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Thalidomide for dermatology: a review of clinical uses and adverse effects

2004; Wiley; Volume: 44; Issue: 1 Linguagem: Inglês

10.1111/j.1365-4632.2004.02445.x

1365-4632

Inacio R. Faver, Samantha Gontijo Guerra, W. P. Daniel Su, Rokea A. el‐Azhary,

Chronic Lymphocytic Leukemia Research

International Journal of DermatologyVolume 44, Issue 1 p. 61-67 Free Access Thalidomide for dermatology: a review of clinical uses and adverse effects Inacio R. Faver MD, Inacio R. Faver MD Inacio R. Faver, MD, and Samantha G. Guerra, MD, are Visiting Clinicians at the Department of Dermatology, Mayo Clinic, Rochester, MN, USA From the Department of Dermatology, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorSamantha G. Guerra MD, Samantha G. Guerra MD Inacio R. Faver, MD, and Samantha G. Guerra, MD, are Visiting Clinicians at the Department of Dermatology, Mayo Clinic, Rochester, MN, USA From the Department of Dermatology, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorW. P. Daniel Su MD, W. P. Daniel Su MD From the Department of Dermatology, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorRokea El-Azhary MD, PhD, Corresponding Author Rokea El-Azhary MD, PhD From the Department of Dermatology, Mayo Clinic, Rochester, MN, USARokea el-Azhary, MD Department of Dermatology Mayo Clinic 200 First Street SW Rochester MN 55905 USASearch for more papers by this author Inacio R. Faver MD, Inacio R. Faver MD Inacio R. Faver, MD, and Samantha G. Guerra, MD, are Visiting Clinicians at the Department of Dermatology, Mayo Clinic, Rochester, MN, USA From the Department of Dermatology, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorSamantha G. Guerra MD, Samantha G. Guerra MD Inacio R. Faver, MD, and Samantha G. Guerra, MD, are Visiting Clinicians at the Department of Dermatology, Mayo Clinic, Rochester, MN, USA From the Department of Dermatology, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorW. P. Daniel Su MD, W. P. Daniel Su MD From the Department of Dermatology, Mayo Clinic, Rochester, MN, USASearch for more papers by this authorRokea El-Azhary MD, PhD, Corresponding Author Rokea El-Azhary MD, PhD From the Department of Dermatology, Mayo Clinic, Rochester, MN, USARokea el-Azhary, MD Department of Dermatology Mayo Clinic 200 First Street SW Rochester MN 55905 USASearch for more papers by this author First published: 23 December 2004 https://doi.org/10.1111/j.1365-4632.2004.02445.xCitations: 17AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Introduction Over the last several years, an interest in thalidomide has been rekindled, particularly with regard to its usefulness in treating certain mucocutaneous diseases that have proved unresponsive to conventional therapies. It has been used successfully in Behçet disease, cutaneous lupus erythematosus, actinic prurigo, prurigo nodularis, cutaneous sarcoidosis, pyoderma gangrenosum, lichen planus, histiocytosis, immune complex vasculitis, Jessner-Kanof disease, pemphigoid disorders, photodermatosis, rheumatoid arthritis, recurrent aphthous ulcers, erythema nodosum leprosum (ENL), leishmaniasis cutanea recidivans, esophageal ulceration in acquired immunodeficiency syndrome (AIDS), severe perianal ulceration in AIDS, and erythema multiforme. More than 40 years have passed since thalidomide was recognized as a teratogenic drug. No other drug has provoked such dramatic changes in the drug regulatory process throughout the world. It is time to reappraise this drug, particularly in light of its newfound uses in dermatology. Thalidomide is now classified as an orphan drug by the US Food and Drug Administration. History Thalidomide was first synthesized in 1953 by the Swiss pharmaceutical firm CIBA, but they discontinued research on the drug. Chemie Grunenthal, a company in the Federal Republic of (West) Germany, synthesized the drug in 1954 and undertook its development. The drug was marketed under the name Contergan in West Germany. In 1956, Contergan was promoted for the treatment of irritability, weak concentration, stage fright, anxiety, depression, and hypothyroidism. Contergan was promoted mainly as a hypnotic. By the end of the 1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries.1 Widulind Lenz, a pediatric geneticist at the University of Hamburg, realized there was an association between thalidomide and escalating cases of