent (16 patients) had a sustained response, 56% with a complete remission, and 44% had a partial response defined as greater than 50% improvement. Of patients with standard-risk chronic GVHD, 24% responded, whereas only 16% of those classified as high risk did. To answer the question of whether thalidomide is appropriate for use in children, a study of 14 children with high-risk or refractory chronic GVHD was conducted.81Doses ranged from 3 to 9.5 mg/kg/d divided into 2 or 4 doses per day. Six patients had a complete response after 2 months of treatment, 4 patients had a partial response or flared with thalidomide taper attempts, and 4 patients were therapeutic failures. Three patients that failed treatment died. All of the patients with a complete response and one with a partial response remained without signs of GVHD when thalidomide was discontinued. Most patients were able to decrease or discontinue other immunosuppressive drugs. It is theorized that thalidomide acts in the antigen recognition activation pathway of graft T lymphocytes to down-regulate normal lymphocyte responses in patients with GVHD.l12This response may be accomplished by allowing the development of antigen-specific suppressor cells, while inhibiting the development of cytotoxic cells.'06 Thalidomide may be mildly beneficial in adults with GVHD depending on the organ systems involved and the severity. In chil-

93

dren, greater than 80% of cases resolve spontaneously.sl Children with primarily mucocutaneous refractory GVHD may benefit from therapy with thalidomide by allowing a decrease in the dose of other immunosuppressive agents. Thalidomide is not useful for prophylaxis of chronic GVHD, however. Patients that received thalidomide prophylactically had a higher rate of GVHD and a higher resultant mortality rate."' Lupus Erythematosus

Thalidomide has been effective in cases of discoid lupus erythematosus (DLE) unresponsive to antimalarial agents and topical or systemic corti~osteroids.~~ In the first 5 cases reported, 100 to 300 mg/d of thalidomide led to improvement of the lesions within 2 weeks and allowed the discontinuation of other agents. The effect of thalidomide therapy was studied further in 60 patients with unresponsive DLE.43 Patients were started on 200 mg of thalidomide twice daily. The dose was tapered monthly after a marked clinical response, until a maintenance dose of 50 to 100 mg was achieved. Of patients 90% (54) had a favorable response, and 65% (39) had complete regression of lesions. Of 41 patients treated for more than 3 months, 11 remained lesion-free for 2 to 8 months after therapy. Thirty patients relapsed, although not as severely, after cessation of thalidomide. All relapses responded after reinstitution of the drug. Two patients with recalcitrant hypertrophic lupus erythematosus improved within 2 weeks of receiving thalidomide, 200 mg/d for 10 days, followed by 100 mg/d for 1 month only. Both patients remained symptom-free for the following year.= Reviews of the use of thalidomide for DLE suggest that 90% of patients improve clinically within 2 weeks and that lesions remit within 1 to 2 months on 100 to 400 mg/d of t h a l i d ~ m i d e Usually .~~ a daily dose of only 100 to 200 mg is Approximately 70% of patients relapse within 1 year, and a maintenance dose of 25 to 50 mg/d may be required.50 An open trial of thalidomide in other lupus variants showed a positive effect not only in 5 patients with DLE, but also in 10 other patients with subacute cutaneous lupus erythematosus (SCLE), disseminated cutaneous

94

RADOMSKY & LEVINE

a complete or near-complete remission, 6 of lupus erythematosus, systemic lupus erythe16 (37%) had a partial remission, and 3 did matosus (SLE), and mixed connective tissue not respond. Eleven patients were maintained disease.'j8 Improvement usually occurred on doses of 25 to 50 mg/d. Therapy was within a few weeks. The use of thalidomide stopped in 8 patients, and 6 of these experiallowed a reduction in prednisone and azathienced a relapse within 2 to 14 weeks. The oprine doses in the patients with SLE, alrelapses all responded to reinitiation of therthough arthralgia usually was not relieved. C3 and immunoglobulin deposits on immuapy. Three additional cases of SLE with cutanenofluoresence examination disappeared, and ous and articular features showed improveerythrocyte sedimentation rate and circulatment with thalidomide treatment.'j The drug ing immune complex levels returned to nearwas administered in doses of 100 to 200 mg/ normal levels. d. Two patients had a dramatic improvement Additional reports show thalidomide's efin cutaneous lesions and articular features fectiveness in these diseases. Two cases of within 1 month. Both patients were mainSCLE unresponsive to hydroxychloroquine tained on 25 to 100 mg/d for 2 years, and topical or systemic corticosteroids subjecallowing a reduction in corticosteroid dose, tively responded to thalidomide, 100 mg/d, but there was no effect on immunologic indiwithin 1 ~ e e k . 6Within ~ 3 to 8 weeks, the ces. lesions had resolved. A study group of 23 patients with SLE and Eleven patients with chronic cutaneous luvarious unresponsive cutaneous lesions repus erythematosus, 7 with DLE, and 4 with ceived thalidomide, 300 mg/d (4 mg/kg/d SCLE unresponsive to chloroquine were studin children).' Eighteen (goo/,) of 20 patients ied.31Thalidomide, 100 to 300 mg/d, was adwho completed the trial obtained a complete ministered and tapered with clinical improveremission within 1month, and 2 had a partial ment. Most showed signs of improvement improvement. Many recurred on withdrawal within a few weeks, and remissions were of thalidomide (7 of 20). Eighteen patients noted within 1 to 2 months. Patients were decreased their average corticosteroid doses treated for a few days to 18 months. Seven by more than 50% ( P < .001). patients had a complete remission, 2 imThe mechanism of action of thalidomide in proved significantly, and 1 had no response lupus erythematosus is unclear. It may exert after 3 months of treatment. Of the patients its effects by inhibiting neutrophil chemotaxis who responded, 6 relapsed after withdrawal and macrophage phagocytosis; inhibiting the of thalidomide. All responded to retreatment synthesis of IgM and its subsequent deand were maintained on doses of 12.5 to 50 position along the basement membrane,5O in mg/d. addition to decreasing other circulating imOne case of chronic cutaneous lupus erymunoglobulins108;stabilizing lysosomal memthematosus resulting in extensive scarring alb r a n e ~ and ~ ~ ; suppressing superoxide and opecia responded within 4 to 8 weeks to thahydroxyl free radical production by neutrolidomide 100 mg/d, despite its resistance to phi1s.l quinacrine, hydroxychloroquine, dapsone, isotretinoin, azathioprine, and p r e d n i ~ o m e . ~ ~ Thalidomide has helped to alleviate cutaneActinic Prurigo ous manifestations in patients with SLE. In a patient with SLE, 100 mg of thalidomide Thalidomide first was used in 34 patients improved discoid lesions within 2 weeks.lo8 with actinic prurigo in the early 1 9 7 0 ~ . ~ ~ There was no evidence of cutaneous disease Thirty t-wo patients had considerable imafter 3 months of therapy. Treatment was provement, 1 had little improvement, and 1 stopped after 4 months, and remission was had no response to therapy. Most improved maintained for 12 months. Thalidomide was studied in 16 patients: 11 within 1 to 2 months, although signs of disease recurred on discontinuation. with DLE, 3 with SCLE, 1 with SCLE and a A subsequent series of 51 patients with acmalar rash, and 1 with a nonspecific patchy tinic prurigo appears to confirm these finderythema previously unresponsive to at least ings." An additional 14 patients were treated two agents.94Eight of these patients met the with 50 to 200 mg/d of thalidomide, and diagnostic criteria for SLE. Most improved improvement was noted within 1 to 3 within 2 weeks and had a maximum benefit weeks.52Eleven had considerable improveby 16 weeks. Seven of 16 (44%) patients had

