Thalidomide: indications in Dermatology

Abstracts

A talidomida, descoberta na Alemanha Oriental, em 1954, mostrou vários efeitos terapêuticos: antiemético, sedativo e hipnótico. De 1959 a 1961, foram descritas cerca de 12.000 crianças nascidas com defeitos teratogênicos. Seu uso foi, conseqüentemente, suspenso. Sheskin, entretanto, recomeçou a usar a droga e verificou efeito benéfico no eritema nodoso leprótico. A talidomida é derivada do ácido glutâmico. Sua eliminação urinária é mínima (1%). Tem ações: antiinflamatória, imunomoduladora e antiangiogênica. Tem sido usada, com certo êxito terapêutico, em algumas entidades mais adiante estudadas. O principal efeito adverso é teratogênico: alterações nos membros, orelhas, olhos e órgãos internos. Supõe-se que esses efeitos teratogênicos decorram da ação antiangiogênica. Outros efeitos adversos: cefaléia, secura da pele e da mucosa da boca, prurido, erupção cutânea, aumento de peso, hipotireoidismo, neutropenia, bradicardia ou taquicardia e hipotensão. Interage com outros fármacos: barbitúrico, clorpromazina, reserpina, álcool, acetaminofen, histamina, serotonina e prostaglandina.

eritema nodoso; prurido; talidomida; talidomida; terapêutica

REVIEW ARTICLE

Thalidomide: indications in Dermatology^*

Rubem David Azulay

Emeritus Professor, UFRJ and UFF. Titular Professor, Souza Marques Technical-Education Foundation and Universidade Gama Filho. Titular-Member of the National Academy of Medicine. Head of the Dermatology Institute, Santa Casa da Misericórdia do Rio de Janeiro Hospital

^{Correspondence}

ABSTRACT

Thalidomide was discovered in East Germany in 1954. It presented with several therapeutic effects: antiemetic, sedative and hypnotic. From 1959 to 1961, roughly 12,000 children born with teratogenic defects were described. Its use was consequently halted. Sheskin started using the drug again and observed its beneficial effect on erythema nodosa leprosum. Thalidomide is derived from glutamic acid. Its urinary elimination is minimal (1%). It has the following actions: anti-inflammatory, immunomodulary and antiangiogenic. It has been used with a successful therapeutic outcome on some entities, which have been studied further.

The main side effect is teratogenic: limb alterations, ears, eyes and internal organs. The teratogenic effects are assumed to result from antiangiogenic action.

Other side effects are cephalea, dry skin and mouth mucous, pruritus, cutaneous eruption, weight gain, hypothyroidism, neutropenia, bradycardia or tachycardia, and hypotension. It interacts with other medicine: barbiturates, chlorpromazine, reserpine, alcohol, acetaminophen, histamine, serotonin and prostaglandin.

Key-words: erythema nodosum; pruritus; thalidomide; thalidomide/adverse effects; therapeutics

INTRODUCTION

Thalidomide was discovered in East Germany in 1954, and used as a sedative and hypnotic antiemetic.¹ As an antiemetic, thalidomide was often administered on pregnant women. The result was that teratogenesis (phocomelia) was observed in roughly 12,000 children born between 1959 and 1961; its use was subsequently prohibited³ In 1997, however, the Food and Drug Administration (FDA) allowed thalidomide to be used on erythema nodosa leprosum (ENL), largely thanks to Sheskin's work in 1965.³

Pharmacology and Pharmacokinetics

Thalidomide is an alpha-N-phtalimidoglutaride, that is, a synthetic derivative of glutamic acid, whose structure has four amino acids. With pH 7.4 it experiences rapid hydrolysis with the formation of 12 hydrolytic elements. By administering 200 mg, a plasmatic concentration of 1.15 + 0.2 micrograms mL could be observed within four to five hours. Elimination through urine is minimal (1%). Its action as a sedative results most likely from activating the sleep center of the cerebral system. It has an inflammatory and antipyretic effect. It reduces phagocytosis by polymorphonuclears, as well as TNF-alpha levels. It prompts innumerable symptoms and signs, like cephalea, anorexia, vomiting, orchitis, arthralgia, myalgia and hepatospenomegaly. In addition to being an anti-inflammatory, it also has immunomodulator properties, as illustrated in the following description:²

• The anti-inflammatory action results from the inhibition of chemotaxis and phagocytosis, the stabilization of the symbiosome membranes and a drop in the formation oxygen-derived radicals, such as superoxide and hydroxyl.