phocomelia in November 1961. He informed the manufacturers of his findings, which resulted in withdrawal of the drug from the market.2 It was William McBride, however, an Australian obstetrician, who received the credit for first reporting the association in a letter to The Lancet in December 1961.3 This was followed by a corroborative report by Lenz in January 1962 which led to general recognition of the problem.4 The total number of cases of thalidomide embryopathy was estimated by Lenz at approximately 4400. Much of the credit for prevention of a thalidomide disaster in the United States goes to Frances Kelsey, who was then a newly appointed medical officer in the New Drug Branch of the Bureau of Medicine, now the Center for Drug Evaluation and Research.5 Dr Kelsey delayed the approval process because of the concerns regarding peripheral neuropathy and the lack of data on use of the drug during pregnancy. The fact that the drug had been received by over 1200 physicians in the United States for clinical trials was then highlighted by the media. The thalidomide experience therefore focused attention on the loopholes in government regulations regarding the investigational use of new drugs, and, consequently, much more stringent regulations concerning the clinical trials of new drugs were implemented.2, 4 Pharmacokinetics Although thalidomide has been used sporadically for more than 40 years, there is little information about its pharmacokinetic behavior in humans.6 This is largely because of the lack of simple, sensitive, and specific analytic methods.6 Thalidomide is absorbed slowly after oral administration; peak levels are reached in 5 h.6 Thalidomide has poor water solubility, and no parenteral preparation is available. Administration with a high-fat meal can delay absorption by approximately 2 h.7 The half-life of thalidomide in humans is approximately 10 h, and total body clearance is about 10 L/ h. The major route of elimination of thalidomide is still undetermined, and it is metabolized only by nonenzymatic hydrolytic cleavage.8 Because thalidomide is not metabolized by the enzyme cytochrome P-450, it is unlikely to interact with drugs metabolized by this enzyme.9 Thalidomide antagonizes the action of histamine, serotonin, prostaglandins, and acetylcholine in vitro and increases the activity of alcohol, barbiturates, chlorpromazine, and reserpine.10 It is unlikely to affect the pharmacokinetics of oral contraceptives.11 Mechanisms of Action The exact mechanisms by which thalidomide exerts its effects are still unknown. Many theories have been proposed to account for its properties. Its effects are extremely varied. Hypnosedative action The sedative hypnotic action of thalidomide and its congeners most likely is mediated by the glutarimide ring substituted in the 3-position with a nonspecific space-filling group (Fig. 1).12 This configuration exists in a number of sedative hypnotic drugs, including glutethimide.12 Thalidomide probably acts by inducing the activation of a sleep center in the forebrain.12 Figure 1Open in figure viewerPowerPoint Structure of thalidomide (N-phthalimidoglutarimide) Immunomodulating and anti-inflammatory effects Thalidomide has several immunomodulatory and anti-inflammatory properties, summarized in Table 1.7, 13 Thalidomide has been shown to decrease the T-helper (CD4) to T-suppressor (CD8) cell ratio in patients with erythema nodosum leprosum by decreasing the number of T-helper cells and increasing the number of T-suppressor cells. It also dose-dependently inhibits polymorphonuclear leukocyte chemotaxis and monocyte phagocytosis through modulation of cytokines without cytotoxicity. The drug selectively inhibits tumor necrosis factor (TNF)-α by enhancing the degradation of TNF-α messenger RNA. Conversely, some data show that thalidomide may increase TNF-α levels in human immunodeficiency virus (HIV)-infected patients by augmenting interleukin (IL)-2 production. Table 1. Molecular effects of thalidomide Decrease in T-helper/T-suppressor cell ratio Inhibition of polymorphonuclear leukocyte chemotaxis Decreased monocyte phagocytosis Decreased TNF-α production Increased interleukin-4 and -5 production Decreased interferon production Increased migration and proliferation of human keratinocytes Decreased generation of superoxide and hydroxyl free radicals Suppression of IgM antibody formation Stabilization