THALIDOMIDE

ment. Eight of these patients were maintained on doses of 50 mg/wk. The other 3 patients remained off thalidomide. Generally accepted doses for actinic prurigo range from 50 to 300 mg/d. Most patients respond within 1 to 2 months, but maintenance doses (15 to 100 mg/d) are generally required because of the high incidence of recurrence. The pathogenesis of actinic prurigo is unknown, but it is suspected that it has an immunologic mechanism similar to that of ENL.51The mechanism of action of thalidomide in both conditions may be similar.

95

do not control the pruritus well, this seems unlikely. It has been proposed that the primary mechanism may be a direct action on proliferated neural tissue in the lesions of prurigo n o d u l a r i ~ . ’ ~ ~ Cutaneous Sarcoidosis

Four cases of sarcoidosis treated with thalidomide have been reported. The first patient was started on 100 mg/d of thalidomide, and cutaneous lesions improved after 2 months.80 A regression of hilar lymphadenopathy also was noted. The second patient was started on Prurigo Nodularis 200 mg/d of thalidomide and increased to 300 mg/d after 2 months.45 A clinical imSheskin also was the first to use thalidoprovement was noted after 4 months, and mide in patients with prurigo n o d u l a r i ~ . ~ after ~ 10 months there was near-complete resoOther cases of recalcitrant prurigo nodularis lution. Thalidomide had no effect on hilar have responded to thalidomide therapy. One lymphadenopathy in this case. patient’s lesions flattened, and pruritus reAnother patient received 200 mg/d of thasolved over 3 months when treated with 100 lidomide for 2 weeks, followed by 100 mg/d mg of thalidomide twice daily.lo3Four pafor 11 weeks.I2 There was improvement in cutaneous lesions, the hilar lymphadenopatients had a notable improvement within l thy regressed, and the serum angiotensinmonth and resolution within 4 to 6 months converting enzyme level normalized. after receiving 100 to 300 mg/d of thalidoIn sarcoidosis, interferon-y, IL-2, and TNfmide.”O An improvement was noted within 1 month and resolution within 4 to 6 months. a are the principal cytokines that mediate the Two patients maintained remission for 2 to granulomatous i n f l a m r n a t i ~ nInterferon-y .~~ and IL-2 are released by activated Thl cells, 3 years. whereas TNF-a is released by macrophage~,4~ A patient with HIV disease and prurigo particularly alveolar macrophages.*OThalidonodularis was treated with 100 mg of thalidomide may be effective in sarcoidosis by inhibmide twice daily5 After 2 months of therapy, iting interferon-y and TNF-a. Thalidomide the lesions and pruritus had lessened. The also inhibits IL-12, which is responsible for pruritus had resolved completely by 5 stimulating interferon-y production in sarmonths. c o i d o ~ i s Thalidomide .~~ also enhances IL-2 Conventional treatment of prurigo noduproduction, which possibly counteracts the laris often is unsatisfactory; thalidomide in effects of interferon-y and TNF-Lx.~~ doses of 100 to 300 mg/d can resolve pruritus within 2 weeks. It has been suggested that treatment be continued for at least 6 monthsz6 Adult Langerhans’ Cell Histiocytosis Improvement can be maintained with lower (Histiocytosis X) doses because recurrences are common. Peripheral neuropathy has been reported in There have been 6 reported cases of Lang70% of cases of prurigo nodularis treated with erhans’ cell histiocytosis treated with thalidot h a l i d ~ m i d eSome . ~ ~ have proposed that this mide. One patient responded to prolonged (5 condition may not be due to thalidomide but years) low-dose (50 mg) thalidomide therapy. to a preexisting mild chronic neuropathy asAnother patient did not respond to 100 mg/ sociated with the disease itself.98 d, which was discontinued eventually beAlthough the exact mechanism of action cause of n e ~ r o p a t h yTwo . ~ ~ other adults with of thalidomide in this disease has yet to be pure cutaneous forms responded rapidly to clarified, several possibilities have been pro100 to 200 mg/d of thalidomide.60* 63 In the posed. The sedative properties of thalidomide first case, the lesions resolved within 1month, may suppress the perception of peripheral and a subsequent biopsy specimen showed stimuli, such as pruritus, and interrupt the no lymphocytic infiltrate. Thalidomide was itch-scratch cyclelo3;because other sedatives

