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Thalidomide

Thalidomide is a drug that was sold during the late 1950s and 1960s as a sleeping aid and to pregnant women as an antiemetic to combat morning sickness and other symptoms. It was synthesized in West Germany in 1953 and marketed by the Stolberg-near-Aachen-based pharmaceutical company Grünenthal from October 1, 1957 to 1961, mainly in Germany and Britain. It was available in around fifty countries, although not in the United States, under at least forty names (such as Talimol, Kevadon, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, etc.). more...

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It was later (1960–61) found to be teratogenic in fetal development, most visibly as a cause of amelia or phocomelia, especially if taken during the first 25 to 50 days of pregnancy. Around 15,000 fetuses were damaged by thalidomide, of whom about 12,000 in 46 countries were born with birth defects, with only 8,000 of them surviving past the first year of life. Most of these survivors are still alive, nearly all with disabilities caused by the drug. In 2003, a World Health Organization newsletter cited evidence that the disabilities and deformities in many thalidomide survivors may be passed on to the survivor's own children through DNA, but many discount this as scientifically unfounded. Those deformed by thalidomide are sometimes referred to (or self-described) as thalidomiders or the derogatory abbreviative, "Flids".

Thalidomide was banned for its initial intended use as sedative. However, it has been found to be effective for other indications such as for leprosy and multiple myeloma. It is now marketed by Celgene as Thalomid with standard warnings for pregnant women to avoid taking it.

The thalidomide tragedy

Thalidomide had passed safety tests performed on animals, primarily because the proper tests — particularly those involving pregnant animals — had not been done. A court trial revealed that some tests were either conducted inadequately, or the results were faked.

There is also some evidence that the tests were carried out on a particular isomer of the drug, which forms a racemic mixture in the body. One element of this mixture has the intended beneficial action, while the other creates the horrific side effects.

The failure of these tests to discover the drug's disastrous consequences highlighted the inadequacy of testing methodologies in use at that time. This resulted in a dramatic increase in animal testing across a broad range of species in varying stages of pregnancy and lifecycle. In fact, later tests did demonstrate that administering thalidomide to rabbits and mice produces characteristic deformities in the offspring, although thalidomide has no effect on pregnant rats' offspring, (see Blake DA, Gordon GB, Spielberg SP. The role of metabolic activation in thalidomide teratogenesis. Teratology 1982;25(2):28A-29A.). If adequate testing had been done, thalidomide would never have been approved for pregnant women. Some opponents of animal testing still incorrectly cite thalidomide as an example of the ineffectiveness of such testing.

In 1960, Chemie Grünenthal decided to expand into the United States, and applied to the Food and Drug Administration for approval to sell the drug. This approval was not expected to be controversial, and the case was given to the agency's newest reviewer, Frances Oldham Kelsey. Kelsey had previously done animal toxicity research (including effects in pregnancy), and refused to clear thalidomide for sale until she obtained better documentation of its effects, especially in light of some unusual neurological side effects being reported in Britain. In fact, the testing had not been performed adequately, and satisfactory documentation was not forthcoming.

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Complete resolution of generalized lichen planus after treatment with thalidomide
From Journal of Drugs in Dermatology, 1/1/05 by Jennifer L. Maender

Abstract

Thalidomide has gained an infamous history due to severe birth defects observed in patients who had taken the drug to control nausea during pregnancy. (1) The medication was withdrawn from the market because of its teratogenicity, but was approved by the FDA in 1998 for the treatment of erythema nodosum leprosum. However, thalidomide has been employed with success by dermatologists for a host of off-label uses including the treatment of lichen planus. (2) Currently, no clinical trials or studies exist to evaluate the efficacy of using thalidomide to treat lichen planus, but case reports have been published in the medical literature supporting its therapeutic benefits. (3-6) TNF-[alpha] is among the many cytokines that have been implicated in the pathogenicity of lichen planus. It is thought that thalidomide acts

**********

Case Report

We describe a patient who experienced complete resolution of generalized lichen planus within 3 months of initiating treatment with thalidomide. A 43-year-old female with diabetes mellitus and hepatitis C was referred to our clinic with a 6-month history of a skin eruption. The patient had previously been diagnosed with lichen planus and was treating the condition with high potency topical corticosteroids without significant improvement. She was not a good candidate for systemic steroids because of her diabetes and hepatitis C. On physical examination, the patient exhibited countless flat-topped, polygonal, violaceous papules distributed among her trunk and extremities (Figures 1, 2, and 3). She was also found to have lacy white patches on her buccal mucosa characteristic of Wickham's striae. Thalidomide therapy was initiated at a dose of 100 mg nightly. The patient had previously had a hysterectomy, which ensured that she would not become pregnant while taking thalidomide. Topical steroids were continued in conjunction with thalidomide.

