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M E D I C A L G R A N D R O U N D S W I L L I A M S, W I L K E , M D , E D I T O R

Thalidomide's tightly controlled "comeback"

Thalidomide, once banned, may find use as an anti-inflammatory agent

L E O N A R D H. CALABRESE, D O Vice chairman, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic

• ABSTRACT Thalidomide has anti-inflammatory properties and shows promise for treating a variety of infectious and autoimmune diseases, but it must be used with strict precautions.

H A L I D O M I D E , removed from the world-wide market 40 years ago because it

caused birth defects, is making a comeback as an anti-inflammatory agent. Long a symbol of the danger of unanticipated and undetected side effects in new pharmaceuticals, thalido-mide is now being tested for a variety erf dif-ferent indications, but only with very strict safeguards.

• THE T H A L I D O M I D E TRAGEDY

Thalidomide was thought to be safe when it was introduced in Canada and Europe as a sedative hypnotic in the mid-1950s, although it was not approved for use in the United States. It was often prescribed to treat morning sickness. But by the early 1960s, reports were becoming more common that women who had taken thalidomide dur-ing pregnancy had given birth to infants with profound birth defects. Thalidomide was quickly removed from most of the worldwide market, but not before an estimated 10,000 to 12,000 children had been born with seri-ous birth dcfects. The ensuing controversy strengthened the power of the U S Food and Drug Administration ( F D A ) to regulate pharmaceuticals. Today, about 5,000 thalido-mide victims survive.

• W H Y T H A L I D O M I D E IS M A K I N G A C O M E B A C K

We have learned much about thalidomide in the 40 years since its original introduction. Although its role as a sedative hypnotic has been assumed by better drugs, carefully con-trolled experiments have shown that thalido-mide has a unique spectrum of useful anti-inflammatory, immunomodulatory, and anti-angiogenic properties. Specifically, thalido-mide:

• Inhibits production of tumor necrosis factor alpha (TNF-alpha), a proin-flammatory cytokine1 '2

• Inhibits leukocyte chemotaxis at the site of inflammation3

• Decreases helper T cells and increases suppressor T cells4.5

• Inhibits angiogenesis.6

It is not yet clear which of these mecha-nisms predominates in the treatment of a par-ticular disease. However, the inhibition of TNF-alpha is attracting particular interest. There is no known "normal" level of TNF-alpha, but we do know that TNF-alpha levels rise markedly in many diseases such as autoim-mune diseases and infections, particularly human immunodeficiency virus (HIV) infec-tion.

• A P P R O V E D USE OF T H A L I D O M I D E : E R Y T H E M A N O D O S U M LEPROSUM

On September 19, 1997, thalidomide received FDA approval for treating the debilitating and disfiguring lesions associated with erythe-ma nodosum leprosum, which occurs in approximately 4 0 % to 5 0 % of patients with lepromatous leprosy. This disease is the only currently approved indication for thalido-

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mide. In fact, thalidomide is the drug of choice in uncomplicated cases.

• EXPERIMENTAL USES OF T H A L I D O M I D E

In preliminary studies in relatively small num-bers of patients, thalidomide has shown some promise as a treatment for a number of infec-tious and autoimmune diseases, including the following.

C o m p l i c a t i o n s of H IV i n f e c t i o n TNF-alpha levels rise with HIV infection and rise as viral load increases.

HIV-associated aphthous ulcers. We have used thalidomide extensively in our HIV patients at the Cleveland Clinic, and some patients whose aphthae have been refractory to other agents have healed within a matter of days after the introduction of thalidomide. One small study found signifi-cant healing of aphthous ulcers using thalidomide 200 mg/day for 4 weeks vs place-bo ( 5 5 % complete healing with thalidomide vs 7 % for placebo).7

HIV-associated wasting syndrome. TNF-alpha appears to have a role in the wasting syndrome of HIV. One study using two dosages of thalidomide, 100 mg/day and 200 mg/day for 8 weeks, found steady and progressive weight gain, 60% of it in lean body mass.8 The 100-mg/day dosage appeared as effective as the 200-mg/day dosage.