96

RADOMSKY & LEVINE

stopped after 2 months, and the patient remained in remission for at least 3 months.60 The other patient was lesion-free after a 3month course of thalid~mide.~~ The other 2 cases, one with multiorgan disease and one with perianal disease, improved within 1 month on 100 mg/d of thalidomide.99Doses were tapered and eventually discontinued. A biopsy specimen in one of the patients contained no histiocytes. One patient’s lesions recurred after 4 months but responded again to 50 mg/d of thalidomide. The other patient’s cutaneous signs of disease remained in remission for 6 months. No beneficial effect of thalidomide was observed on the visceral disease. Although the mechanism by which thalidomide affects Langerhans’ cell histiocytosis has not been elucidated, it appears to be effective in controlling the cutaneous manifestations clinically and microscopically. Jessner’s Lymphocytic Infiltration of the Skin

A single prospective, double-blind, crossover trial assessed the efficacy of 100 mg/d of thalidomide for the treatment of Jessner’s lymphocytic infiltration of the skin in 28 pat i e n t ~Thirteen .~~ patients received thalidomide, and 15 received placebo. Of the 13 patients, ll achieved a clinical remission. None of the patients in the placebo group responded. During the second treatment period, 10 of 11 who had responded initially to thalidomide received placebo. Four remained in remission throughout the second 2-month period, whereas 6 had a relapse after approximately 1 month. Fourteen other patients received thalidomide. Nine of these patients achieved a clinical remission by the end of the 2-month period, and 2 withdrew because of neuropathy. Several treatments for Jessner ’s lymphocytic infiltration of the skin have been tried with only limited success. Thalidomide may be useful in recalcitrant cases; however, the risks must be weighed carefully in this often self-limited disease. Toxic Epidermal Necrolysis

An elevated level of TNF-01had been implicated in the pathogenesis of toxic epidermal necrolysis. Because thalidomide has been

shown to be a potent inhibitor of TNF-a, it was used in a randomized, double-blind, placebo-controlled trial.”’ Twenty-two patients were enrolled in the study. Ten of 12 patients who received thalidomide in doses of 400 mg/d for 5 days died. Only 3 of 10 in the placebo group died (relative risk, 2.78; P = 03). These results led to the premature closure of this trial. It then was discovered that thalidomide led to a paradoxic increase in TNF01 that may have resulted in the increased mortality.’l* Thalidomide may stimulate T cells in vivo, and in diseases in which Tcell activation contributes to the pathologic process, this may be detrimental.42Shortly after this study was reported, keratinocyte death in toxic epidermal necrolysis was shown to be unrelated to TNF production but related to the system of Fas receptors on keratin~cytes.~~ Regardless of the actual mechanism, based on this study, thalidomide should not be used in the treatment of toxic epidermal necrolysis. Erythema Multiforme

Thalidomide first was reported to be effective in a single case of recurrent erythema multiforme affecting the lips, hands, feet, and glans penis.* The patient had several attacks per year with only a few weeks of diseasefree states in between attacks. The lesions healed within a few days of receiving 200 mg/d of thalidomide. The patient remained asymptomatic for 6 months at half the dose. Two other patients with recurrent erythema multiforme were reported to have fewer and less severe attacks after treatment with thalidomide.68Two additional patients with recurrent erythema multiforme responded to 100 mg/d of thalidomide, but both patients relapsed after decreases in dose and ultimately discontinued therapy because of neuropathy.64 Pyoderma Gangrenosum

Several patients with pyoderma gangrenosum have been treated with thalidomide. For one patient, doses of 100 mg/d resulted in complete remission for 2 years, but therapy was discontinued because of peripheral neuropathy, resulting in a prompt relapse? Another patient had healing with scarring but

THALIDOMIDE

97

no new lesions during 6 months of treatment with thalidomide.34Two patients with pyoderma gangrenosum of the penis were treated initially with systemic corticosteroids and minocycline.20One patient improved within 5 days when thalidomide, 100 mg/d, was added to this regimen. Pyoderma gangrenosum associated with Behqet’s syndrome has been shown to respond to thalidomide therapy. One patient improved dramatically on 400 mg/d of thalidomide for 4 days.66Another patient responded to 400 mg/d of thalidomide over a 2-month period.82In both cases, thalidomide and systemic corticosteroids were tapered over 6 months without recurrence of oral or cutaneous lesions.

to improve with treatment.@Subsequently a randomized, double-blind, crossover trial of thalidomide for refractory uremic pruritus was conducted after the observation that pruritus improved with thalidomide treatment in a dialysis patient with leprosy.89Twenty-nine patients entered the study and were given thalidomide, 100 mg, or placebo daily for 1 week. Eighteen patients completed the study. The benefits of thalidomide were clear in 67% of patients, corresponding to an 80% reduction in pruritus compared with placebo (P < 05). Patients with less severe symptoms seemed to respond better. The mechanism of this effect is not understood but may be related to interference with inflammatory process mediator^.^^

Lichen Planus

Postherpetic Neuralgia

Thalidomide has been shown to have a dramatic effect on severe oral lichen planus. Three previously unresponsive cases responded to thalidomide in doses of 25 to 150 mg/d given for 15 to 36 months without recurrence or side effects.I6, A single patient with a generalized eruptive form did not improve.