of lysosomal membranes Antagonism of prostaglandin E2 and F2, histamine, serotonin, acetylcholine Antiangiogenesis Inhibition of HIV-1 replication HIV, human immunodeficiency virus; IgM, immunoglobulin M; TNF, tumor necrosis factor. Thalidomide, in vitro, converts lymphocyte response from Th1 to Th2. The Th1 response is related to cell-mediated inflammatory reactions and produces large quantities of interferon (IFN)-γ, TNF-β, and IL-2. Th2 cells regulate the humoral reactions and produce IL-4, IL-5, and very small quantities of IFN-γ. Nasca et al.14 investigated the effect of thalidomide on human keratinocyte proliferation and migration and observed, using a thymidine incorporation assay, that therapeutic concentrations of thalidomide induced a greater than 2.5-fold increase in the proliferative potential of the cells. Thalidomide also increased keratinocyte migration on a collagen matrix by more than 2-fold over control in the colloidal gold assay and by more than 3-fold over control in the scratch assay. Anticancer effects In vitro research has suggested that thalidomide has a cytostatic activity on cultured HeLa cells15 and on chicken embryo blood cells.16 Other researchers also suggested an antitumor effect of thalidomide and some of its congeners,17 although multiple studies did not support these early findings.18 Recently, it has been shown that the anticancer activity of thalidomide appeared to be related to its antiangiogenic properties (inhibition of vascular endothelial growth factor).13 Thalidomide also displayed antiemetic activity in patients receiving chemotherapy for cancer.18 Clinical Dermatologic Uses Erythema nodosum leprosum (ENL) Sheskin first reported the dramatic response of ENL to thalidomide in 1965.19 He serendipitously discovered the beneficial effects of thalidomide when he treated a manic female patient with thalidomide for an episode of psychosis. She coincidentally had ENL, which quickly resolved.19 A World Health Organization controlled trial carried out in four countries confirmed his findings.20 Thus, thalidomide rapidly became the drug of choice for treatment of ENL.21 Although it is not thought to have a direct effect on Mycobacterium leprae, the exact mechanism of action of thalidomide in ENL is unknown.22 Patients with ENL have been found to have elevated levels of TNF-α and IFN-γ, which are reduced by treatment with thalidomide. It also down-regulates expression of intercellular adhesion molecule-1 and major histocompatibility complex class II antigens on epidermal keratinocytes.23 Thalidomide dramatically reduces the reactional neuritis, iritis, and iridocyclitis sometimes associated with ENL.19, 20 The optimal initial effective dosage is 300–400 mg/day, with a maintenance dosage of 50–100 mg/day. Almost 50% of patients require treatment for 6 years or more.19, 20 Chronic graft-versus-host disease (GVHD) In 1986, Vogelsang et al.24 reported the use of thalidomide in treating acute GVHD in a rat bone marrow transplant model. It was shown to be effective in both acute and chronic GVHD. In 1992, Vogelsang et al.25 conducted a large study in which 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with high-risk chronic GVHD were treated with thalidomide. The study concluded that thalidomide appeared to be a safe and effective treatment for chronic GVHD. Thalidomide may act at an early stage in the antigen recognition-activation pathway of graft T lymphocytes, down-regulating normal lymphocyte responses.26 Thalidomide is not useful for prophylaxis of chronic GVHD, however. Patients who received thalidomide prophylactically had a higher rate of GVHD and a higher resultant mortality rate.27 The suggested initial dosage of thalidomide in adults was 100 mg 4 times a day and was increased to 200–400 mg 4 times a day, depending on the response observed and the occurrence of adverse effects.28 In children, dosages ranged from 3 to 9.5 mg/kg of body weight divided into 2–4 doses per day.29 Cutaneous lupus erythematosus Multiple studies have now confirmed the excellent response of discoid lupus erythematosus to thalidomide.30, 31 Knop et al.32 reported on 60 patients with chronic discoid lupus erythematosus who were treated for 2 years. Ninety per cent of these patients had a complete or marked regression of disease. When treatment with thalidomide was stopped, however, 71% of patients relapsed. In this study, 