HIV-associated diarrhea. Several small, controlled trials have found that thalidomide decreases the number of stools.9-11

A u t o i m m u n e diseases Rheumatoid arthritis. The data to sup-

port the use of thalidomide in rheumatoid arthritis are not robust. Several uncontrolled trials suggested :hat thalidomide in moderate-ly high doses of 300 to 600 mg/day may be effective, but many patients find these amounts difficult to tolerate.12 A study of low-dose thalidomide (100 mg/day) in combina-tion with low-cose methotrexate, which was reported during the 1998 annual meeting of the American College of Rheumatology last year, was more promising.13

Discoid lupus erythematosus and Behcet disease. Several studies have found thalido-

FIGURE 1. Top, oral ulcer in a male pat ient w i t h lupus erythematosus. The ulcer fa i led to respond t o cyclosporine and cort icosteroid therapy. Bot tom, lesion resolut ion af ter 4 weeks of 200 mg/day tha l idomide therapy.

mide effective in treating discoid lupus erythe-matosus14 (FIGURE 1) and Behcet disease,15 a multisystem syndrome of oral, genital, and ocular inflammation.

O t h e r d iseases Thalidomide is currently being tested for use in other diseases, including graft-versus-host disease,16 HIV infection itself, tuberculosis, sepsis, inflammatory bowel disease, autoim-mune neurologic disease, bacterial meningitis, cancer cachexia, and Kaposi's sarcoma. Because thalidomide may also have antiangio-genic properties, it is also being investigated as a treatment for some solid tumors.

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M E D I C A L G R A N D R O U N D S

TNF-alpha levels rise as HIV viral load increases

• PREVENTING N E W BIRTH DEFECTS

Even a single dose of thalidomide taken in early pregnancy can cause birth defects such as pho-comelia (absence of the arms and legs, with the hands and feet attached to the shoulders and hips, respectively). Therefore, all physicians, pharmacists, and patients who prescribe, dis-pense, or take thalidomide must register with thalidomide's manufacturer (Celgene; Warren, NJ; 1-888-423-5436) and agree to follow a rigor-ous protocol devised jointly by the FDA and Celgene, called S T E P S (System for Thalidomide Education and Prescribing Safety).

Women of childbearing potential must understand the risks and agree to use a reliable form of contraception. Moreover, the physi-cian must warrant that the patient is compe-tent and willing to do so, and the patient must undergo pregnancy testing before starting thalidomide, at 2 weeks, and every month thereafter.

The drug should not be stored in a shared medicine cabinet where it may be taken inad-vertently by anyone other than its intended recipient.

• OTHER SIDE EFFECTS A N D COST

Side e f f e c t s Neuropathy is the other major complica-

tion of thalidomide therapy, although its prevalence is difficult to ascertain. Neuropathy is reversible in most patients if the drug is promptly stopped at the first signs of dysesthe-sia. Whether electromyelographic monitoring is helpful is still a subject of debate.

Somnolence. Thalidomide's remaining side effects are rather modest. In the study of Kaplan et al in HIV-associated wasting,8 the most frequently reported adverse effect was somnolence, which is in keeping with thalido-mide's original indication as a sedative hyp-notic. Other common adverse effects are mucous membrane dryness and constipation.

Cost Thalidomide is expensive. At approximately $7.50 per 50-mg tablet, a 100-mg/day dosage costs $450 per month. This expense precludes its use as a first-line drug, except for erythema nodosum leprosum. "

• REFERENCES 1. Sampaio EP, Sarno EN, Galilly R, e t al. Tha l idomide selec-

tively inhibits tumor necrosis factor a product ion by stim-ulated h u m a n monocytes. J Exper M e d 1991; 173:699-703 .