Thalidomide has been shown to be effective in severe postherpetic n e ~ r a l g i a .Most ~ patients responded well initially, but neuralgic pain returned after approximately 3 weeks in some. A higher maintenance dose is being investigated. Miscellaneous Disorders

Kaposi’s Sarcoma

A 14-year-old girl with vertically transmitted HIV disease was treated with thalidomide (3 mg/kg/d) for corticosteroid-unresponsive oral ulcers.90During therapy, there was a concomitant decrease in the size of existing Kaposi’s sarcoma lesions, and no new lesions developed. There also was corresponding decrease in the Kaposi’s sarcoma-associated herpesvirus DNA level in peripheral blood samples. It was suggested that the regression of the Kaposi’s sarcoma lesions might have been due to the withdrawal of corticosteroids rather than the treatment with thalidomide.% Given its properties of inhibiting TNF-a,inhibiting angiogenesis, altering T-lymphocyte cytokine production, and inhibiting viral load (possibly Kaposi’s sarcoma-associated herpesvirus DNA), thalidomide may be beneficial in the treatment of Kaposi’s sarcoma, but further experience is needed. Pruritus and Uremic Pruritus

In an open trial of thalidomide, one patient with severe pruritus of unknown cause failed

Reports have described the efficacy of thalidomide in 2 of 3 patients with immune complex vasculitis and in 2 of 3 patients with pemphigoid, one with bullous pemphigoid and the other with cicatricial pemphigoid.68 Neither of two patients with psoriasis nor two with balanitis circinata responded to thalidomide treatment.68 ADVERSE EFFECTS Teratogenicity

Teratogenicity is the most worrisome side effect, based on the devastating European experience of the 1960s. Thalidomide is classified as Pregnancy category X. Doses as small as 100 mg ingested within the first 35 to 50 days of pregnancy can result in severe deformities.*O* Whether thalidomide has an effect on spermatogenesis is uncertain.32 The teratogenic effects have been classified r i g o r o ~ s l yand ~ ~ include (1)deformities of the upper and lower extremities (amelia, phocomelia, bone hypoplasia, absence of bones); (2)

98

RADOMSKY & LEVINE

abnormalities of the external ear (anotia, micro pinna, small or absent auditory canals) and abnormalities of the eye (anophthalmos, micropthalmos), with or without an associated facial palsy; and (3) defects of the internal organs (congenital heart disease, anomalies of the genitalia, gastrointestinal tract, or urinary tract). Mortality of 40% has been reported at or shortly after birth. Despite many years of research, the exact mechanisms of teratogenicity have not been clarified but may be related to the antiangiogenic properties of thalidomide14or to any of at least 16 other as yet untested hypo these^.^^ With a heightened awareness of this potential disaster, it is hoped that the teratogenic effects of thalidomide can be avoided by selecting patients appropriately and offering contraceptive counseling as well as effective contraceptive measures.

reduction or discontinuation. Other side effects include dizziness, mood changes, headache, dry mouth or skin, nausea, constipation, increased appetite, weight gain, rash, pruritus, edema, hypothyroidism, neutropenia, bradycardia or tachycardia, and hypotension. DRUG INTERACTIONS

Thalidomide increases the activity of barbiturates, chlorpromazine, reserpine, and alcohol.’O1 It may increase serum levels and the associated toxicity of a~etaminophen.~~ It appears to antagonize histamine, serotonin, acetylcholine, and prostaglandins in vitro. Thalidomide should be used cautiously with drugs that cause drowsiness or neuropathy or that may reduce the effectiveness of oral contraceptives (i.e., HIV protease inhibitors, rifampin, rifabutin, phenytoin, and carbamazepine).

Peripheral Neuropathy

Peripheral neuropathy is the most troublesome of the remaining side effects of thalidomide because it can be slow to resolve if it does at all.95There is no evidence that the neuropathy is related to the dose taken or the total amount of drug received.13 The incidence of peripheral neuropathy has been reported to be 0.5% to greater than 70%, with a reported increased risk in women and the elderly.l0’ It typically presents as symmetric painful parenthesias of the hands and feet accompanied by sensory loss in the lower extremities, with or without muscle weakness or cramps. Signs of pyramidal tract involvement and carpal tunnel syndrome have been reported.95Electrophysiologic findings show axonal neuropathy with reduced sensory nerve action potential amplitude. Increased latency in somatosensory-evoked potentials has been shown in the absence of clinical abnormalities. Biopsy findings are consistent with the loss of large-diameter fibers without segmental demyelination, in addition to increased numbers of small fibers suggestive of regeneration.’O’ Miscellaneous Side Effects

The most common side effect of thalidomide is the one it was initially marketed for-its sedative effect. This effect tends to diminish over time but may require a dose

REGULATORY GUIDELINES

Given thalidomide’s history and the concerns of the FDA, the manufacturers has developed the System for Thalidomide Education and Prescribing Safety (STEPS) program to control and monitor the use of thalidomide. Physicians, pharmacists, and patients must be registered and agree to comply with specific regulations before thalidomide can be obtained. Patients must be counseled on the risks and benefits of therapy and must receive oral and written information about thalidomide. The physician must provide contraceptive counseling. Pregnancy testing is mandatory before, during, and after therapy in women of childbearing age. The patient’s informed consent form must be presented to the pharmacist and submitted to the National Registry before dispensing the patient’s first prescription for thalidomide. The prescription must be filled within 7 days of being written. The pharmacist may dispense the capsules only in their intact blister packs. A maximum of 4 weeks may be dispensed at one time. There are no automatic refills-all subsequent refills require a new prescription and can only be dispensed if fewer than 7 days of therapy remain on the prior prescription. The pharmacy is required to accept any unused thalidomide capsules that are returned by the patient. All suspected cases of fetal exposure must be reported to the FDA and the manu-

THALIDOMIDE

99

Table 1. THALIDOMIDE GENERAL DOSING GUIDELINES Disease

HIV-associated aphthous ulceration Jessner’s lymphocytic infiltration of the skin Kaposi’s sarcoma Lichen planus Lupus erythematosus DLE SCLE SLE Postherpetic neuralgia Prurigo nodularis Pyoderma gangrenosum Uremic oruritus DLE = Discoid lupus erythematosus; SCLE