25% of patients complained of polyneuritic symptoms. The authors suggested that lower dosages than those used in the study, 400 mg/day, might be more appropriate for achieving therapeutic benefit with fewer adverse effects. A maintenance dosage of 25–50 mg/day is recommended to prevent relapse.33 The mechanism of action of thalidomide in discoid lupus erythematosus is unclear. It may exert its effects by inhibiting neutrophil chemotaxis and macrophage phagocytosis or by inhibiting the synthesis of IgM and its subsequent deposition along the basement membrane.34 Recurrent aphthous stomatitis Several open (non-placebo-controlled) studies, summarized by Gunzler,35 showed that marked improvements occurred in a series of 300 patients with mild to severe aphthous stomatitis treated with thalidomide. In 1990, a multicenter crossover trial compared thalidomide with placebo in patients with severe recurrent aphthous stomatitis.36 Complete remission was achieved in 32 patients who received thalidomide and in six patients who received placebo. Most patients receiving thalidomide who did not achieve complete remission had a dramatic improvement with regard to the number of oral aphthae. The dosage of thalidomide used was 100 mg daily for 2 months. Adverse effects led to treatment interruption in 11 patients. Neurosensory adverse effects included drowsiness, headache, and mood alteration, including one case of psychosis. These effects disappeared a few days after discontinuing thalidomide therapy. Two cases of paresthesias with objective electrical sensory abnormalities were recorded in this study, but the authors believed that it was unlikely that thalidomide was directly responsible. It is noteworthy that the effect of thalidomide was only suppressive and that relapse occurred regularly after stopping use of the drug. Thalidomide is effective in treating aphthous ulcers associated with HIV infection. Numerous reports describe its benefits in this situation, but no controlled trials have been undertaken to substantiate this anecdotal experience.7 Thalidomide may be functioning in these patients by inhibiting the increased chemotaxis of polymorphonuclear leukocytes.7 Behçet syndrome Saylan and Saltik37 reported the use of thalidomide in 22 patients with Behçet syndrome, most of whom had long-standing disease refractory to multiple treatments. They found that use of the drug (400 mg/day for the first 5 days, followed by 200 mg/day for 15–60 days) resolved oral and genital lesions. In this group, adverse effects included somnolence, sweating, and headache, but none was severe enough to require the dosage to be changed. Jorizzo et al.38 reported good response with sequential 4-week on, 4-week off therapeutic cycles in four patients, with a dosage of 200 mg daily during the active disease. It has been proposed that the typical lesions are produced by an interaction between circulating immune-complex-mediated vascular damage and the increased chemotactic activity of neutrophil migration. Changes in circulating immune complexes, neutrophil migration, and neutrophil adhesion molecules have been studied. No significant changes in these parameters could be attributed to treatment with thalidomide, despite its purported inhibition of neutrophil chemotaxis. Thalidomide may act in Behçet syndrome by decreasing the generation of superoxide and hydroxyl free radicals capable of causing tissue damage at sites of inflammation. Various diseases in which thalidomide has been reported to be effective are listed in Table 2. Table 2. Conditions treated with thalidomide Actinic prurigo39 Langerhans cell histiocytosis44 Prurigo nodularis40 Kaposi sarcoma13 Polymorphous light eruption41 Lupus erythematosus profundus49 Pemphigoid disorders42 Colitis50 Palmoplantar pustulosis43 Severe perianal ulceration in AIDS51 Pustular vasculitis38 Leishmaniasis cutanea recidivans52 Histiocytosis44 Cold hemagglutinin disease53 Postherpetic neuralgia7 Lichen planus54 Uremic pruritus7 Erosive lichen planus21 Pyoderma gangrenosum45 Immune complex vasculitis42 Erythema multiforme46 Jessner-Kanof disease55 Cutaneous lymphoid hyperplasia13 Porphyria cutanea tarda13 Sarcoidosis47 Photodermatosis56 Esophageal ulceration in AIDS48 Rheumatoid arthritis57 AIDS, acquired immunodeficiency syndrome. Adverse Effects The toxicity of thalidomide has been well established. Physicians who have practised in