2. More i ra AL, Sampaio EP, Zmuidz inas A, Frindt P, Smi th KA, Kaplan G. Thal idomide exerts its inhib i tory act ion o n t u m o r necrosis factor a by enhancing m R N A d e g r a d a -t ion. J Exper M e d 1993; 177 :1675-1680 .

3. Faure M , Th ivo le t J, Gaucherand M . Inhibi t ion of P M N leukocyte Chemotaxis by tha l idomide . Arch D e r m a t o l Res 1980; 269 :275 -280 .

4. M c H u g h SM, Rifkin IR, D e i g h t o n J, e t al. The i m m u n o s u p -pressive d rug thal idomide induces T helper cell t ype T (Th2) and concomitantly inhibits Th1 cytokine product ion in mi togen- and ant igen-st imulated h u m a n per iphera l b lood m o n o n u d e a i cell cultures. Clin Exper I m m u n o l 1995; 99 :160 -167 .

5. Gad SM, Shannon EJ, Krotoski W A , e t a l . T h a l i d o m i d e induces imbalances in T- lymphocyte sub-populat ions in t h e circulating blood of heal thy males. Lepr Rev 1985; 56 :35 -39 .

6. D ' A m a t o RJ, Loughnan MS, Flynne E, Fo lkman J. T h a l i d o m i d e is an inhibitor of angiogenesis. Proc Nat l Acad Sei USA 1994; 91:4082^1085.

7. Jacobson JM, Greenspan JS, Spritzler J, e t al. T h a l i d o m i d e for t h e t r e a t m e n t cf oral aphthous ulcers in pat ients w i t h h u m a n immunodeficiency virus infection. N Engl J M e d 1997; 336:1487-1493.

8. Kaplan G, Schambelan M , Gott l ieb M , e t al. T h a l i d o m i d e reverses cachexia in HlV-wast ing syndrome. 5 th Conference o n Retroviruses and Opportunist ic Infections, Chicago, 1998, abstract no. 476 .

9. Sharpstone D, R o w b o t t o m A, Nelson M , Gazzard B. T h e t r e a t m e n t of microsporidial d iar rhoea w i t h t h a l i d o m i d e . AIDS 1995; 9:658-659.

10. Quinones F, Sierra-Madero J, Calva-Mercado JJ, Ruiz-Palacios G M . Thalidomide in patients w i t h HIV infection and chronic diarrhea: Double-bl ind, placebo-controlled clin-ical trial. 4 th Conference o n Retroviruses and Opportunistic Infections. Washington, 1997, abstract no. 682.

11. Sharpstone D, R o w b o t t o m A, Francis N, e t al. Tha l idomide: A novel therapy for microsporidiosis. Gastroentero logy 1997; 112:1823-1829 .

12. Gut ierrez-Rodriguez O. Tha l idomide: A promising n e w t r e a t m e n t for rheumatoid arthritis. Arthrit is R h e u m 1984; 27 :1118 -1121 .

13. Scoville CD. O p e n trial using m e t h o t r e x a t e a n d tha l ido-mide in t h e t rea tment of rheumato id arthri t is (abstract). Ar th Rheum 1998; 41 (9Suppl):S60.

14. Lo JS, Berg RE, Tomecki KJ. T r e a t m e n t of discoid lupus erythematosus. Int J D e r m a t o l 1989; 2 8 : 4 9 7 - 5 0 7 .

15. H a m u r y u d a n V, Mat C, Sa ip S, e t al. T h a l i d o m i d e in t h e t r e a t m e n t o f the m u c o c u t a n e o u s lesions o f Behcet 's syndrome: A r a n d o m i z e d , d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d t r ia l . A n n I n t e r n M e d 1 9 9 8 ; 1 2 8 : 4 4 3 - 4 5 0 .

16. Vogelsang GB, Farmer ER, Hess A D , e t al. T h a l i d o m i d e for t h e t r e a t m e n t of chronic graft-versus-host disease. N Engl J M e d 1992; 326:1055-1058.

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