=

Dose (mg/d)

Duration

Oral: 100 Orogenital: 100400 Chiihren: 3-9 mg/kg/d 100

2 wk-6 mo 7 d-12 wk 3 d-12 wk 2 mo

100-200 Children: 3 mg/kg/d 25-150

3 wk

100-400 100 50-300 Children: 4 mg/kg/d 100-300 100400 100-400 100

1-12 mo 3-8 wk 2 wk-2 y

Maintenance Dose (rng/d)

15-20

15-36 mo 25-100 12.5-50 25-100

3 wk 6-14 mo 4 d-2 y 1 wk

subacute cutaneous lupus erythematosus; SLE

=

systemic lupus erythematosus.

tained on the minimally effective dose, and a further taper should be attempted every 3 to 6 months thereafter.

facturer. Because the risk of teratogenicity cannot be eliminated totally, each capsule and package contains a no pregnancy warning as well as photographs of infants with limb defects.

Monitoring Guidelines

Thalidomide (Thalomid) is available as 50mg capsules. The average wholesale price is approximately $7.50 per 50-mg capsule. An average 200-mg daily dose costs approximately $840 per month (28-day supply). GENERAL GUIDELINES Therapeutic Guidelines

1. Thalidomide should be used only in severe disabling conditions and only after other treatment options have failed. 2. Dosing should be initiated at 100 to 300 mg daily or based on specific regimens used to treat a particular disease (Table 1).The dose should be given with water at bedtime or at least 1 hour after the evening meal. 3. Therapy should be continued until signs and symptoms of active lesions have diminished, usually 2 to 8 weeks. 4. The dose should be tapered by 50 mg every 2 to 4 weeks. 5. If necessary, the patient may be main-

Thalidomide has many uses but is associated with several major potential problems.76 Careful monitoring is absolutely essential. Unreliable patients are poor candidates for this form of therapy. Woman of childbearing potential must use effective contraceptives and discontinue treatment if a pregnancy is contemplated. Frequent pregnancy testing is necessary. Nursing mothers should not use thalidomide. Men also must practice protected sex while on this drug. The accompanying box provides an outline of general monitoring guidelines.

’ ~

Thalidomide General Monitoring Guidelines I. Female patients A. Must not take thalidomide if they are or are planning to become pregnant 1. Pregnancy testing a. Negative pregnancy test within 24 hours of starting treatment b. Weekly testing for the first month of therapy Then c. Monthly testing while on ther-

100

RADOMSKY & LEVINE

apy and for 4 weeks after the last dose (regular menstrual cycles) or d. Testing every 2 weeks while on therapy and for 4 weeks after the last dose (irregular menstrual cycles) B. Must abstain from sexual intercourse or use two effective (at least one highly effective) birth control methods at the same time for 1 month before therapy, throughout therapy, and for 1 month after the last dose 1. Highly effective methods a. Implantable hormone capsules b. Injectable contraception c. Intrauterine device d. Oral contraceptive pills e. Tuba1 ligation 2. Additional effective methods a. Cervical cap b. Condoms c. Diaphragm C. Must not take thalidomide if they are nursing These steps must be taken if there is a history of infertility, unless a hysterectomy has been performed or the patient has been without menstrual periods (post-menopausal) for more than 24 months. If pregnancy occurs, thalidomide must be stopped immediately, and the patient should be referred to a physician experienced in reproductive toxicity for further counseling. All suspected fetal exposures must be reported to the FDA and the manufacturer. II. Male patients A. Must abstain from sexual intercourse or use a condom while on therapy and for 1 month after the last dose B. Must not donate sperm 111. All patients A. Should report symptoms of peripheral neuropathy, including numbness, tingling, or pain in the hands or feet B. Should have a clinical neurologic examination at 1. Baseline 2. Monthly for 3 months Then 3. Every 6 months C. Should consider electrophysiologic testing, consisting of measurement of sensory nerve action potential amplitudes in at least 3 nerves (median, radial, sural) at 1. Baseline 2. Every 6 months, or with each 10g increase in cumulative dose 3. Consider for frequent testing if there is a decrease >30% in sen-

sory nerve action potential amplitude 4. Discontinue therapy if clinical symptoms or signs are present or if there is a decrease in sensory nerve action potential amplitude >40% D. Must not donate blood E. Must not share thalidomide or give it to others F. Should avoid drinking alcohol or taking other medications that cause drowsiness. Because thalidomide causes sedation, it may impair one’s ability to drive or operate machinery IV. Special patient populations A. Thalidomide should not be started if the absolute neutrophil count is <750/mm3, and therapy should be reevaluated if the absolute neutrophil count drops below this level B. HIV RNA should be measured at 1 month, 3 months, and every 3 months thereafter. Data from Powell RJ, Gardner-Medwin JMM: Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J 70:901-904,1994.

Peripheral neuropathy is a common adverse reaction to thalidomide. Many physicians choose to obtain baseline electrophysiologic tests of sensory nerve action potential amplitudes and repeat this test every 6 months. Others choose to follow the patient clinically and discontinue therapy if symptoms arise. Sedation is another common side effect of thalidomide therapy. Patients should be advised to abstain form using other sedatives, including alcohol, while using this medication.

SUMMARY

Thalidomide has been successful in the treatment of several dermatologic conditions unresponsive to other agents. Further experience may lead to a better understanding of its mechanism of action in these various diseases. Thalidomide should be considered an extremely valuable therapeutic option in selected patients when the benefits clearly outweigh the risks of teratogenicity and peripheral neuropathy.