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When the patient returned for her 1- and 2-month follow-up office visits, she denied having any side effects related to the medication. The papules were noticeably flatter than on her initial visit, and the color was fading from purple to brown. After 3 months of thalidomide administration, the patient was cleared of skin lesions, and only post-inflammatory hyperpigmentation was evident (Figures 4, 5, and 6). Thalidomide was discontinued, and the patient was advised to return if she developed any recurrences. One year has passed without a relapse.

Because there are relatively few case reports in the literature detailing the therapeutic efficacy of thalidomide, more investigation into thalidomide as a treatment for lichen planus would be useful. Certain patients seem to have a better response to the medication than others. Naafs and Faber (3) described resolution of oral erosive disease in one patient, while another patient with generalized lichen planus had no improvement during administration of thalidomide. Perez et al (4) reported a case of generalized lichen planus with penile lesions where clearance was achieved without difficulty. Dereure et al (5) and Camisa and Popovsky (6) described 3 other patients with severe disabling lichen planus who were resistant to therapy with corticosteroids, phototherapy, etretinate, azathioprine, and cyclosporine. In each of the 3 cases, the patients experienced excellent responses to thalidomide therapy with complete resolution of the eruptions. Lichen planopilaris has also been successfully treated with thalidomide. (9,10)

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Commonly encountered side effects of thalidomide administration include sedation, constipation, and headache. These side effects are often dependent on dosage. Therefore, it is beneficial to begin therapy at the lowest dosage possible and titrate to efficacy to keep the risks of undesired side effects low. (8) However, the side effect most likely to limit therapy with thalidomide is peripheral neuropathy. There has been controversy in the literature as to whether or not this is a dose-dependent side effect, but it is clear that all patients on thalidomide should be monitored closely for development of peripheral neuropathy. Treatment should be discontinued if patients complain of numbness or tingling in their hands and/or feet, muscle cramps, or proximal muscle weakness. (11,12) In addition, because thalidomide is a severe teratogen, care must be taken when selecting patients to treat with this therapy. Our patient had undergone a hysterectomy; however, in patients capable of childbearing, strict adherence to contraception guidelines must be ensured. (13) The manufacturer of thalidomide, Celgene, has a program called the System for Thalidomide Education and Prescribing Safety (STEPS), which all physicians prescribing thalidomide must follow. Frequent pregnancy testing and writing prescriptions for no more than a 28-day regimen requires patients to have close follow-up while taking the medication. Males taking thalidomide should also practice contraception with their partners, as thalidomide has been found in semen samples of men taking the drug. (14)

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Although it remains unclear exactly what mechanism thalidomide effects to bring about resolution of the skin lesions of lichen planus, the medication has sufficient anecdotal evidence to support its consideration as a valid treatment option. We believe that in patients who have not responded to other, more traditional modalities, thalidomide may be an efficacious and relatively safe (with proper monitoring and precautions) treatment for refractory lichen planus.

References

1. Stirling DI. Thalidomide and its impact in dermatology. Semin in Cutan Med Surg. 1998;17:231-42.

2. Calabrese L, Fleischer AB. Thalidomide: current and potential clinical applications. Am J Med. 2000;108:487-95.

3. Naafs B, Faber WR. Thalidomide therapy: an open trial. Int J Dermatol. 1985;24:131-4.

4. Perez Alfonzo R, Weiss E, Piquero Martin J, Rondon Lugo A. Generalized lichen planus with erosive lesions of the penis, treated with thalidomide. Report of a case and review of the literature. Med Cutan Ibero Lat Am. 1987;15:321-6.

5. Dereure O, Basset-Seguin N, Guilhou JJ. Erosive lichen planus: dramatic response to thalidomide. Arch Dermatol. 1996;118:536.

6. Camisa C, Popovsky JL. Effective treatment of oral erosive lichen planus with thalidomide. Arch Dermatol. 2000;136:1442-3.

7. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med. 1991;173:699-703

8. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol. 1996;35:969-79.

9. George SJ, Hsu S. Lichen planopilaris treated with thalidomide. J Am Acad Dermatol. 2001; 45: 965-6.

10. Boyd AS, King LE. Thalidomide-induced remission of lichen planopilaris. J Am Acad Dermatol. 2002; 47:967-8.

11. Hess CW, Hunziker T, Kupfer A, Lundin HP. Thalidomide induced peripheral neuropathy. A prospective clinical, neurophysiological and pharmacogenetic evaluation. J Neurol. 1986;233:83-9.

12. Chaudhry V, Cornblath DR, Corse A, Freimer M, Simmons-O'Brien E, Vogelsang G. Thalidomide-induced neuropathy. Neurology. 2002;59:1872-5.

13. McBride WG. Thalidomide embryopathy. Teratology. 1977;16:79-82.

14. Teo SK, Harden JL, Burke AB, Ong F. Thalidomide is distributed into human semen after oral dosing. Drug Metab Dispos. 2001;29:1355-57.

Jennifer L. Maender MD, Ravi S. Krishnan MD, Tiffany A. Angel MD, Sylvia Hsu MD

Department of Dermatology, Baylor College of Medicine, Houston, Texas

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