• Immunomodulary action results from inhibiting the tumoral necrosis factor of interferon-a, interleukin 12 and from an increase in interleukin types 2, 4 and 5, suppression of the formation of IgM antibodies and the proliferation of T-lymphocytes.

• Angiogenic inhibition results from antagonism between the following elements: E₂ and F₂ prostaglandins, histamine, serotonin and acetylcholine; a rise or fall in the human immunodeficiency (HIV) virus expression - 1.

Therapy

Thalidomide has been successfully used on innumerable diseases, as described in the following report.

• Erythema nodosum leprosum (ENL) - In 1965, Sheskin³ treated six cases within 24 hours, with a favorable response after using 300 mg daily. Later, he published another paper that included 4,522 patients with 99% of good results. In 1% of cases, the erythema nodosa worsened.⁶ The initial dose was 400 mg daily and maintenance was 50-100 mg daily. The time of treatment lasted from a few days to six months. It is also worth mentioning that most cutaneous lesions responded within a 24-to-48 hour period. Other symptoms or signs were hepatospenomegaly, orchitis, anorexia, cephalea, insomnia, arthralgias, myalgia and vomiting, which took longer to improve. Other symptoms were leucopenia and an alteration in the hemosedimentation rate. In Brazil, the first study to confirm Sheskin's observations³ was carried out by Sampaio and Proença in 1966⁴. In the same year, Opromolla et al.⁵ confirmed these observations. It is worth noting that, in spite of leprosy having a predilection for the nerves, Sheskin observed an improvement of this symptomatology, albeit aware of the neurotoxicity thalidomide presents. The author's personal experience in treating ENL has demonstrated thalidomide to be the best therapeutic weapon.

• Aphtous stomatitis - Mascaró et al.⁷ were the first to demonstrate the usefulness of treating mucocutaneous aphtae with thalidomide. Later studies confirmed this therapeutic finding. The most important one was carried out by Ramselaar et al.,⁸ who studied 67 patients, and observed complete remission in 48% of them. In the placebo group, the therapeutic response was favorable up to 9%. The therapeutic action of thalidomide results from the inhibition of a chemotaxic increase in polymorphonuclear leukocytes.⁹

• Nodular Prurigo - The first one to observe the effect of thalidomide on this dermatosis was the Brazilian, Osmar Mattos,¹⁰ who successfully treated a patient diagnosed with the disease. In 1975 Sheskin¹¹ also observed that nodular prurigo treated with thalidomide obtained good results. Grosshans et al.¹² observed that within two weeks the 100-300 mg daily thalidomide dose dealt successfully with the problem. Nonetheless, they suggested continuing treatment for six months. The present author had the opportunity of treating a case with good results by using 200 mg daily. The improvement seems to result from the drug's direct action on the proliferation of nervous tissue in this entity.¹³

• Actinic prurigo - In 1970, Londono¹⁴ treated 34 patients and obtained good results in 30 cases over a period varying from one to two months. There was recurrence of the condition after the drug was halted. This was also confirmed by other authors.^15,16

• Behcet's syndrome - In 1982, Saylan and Saltik¹⁷ ecarried out the first therapeutic trial on Behcet's syndrome with thalidomide. The trial dealt with 22 patients who had ulcerated genital lesions. They used 400 mg daily for five days, and thereafter 200 mg daily for more than five days. The lesions scarred quickly. Discreet recurrences did arise, and in most cases, there was a spontaneous disappearance of the later lesions, which was also confirmed by other studies. Among the latter, one can cite Hannuryudam et al.¹ qin which 96 male patients were treated using a daily dose of 100 or 300 mg, or a placebo for 24 weeks. The results were as follows: seven patients (22%) had complete regression, while none of the 32 who received a placebo showed a satisfaction result. The drug's action on this disease is due to the following mechanisms: reduction of cellular immunity and inhibition of the chemotaxis of neutrophils. There are diverging opinions regarding these mechanisms. Hamza believes the therapeutic effect is due to a drop in production of superoxide and hydroxyl radicals with the capacity to cause lesions in the inflammation areas.

• Graft versus host disease - In 1990 Wood and Procter²⁰ observed good results from using thalidomide on this condition. Vogelsang and cols.²¹ observed 44 patients. There was complete therapeutic response in 14 of them, although in 12 patients the response was partial. In 18 there was not response at all.