THALIDOMIDE

References 1. Atra E, Sat0 EI: Treatment of the cutaneous lesions of systemic lupus erythematosus with thalidomide. Clin Exp Rheumatol 11:487493, 1993 2. Bahmer FA, Zaun H, Luszpinski P: Thalidomide treatment of recurrent erythema multiforme. Acta Derm Venereol62449-450, 1982 3. Ball SC, Sepkowitz KA, Jacobs J L Thalidomide for treatment of oral aphthous ulcers in patients with human immunodeficiency virus: Case report and review. Am J Gastroenterol92169-170, 1997 4. Bamhill RL, McDougall AC: Thalidomide: Use and possible mode of action in reactional lepromatous leprosy and in various other conditions. J Am Acad Dermatol 7:317-323, 1982 5. Berger TG, Hoffman C, Thieberg MD: Prurigo nodularis and photosensitivity in AIDS: Treatment with thalidomide. J Am Acad Dermatol33:837438, 1995 6. Bessis D, Guillot B, Monpoint S, et a 1 Thalidomide for systemic lupus erythermatosus. Lancet 339:549550, 1992 7. Bowers PW, Powell RJ: Effect of thalidomide on orogenital ulceration. BMJ 287799400, 1983 8. Bowers PW, Powell RJ: Effect of thalidomide on orogenital ulceration. BMJ 2871550, 1983 9. Buckley C, Sarkany I, Bayoumi AHM Pyoderma gangrenosum with severe pharyngeal ulceration. J R SOCMed 83590-591,1990 10. Calderon P, Anzilotti M, Phelps R Thalidomide in dermatology: New indications for an old drug. Int J Dermatol36:881-887,1997 11. Calnan CD, Meara RH: Actinic prurigo (Hutchinson’s summer prurigo). Clin Exp Dermatol 2:365372, 1977 12. Carlesimo M, Giustini S, Rossi A, et a1 Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 32866-869, 1995 13. Crawford CL: Use of thalidomide in leprosy. Adverse Drug React Toxicol Rev 13177-192,1994 14. DAmato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:40824085, 1994 15. D’Arcy PF, Griffin JP: Thalidomide revisited. Adverse Drug React Toxicol Rev 13:65-76,1994 16. Dereure 0, Basset-Seguin N, Guilhou JJ: Erosive lichen planus: Dramatic response to thalidomide. Arch Dermatol 1321392-1393, 1996 17. DeVincenzo JP, Burchet SK Prolonged thalidomide therapy for human immunodeficiency virusassociated recurrent severe esophageal and oral aphthous ulcers. Pediatr Infect Dis J 15:465-467, 1996 18. Efthimiou J, Spiro SG: Effect of thalidomide on orogenital ulceration. BMJ 2871550, 1983 19. Eisenbud L, Horowitz I, Kay B: Recurrent aphthous stomatitis of the Behcet’s type: Successful treatment with thalidomide. Oral Surg Oral Med Oral Pathol Oral Radio1 Endod 64:289-292, 1987 20. Farrell AM, Black MM, Bracka A, et a1 Pyoderma gangrenosum of the penis. Br J Dermatol 138:337340, 1998 21. Field EO, Gibbs JE, Tucker DF, et al: Effect of thalidomide on the graft versus host reaction. Nature 211:1308-1310,1966 22. Georgala S, Katoulis AC, Hasapi V, et al: Thalidomide treatment for hypertrophic lupus erythematosus. Clin Exp Dermatol23141,1998 23. Ghigliotti G, Repetto T, Farris A, et al: Thalidomide:

101

Treatment of choice for aphthous ulcers in patients seropositive for human immunodeficiency virus. J Am Acad Dermatol28:271-272,1993 24. Gorin I, Vilette B, Gehanno P, et al: Thalidomide in hyperalgic pharyngeal ulceration of AIDS. Lancet 335:1343, 1990 25. Grinspan D Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol 1285-90, 1985 26. Grosshans E, Illy G: Thalidomide therapy for inflammatory dermatoses. Int J Dermatol 23:598402, 1984 27. Guillaume JC, Moulin G, Dieng MT, et a1 Crossover study of thalidomide vs. placebo in Jessner’s lymphocytic infiltration of the skin. Arch Dermatol 131:1032-1035, 1995 28. Hamuryudan V, Mat C, Saip S, et al: Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:443450,1998 29. Hamza M: Behcet’s disease, palmoplantar pustulosis and HLA-B27 treatment with thalidomide. Clin Exp Rheumatol 8:427, 1990 30. Hamza M H Treatment of Behcet’s disease with thalidomide. Clin Rheumatol5:365-371, 1986 31. Hasper M F Chronic cutaneous lupus erythematosus: Thalidomide treatment of 11patients. Arch Dermatol 119:812-815, 1983 32. Hasper MF, Klokke AH: Thalidomide in the treatment of chronic discoid lupus erythematosus. Acta Derm Venereol 62321-324, 1982 33. Hastings RC, Trautman JR, Enna CD, et a1 Thalidomide in the treatment of erythema nodosum leprosum: With a note on selected laboratory abnormalities in erythema nodosum leprosum. Clin Pharmacol Ther 11:481487, 1970 34. Hecker MS, Lebwohl MG: Recalcitrant pyoderma gangrenosum: Treatment with thalidomide. J Am Acad Dermatol38:490-491, 1998 35. Heney D, Lewis IJ, Bailey CC: Thalidomide for chronic graft-versus-host disease in children. Lancet 21317,1988 36. Heney D, Norfolk DR, Wheeldon J, et al: Thalidomide treatment for chronic graft-versus-host disease. Br J Haematol 7893-27, 1991 37. Holm AL, Bowers KE, McMeekin TO, et al: Chronic cutaneous lupus erythematosus treated with thalidomide. Arch Dermatol 129:1548-1550, 1993 38. Iyer CGS, Languillon J, Ramanujam K, et al: WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. Bull WHO 45:719732, 1971 39. Jacobson JM, Greenspan JS, Spritzler J, et al: Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 336:1487-1493, 1997 40. Jenkins JS, Powell RJ, Allen BR, et al: Thalidomide in severe orogenital ulceration. Lancet 21424-1426, 1984 41. Jorizzo JL, Schmalstieg FC, Solomon AR, et al: Thalidomide effects in Behcet’s syndrome and pustular vasculitis. Arch Intern Med 146:878-881, 1986 42. Klausner JD, Kaplan G, Haslett PAJ: Thalidomide in toxic epidermal necrolysis. Lancet 353:324, 1999 43. Knop J, Bonsmann G, Happle R, et al: Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol 108:461466, 1983