countries where thalidomide was widely marketed before its teratogenicity was recognized still vividly remember images of the characteristic thalidomide embryopathy, particularly the phocomelia. Strict surveillance and careful monitoring should prevent this disastrous effect. The other major adverse effects are neurotoxicity and peripheral neuropathy. Other adverse effects include drowsiness, headache, nausea, constipation, xerostomia, dizziness, ankle edema, and mood changes. Erythematous and papulovesicular transient eruptions,21 weight gain,21 allergic vasculitis, thrombocytopenic purpura,35 myxedema,55 hyperglycemia and diabetes,58 deep vein thrombosis,59 transient secondary amenorrhea,60 toxic epidermal necrolysis,27 leukopenia,61 sinus bradycardia,62 decreased libido,63 peripheral edema,64 brittle nails,10 red palms,10 and pruritus10 also have been reported. Cutaneous adverse effects were common but were mainly minor.65 Hall et al.65 divided the cutaneous effects in patients with multiple myeloma into the categories minor, moderate, and severe. Minor skin eruptions did not require discontinuation of thalidomide treatment. Moderate eruptions required alteration in the scheduled dosing. Severe eruptions, including toxic epidermal necrolysis,65, 66 erythema multiforme, and erythroderma, occurred in three patients, which resulted in discontinuation of thalidomide treatment. Teratogenicity Teratogenicity is the most severe adverse effect, as was seen with the disaster of the European experience in the 1960s.7 Thalidomide is classified as pregnancy category X. Doses as small as 100 mg ingested between 20 and 40 days of gestation can result in severe deformities.7 The teratogenic effects include deformities of the upper and lower extremities (amelia, phocomelia, bone hypoplasia, and absence of bones), abnormalities of the external ear (anotia, micro pinna, and small or absent auditory canals), abnormalities of the eye (enophthalmos and microphthalmos), neural tube abnormalities,21 and defects of the internal organs. The intact phthalimide or phthalimidine group appears to be responsible for the teratogenic activity, but the mechanism has not been conclusively demonstrated. Hypothetical explanations for its teratogenicity include vitamin or amino acid antagonism, acylation of biogenic amines, interaction with various enzymes or nucleic acids, interference with energy metabolism, and interference with hydroxy-proline biosynthesis.67 The antiangiogenic properties of thalidomide also may be related to its teratogenicity. Whether thalidomide has an effect on spermatogenesis is unknown.7 The US Food and Drug Administration requires that female patients have a blood or urine pregnancy test before starting treatment with thalidomide. These tests must be repeated every month while taking thalidomide and 4 weeks after the last dose. More frequent pregnancy tests may be needed if the patient has an irregular menstrual period or vaginal bleeding. Female patients should abstain from sexual intercourse or use two highly effective birth control methods simultaneously for at least 1 month before receiving thalidomide. These methods must be continued until 1 month after the last dose. The recommendation for male patients is to abstain from sexual intercourse or use a condom during intercourse while, and for 1 month after, taking thalidomide. Neurotoxicity The neurotoxic effects of thalidomide had been reported even before the disclosure of teratogenicity and were first noted by Florence in 1960.55 This was followed by reports describing the predominantly sensory, symmetrical distal polyneuropathy.68 There is still much controversy about the frequency of polyneuropathy; an early estimation of a 0.5% incidence in patients taking thalidomide has been contested by several authors who suspect it to be much higher, 25% or more.69 It is not yet clear if the neuropathy is dose-dependent.70 Some authors suspect further progression of neuropathy after discontinuing the medication. Because peripheral neuropathy is a relatively common finding and may actually be due to several dermatologic diseases, proper prospective studies are required to evaluate the precise risk of neuropathy due to thalidomide. Hess et al.71 performed a prospective study on nine patients whose daily dose of thalidomide varied from 25 to 200 mg, monitoring them by clinical examination and measuring