• Discoid and systemic lupus erythematosus - Knope and cols.²² treated 60 cases of chronic lupus erythematous. There was complete regression in 90% of cases. The dose used was 400 mg daily. Nevertheless, in 71% of cases there was recurrence when treatment was stopped. An occurrence of polyneuritis in 25% of cases should also be mentioned. In its systemic form, there was an improvement of cutaneous and joint lesions, however not in relation to the viscerae.²³

• Sarcoidosis - The treatment with thalidomide (200 mg daily for two weeks, followed by 100 mg daily for 11 weeks) improved the cutaneous lesions, hilar lymphadenopathy and Kaposi's sarcoma. This response was attributed to macrophage inhibition.²⁴

• Langerhans cell histiocytosis in adults (histiocytosis X) - There are various reports on thalidomide's therapeutic effect here, but treatment doses and time have fluctuated according to various authors.²⁵

• Jessner's lymphocytic infiltrate - Guillaume²⁶ studied 28 patients. Thirteen patients received thalidomide and 15 placebos. Of the 13 treated, 11 had remission whereas the 15 who received the placebo showed no improvement.

• Toxic epidermal necrolysis - 12 patients were treated with thalidomide (400 mg daily for five days). However, 10 had a lethal outcome. In the 10-patient placebo group, three died. This is not a good indication for the therapeutic use of thalidomide. This experiment was done because there were high levels of TNF-a in the pathogenesis of this disease and thalidomide is known to be a powerful inhibitor of TNF-a.²⁷

• Pyoderma gangrenosum - observed complete remission in one patient treated with 100 mg daily for two years. But due to neuropathy, the drug was halted with recurrence. Farrell and cols.²⁹ treated two cases with corticosteroids and minocycline. One of latter associated with thalidomide in a 100 mg daily dose for five days, with an improvement of the condition.

• Lichen planus - In a 25-150 mg daily dose, thalidomide produced a regression of the oral lichen planus lesions.³⁰

• Kaposi's sarcoma - There has only been one observation suggesting an improvement of this sarcoma.³¹

• Uremic pruritus - Twenty-nine patients treated with thalidomide showed signs of improvement.³²

• Postherpetic neuralgia - Treatment with thalidomide is effective, although with recurrence three weeks after halting the drug³³

• Erythema multiforme - Various cases were treated with thalidomide (100 mg daily), showing good results, but with posttreatment recurrence.³⁴

Side Effects

Teratogeny is a main effect. McBride¹ classified these effects into three groups:

• Deformity of the extremities: absence of limbs, phocomelia, bone hypoplasia, absence of bones;

• Abnormality of the ears and eyes: absence of the ear, microauricular, absence or reduced auditory canal, anophthalmia, microphthalmia with or without associated facial paralysis;

• Alterations of internal organs: dcongenital cardiac disease, genital abnormality of the gastrointestinal tract and urinary tract;

• Mortality (40%) immediately after birth.

These teratogenic defects result from the antiangiogenic effects of thalidomide. Another important adverse reaction is peripheral neuropathy.

Some minor side effects are: cephalea, dryness of the skin and mouth mucosa, pruritus, cutaneous eruption, weight gain, hypothyroidism, neutropenia, bradycardia or tachycardia and hypotension.

Interaction with other medicines

Those that stand out are: barbiturics, chlorpromazine, reserpine, alcohol, acetaminophen, histamine, serotonin, acetylcholine and prostaglandin.

CONCLUSION

After thalidomide use was prohibited due to its teratogenic effects, it was taken up again for treating erythema nodosa leprosum and showed a satisfactory result. Nevertheless, its use is still very controversial, especially regarding the beneficial and/or adverse effects of the drug, its mechanisms of action and its real therapeutic indications. Since then, it has been administered for diverse dermatoses with relative success. We should like to call attention to the fact that, after halting the drug, the dermatosis usually recurs.

REFERENCES

Received on October 19, 2002.

Approved by the Consultive Council and accepted for publication on October 16, 2003.

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Correspondence to

Prof. Rubem David Azulay

Av. Atlântica, 3.130 apt. 701 - Copacabana

22070-000 RJ Rio de Janeiro

Fax: [phone]

*

Work done at Dermatology Institute, Sta. Casa de Misericórdia do Rio de Janeiro.

Publication Dates

• Publication in this collection
  29 May 2006
• Date of issue
  Oct 2004

History

• Accepted
  16 Oct 2003
• Received
  19 Oct 2002