102

RADOMSKY & LEVINE

44. Kurkcuoglu N, Atakan N, Eksioglu M: Thalidomide in the treatment of recurrent necrotic mucocutaneous aphthae. Br J Dermatol 112632, 1985 45. Lee JB, Koblenzer P S Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: A case report. J Am Acad Dermatol39:835-838, 1998 46. Levine AM: Editorial response: Regression of AIDSrelated Kaposi’s sarcoma during therapy with thalidomide. Clin Infect Dis 23:504,505, 1996 47. Levy R Thalidomide in toxic epidermal necrolysis. Lancet 353:324, 1999 48. Lewis DA, Amerasinghe CN, Murphy SM: Successful treatment of Behcet’s syndrome in an African female patient with thalidomide. Int J STD AIDS 7518-520, 1996 49. Lim SH, McWhannell A, Vora AJ, et a1 Successful treatment with thalidomide of acute graft-versushost disease after bone-marrow transplantation. Lancet 1:117, 1988 50. Lo JS, Berg RE, Tomecki KJ: Treatment of discoid lupus erythematosus. Int J Dermatol 28:497-507, 1989 51. London0 F Thalidomide in the treatment of actinic prurigo. Int J Dermatol 12:326-328, 1973 52. Love11 CR, Hawk JLM, Calnan CD, et al: Thalidomide in actinic prurigo. Br J Dermatol 108467471, 1983 53. Makonkawkeyoon S, Limson-Pobre RNR, Moriera AL, et al: Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 9035974-5978, 1993 54. Mascaro JM, Lecha M, Torras H: Thalidomide in the treatment of recurrent, mecrotic, and giant mucocutaneous aphthae and aphthosis. Arch Dermatol 115:636-637, 1979 55. McBride WG: Thalidomide embryopathy. TeratolOgy 1679-82, 1977 56. McCarthy DM, Kanfer E, Taylor J, et al: Thalidomide for graft-versus-host: disease. Lancet 21135, 1988 57. McFadyen RE: Thalidomide in America: A brush with tragedy. Clio Med 11:79-93, 1976 58. McHugh SM, Rifkin IR, Deighton J, et al: The immunosuppressive drug thalidiomide induces T helper cell type 2 (Th2) and concomitantly inhibits Thl cytokine production in mitogen-and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol99:160-167, 1995 59. Menni S, Imondi D, Brancaleone W, et al: Recurrent giant aphthous ulcers in a child: Protracted treatment with thalidomide. Pediatr Dermatol 10283285, 1993 60. Meunier L, Marck Y, Ribeyre C, et al: Adult cutaneous Langerhans cell histiocytosis: Remission with thalidomide treatment. Br J Dermatol 132168, 1995 61. Miller JL: Thalidomide recommended for approval under tight restrictions. Am J Health Syst Pharm 542270-2271,2277-2278, 1997 62. Minor JR, Piscitelli SC: Thalidomide in diseases associated with human immunodeficiency virus infection. Am J Health Syst Pharm 53:429431, 1996 63. Misery L, Larbre 8, Lyonnet S, et al: Remission of Langerhans cell histiocytosis with thalidomide treatment. Clin Exp Dermatol 18:487, 1993 64. Moisson YF, Janier M, Civatte J: Thalidomide for recurrent erythema multiforme. Br J Dermatol 1269-93, 1992 65. Moriera AL, Sampaio EP, Zmuidzinas A, et al: Thalidomide exerts its inhibitory action on tumor necrosis factor cx by enhancing mRNA degradation. J Exp Med 1771675-1680, 1993

66. Munro CS, Cox NH: Pyoderma gangrenosum associated with Behcet’s syndrome-response to thalidomide. Clin Exp Dermatol 13:408-410, 1988 67. Naafs B, Bakkers EJM, Flinterman J, et al: Thalidomide treatment of subacute cutaneous lupus erythematosus. Br J Dermatol 10783-86, 1982 68. Naafs B, Faber WR Thalidomide therapy: An open trial. Int J Dermatol24131-134, 1985 69. Neubert R, Helge H, Neubert D: Thalidomide and the immune system: 4. Down-regulation of the CD26 receptor, probably involved in the binding of HIV components to T cells in primates. Life Sci 56:407420, 1995 70. New uses of thalidomide. Med Lett Drugs Ther 3815-16, 1996 71. Odeka EB, Miller V Thalidomide in oral Crohn’s disease refractory to conventional medical treatment. J Pediatr Gastroenterol Nutr 25250-251, 1997 72. Parker PM, Chao N, Nadamanee A, et al: Thalidomide as salvage therapy for chronic graft-versushost disease. Blood 86:3604-3609, 1995 73. Paterson DL, Georghiou PR, Allworth AM, et al: Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis 20:250-254, 1995 74. Peyron JL, Meynadier J: The pharmacological basis for the treatment of photodermatoses. Biochimie 68~899-904, 1986 75. Poli G, Kinter A, Justement JS, et al: Tumor necrosis factor cx functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci U S A 87782-785,1990 76. Powell RJ, Gardner-Medwin JMM: Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J 70:901-904, 1994 77. Radeff 8, Kuffer R, Samson J: Recurrent aphthous ulcer in patients infected with human immunodeficiency virus: Successful treatment with thalidomide. J Am Acad Dermatol23:523-525, 1990 78. Ramselaar CG, Boone RM, Kluin-Nelemans HC: Thalidomide in the treatment of neuro-Behcet’s syndrome. Br J Dermatol 115:367-370, 1986 79. Revuz J, Guillaume JC, Janier M, et al: Crossover study of thalidomide vs. placebo in severe recurrent aphthous stomatitis. Arch Dermatol 126:923-927, 1990 80. Rousseau L, Beylot-Barry M, Doutre MS, et al: Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol 134:10451046, 1998 81. Rovelli A, Arrigo C, Nesi F, et a1 The role of thalidomide in the treatment of refractory chronic graftversus-host disease following bone marrow transplantation in children. Bone Marrow Transplant 21:577-581, 1998 82. Rustin MHA, Gilkes JJH, Robinson TWE: Pyoderma gangrenosum associated with Behcet’s disease: Treatment with thalidomide. J Am Acad Dermatol 23:941-944, 1990 83. Sampaio EP, Kaplan G, Miranda A, et a 1 The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J Infect Dis 168:408414, 1993 84. Sampaio EP, Sam0 EN, Galilly R, et al: Thalidomide selectively inhibits tumor necrosis factor production by stimulated human monocytes. J Exp Med 173:699-703, 1991 85. Saurat JH, Camenzind M, Helg C, et al: Thalidomide for graft-versus-host: disease after bone marrow transplantation. Lancet 1:359, 1988