several neurophysiologic parameters. After 3 months, three patients had clinical and electrophysiologic evidence of early neuropathy, and another two patients showed electrophysiologic evidence suggesting early neuropathy. These authors also found a possible relationship between the slow acetylator phenotype and the development of thalidomide-induced neuropathy.71 Subsequent studies on thalidomide and chronic GVHD, however, reveal much less neurotoxicity than previously described.25 Vogelsang72 encountered peripheral neuropathy in 10% of patients treated with high-dose thalidomide, from 800 to 1600 mg daily. The median duration of thalidomide therapy was 240 days (range, 2–700 days). They also found that the symptoms were rapidly reversible if use of the drug was discontinued at the first sign of a problem. Thalidomide treatment had been successfully restarted in several patients without recurrent neurologic complications, although electrophysiologic nerve conduction studies were not performed in this study. It is possible that a patient's susceptibility to neurotoxicity may be modified by other disease processes or concomitant or previous medical therapy. Immunologic factors may play a protective role against neurotoxicity in chronic GVHD. Also, the experience of various leprologists would suggest that neurotoxicity is uncommon in patients treated with thalidomide for ENL.73 Chronic treatment of rabbits with thalidomide (100 mg/kg per day) produced progressive decrements in sural nerve conduction velocity that were unassociated with qualitative and quantitative morphologic changes in nervous tissue.74 No morphologic abnormalities were found in 20 other regions of the central nervous system and peripheral nervous system. Another study, however, found six patients with selective loss of large-diameter fibers in sural nerve biopsies performed 2–6 years after the end of thalidomide therapy.70 In order to monitor the subclinical development of peripheral neuropathy, baseline nerve conduction studies are recommended. Also, sensory nerve action potential amplitudes need to be measured in at least three peripheral nerves, usually the median, radial, or sural. A fall from baseline values of more than 40% on repeat testing should lead to discontinuation of the treatment, and a decrease of 30 to 40% should lead to a review of its use. Follow-up testing is recommended after every 10 g cumulative dose or every 6 months. If symptoms develop during the treatment, the patient should stop taking the drug immediately and ask for advice.75 General guidelines7 1 Thalidomide should be used only in severe disabling conditions and only after other treatment options have failed. 2 Dosing should be initiated at 100–300 mg/day and should be administered with water at bedtime. 3 Thalidomide should be taken until signs and symptoms of active disease have decreased, usually 2–8 weeks. 4 The dose should be tapered by 50 mg every 2–4 weeks. 5 If maintenance of the therapy is necessary, the minimal effective dose should be given and a further taper should be attempted every 3–6 months thereafter. Conclusions It is noteworthy that relatively little is known about the pharmacology of thalidomide, despite the fact that 50 years have elapsed since the drug was first synthesized, and 40 years have elapsed since this drug was recognized for its teratogenicity. It has left a legacy of malformed victims, most of whom are still living. In addition to using thalidomide to treat ENL and chronic GVHD, physicians should keep it in mind as an alternative therapy for other diseases. The neurotoxicity and other adverse effects of thalidomide clearly need further study. Until the results of such studies are available, this drug should be used with great caution and continuous monitoring. We recommend that thalidomide be used with full patient informed consent, weighing the risk/benefit ratio, and with baseline clinical or electrophysiologic assessment. It is also possible that the pharmaceutical industry will study thalidomide with greater scrutiny, in view of its newfound clinical indications. It is hoped that less teratogenic and neurotoxic derivatives and congeners of thalidomide may be developed in the future. References 1 Randall T. Thalidomide has 37-year history. J Am Med Assoc 1990; 263: 1474. CrossrefGoogle Scholar 2 Lenz W. 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