THALIDOMIDE 86. Saylan T, Saltik I: Thalidomide in the treatment of Behcet’s syndrome. Arch Dermatol 118:536, 1982 87. Sheskin J: Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther 6:303-306, 1965 88. Sheskin J: The treatment of lepra reaction in lepromatous leprosy: Fifteen years experience with thalidomide. Int J Dermatol 19:318-322, 1980 89. Silva SRB, Viana PCF, Lugon NV, et a1 Thalidomide for the treatment of uremic pruritus: A crossover randomized double-blind trial. Nephron 67970273, 1994 90. Soler RA, Howard M, Brink NS, et a1 Regression of AIDS-related Kaposi’s sarcoma during therapy with thalidomide. Clin Infect Dis 23:501-503, 1996 91. Soler RA, Migliorati C, van Waes H, et a1 Thalidomide treatment of mucosal ulcerations in HIV infection. Arch Dis Child 7464-65, 1996 92. Stephens TD: Proposed mechanisms of action in thalidomide embryopathy. Teratology 38:229-239, 1988 93. Stevens RJ: The place of thalidomide in the treatment of inflammatory disease. Lupus 5957-258, 1996 94. Stevens RJ, Andujar C, Edwards CJ, et al: Thalidomide in the treatment of the cutaneous manifestations of lupus erythematosus: Experience in sixteen consecutive patients. Br J Rheumatol 36:353-359, 1997 95. Stirling DI: Thalidomide and its impact in dermatology. Semin Cutan Med Surg 17231-242,1998 96. Stirling D, Sherman M, Stauss S Thalidomide: A surprising recovery. J Am Pharm Assoc NS37306313, 1997 97. Strazzi S, Lebbe C, Geoffray C, et al: Aphthous ulcers in HIV-infected patients: Treatment with thalidomide. Genitourin Med 68:424-425, 1992 98. Thalidomide in dermatology and leprosy. Lancet 280-81,1985 99. Thomas L, Ducros 8, Secchi T, et a1 Successful treatment of adult’s Langerhans cell histiocytosis with thalidomide: Report of two cases and literature review. Arch Dermatol 129:1261-1264, 1993 100. Torras H, Lecha M, Mascaro JM: Thalidomide treatment of recurrent necrotic giant mucocutaneous aphthae and aphthosis. Arch Dermatol118:875,1982 101. Tseng S, Pak G, Washenik K, et al: Rediscovering

103

thalidomide: A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 35~969-979, 1996 102. Turk BE, Jiang H, Liu JO: Binding of thalidomide to a,-acid glycoprotein may be involved in its inhibition of tumor necrosis factor (Y production. Proc Natl Acad Sci USA 93:7552-7556, 1996 103. van den Broek H: Treatment of prurigo nodularis with thalidomide. Arch Dermatol 116:571-572, 1980 104. Verberkmoes A, Boer K, Wertheim PME, et a1 Thalidomide for genital ulcer in HIV-positive woman. Lancet 347:947, 1996 105. Vogelsang GB, Farmer ER, Hess AD, et al: Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 326:1055-1058, 1992 106. Vogelsang GB, Hess AD, Santos G W Thalidomide for treatment of graft-versus-host disease. Bone Marrow Transplant 3:393-398, 1988 107. Vogelsang GB, Taylor S, Gordon G, et al: Thalidomide, a potent agent for the treatment of graftversus-host disease. Transplant Proc 18:904-906, 1986 108. Warren KJ, Nopper AJ, Crosby DL: Thalidomide for recalcitrant discoid lesions in a patient with systemic lupus erythematosus. J Am Acad Dermatol 39:293-295, 1998 109. Weidle PJ: Thalidomide for aphthous ulcers in patients infected with the human immunodeficiency virus. Am J Health Syst Pharm 53:368, 371-372, 378,1996 110. Winkelmann RK, Connolly SM, Doyle JA, et a1 Thalidomide treatment of prurigo nodularis. Acta Derm Venereol 64:412417, 1984 111. Wolkenstein P, Latarjet J, Rougeau JC, et al: Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 352:15861589, 1998 112. Wood PMD, Proctor SJ: The potential use of thalidomide in the therapy of graft-versus-host disease-a review of clinical and laboratory information. Leuk Res 14:395-399, 1990 113. Youle M, Clarbour J, Farthing C, et al: Treatment of resistant aphthous ulceration with thalidomide in patients positive for HIV antibody. BMJ 298:432, 1989

Address reprint requests to Norman Levine, MD Section of Dermatology University of Arizona College of Medicine 1605 North Campbell Avenue Tucson, AZ 85724-5038 e-mail: nlevineQu.arizona.edu