Seattle Treatment Education Project (STEP) Perspective, Vol. 7, No. 1 - Spring 1995; A Publication of the Seattle Treat- ment Education Project, 127 Broadway E. Ste. 200, Seattle, WA 98102 * (206) 329-4857. Published 3 times a year
Dimitra A. Manesis, M.D.

The sedative thalidomide was withdrawn from the open market in 1962, when it was recognized to cause birth defects. Recently, it has come back into use (under severly restricted clinical trials) for indications such as Hansen's disease (leprosy), discoid lupus erythematosus (an autoimmune disease), and Behcet's syndrome (an autoimmune disease involving recurrent apthous ulcers). Thalidomide has also recently been reported to be effective therapy for painful oral (mouth) ulcerations associated with AIDS which do not respond to the usual treatment options available.[1]

Apthous ulcers are of unknown cause. They can occur on the mouth and genital and rectal areas. There are a variety of other kinds of mouth ulcers in those persons infected with HIV which may be associated with fungal, bacterial or viral infections, and cancer such as non-Hodgkin lymphoma, but this article just deals with the apthous type.[2]

Apthous ulcers have been categorized by size and location into three distinct types: minor, major, and herpetiform. Herpetiform ulcers appear clinically similar to ulcers caused by the herpes simplex virus with large numbers of small (1mm) descrete ulcers. Minor apthous ulcers, the most common form, occur singly or in groups of 2-5 as small, round ulcers (2-4mm) with well-defined depressed base, yellowish center, and an outer zone of redness. They usually last 5 to 10 days and are limited to the superficial layers of the mucosa (lining) of the mouth and heal without scarring. Major apthous ulcers are larger (1-3cm), range from one to ten in number, involve the deeper muscular or glandular layer of the mouth, and can persist for as long as 3 to 6 weeks. In contrast to minor apthous ulcers, scarring frequently occurs after healing.[2]

Apthous ulcers can recur. In HIV-positive immunocompromised persons, the lesions tend to occur and recur with increased frequency, size, and duration and involve other areas of the gastrointestinal tract, including the esophagus (food tube from mouth to stomach), genital area, and anus compared to the nonimmunocompromised person. Lesions in all areas can be very painful. Lesions in the mouth can be debilitating because they can interfere with eating, ability to take oral medications, and speaking. Lesions in the esophagus can cause difficulty and pain with swallowing.[2]

Oral lesions in persons with HIV can serve as clinical markers of disease progression. The Center for Disease Control and Prevention (CDC) lists oropharyngeal candidiasis (thrush) and oral hairy leukoplakia in the classification of HIV-associated illness. Other oral lesions with strong associations to immune deterioration may also serve as staging criteria in HIV disease. The prevelance of major apthous ulcers (MjAUs) in studies range from one to three percent in HIV-positive individuals. In one study, all the persons diagnosed with MjAUs had CD4 counts less than 100, most with CD4 counts less than 50.[2]

By definition, no specific bacteria or virus can be found as the cause of apthous ulcers when the lesions are biopsied. Many reports suggest immune dysfunction, stress, vitamin deficiency, allergies, diet, and viral infections as factors associated with apthous ulcer formation. Because the cause of these ulcers is not understood, the mechanism of action of drugs that appear to be effective in the treatment is also poorly understood, and the treatment is empiric, based on reported successes. There have been reported successs using topical treatments applied directly to the lesions. These include topical tetracycline, topical corticosteriods, and injection of steriods into the ulcer. Topical anesthetics, such as viscous lidocaine, can be used for pain relief. Some people may require sytemic corticosteriods (taken by mouth and absorbed in the bloodstream) such as prednisone, which supresses inflammation and the immune response. Prednisone, however, can have detrimental effects on an already compromised immmune system. Therefore, short courses are usually used. When the above mentioned treatments fail, case reports have shown successes with thalidomide.[3]

Thalidomide possesses no antibacterial activity. It has been used in a variety of diseases with an autoimmune character, however, the reason it works to modulate the immune system is not known. It also is unclear whether or not thalidomide will accelerate the deterioration of the immunolgical status of HIV- positive persons. One study suggests that thalidomide may suppress HIV viral replication and decrease viral burden.[4] Thalidomide is also an inhibitor of tumor necrosis factor, TNF. Low levels of TNF are necessary for the human body to fight infection. Higher levels of TNF lead to systemic toxicity and fever, malaise, muscle weakness, and wasting.[4]

Thalidomide was made and marketed in Germany in the 1950's as a sedative. The lethality in the case of an overdosage of thalidomide was so low that a dose killing 50% of animals (LD50) could not be established. It was then used in pregnant women as a "safe" alternative to barbiturates. In 1961 thalidomide was linked to an epidemic of malformed babies. The incidence of malformed babies paralleled the sales of thalidomide, and dropped after it was withdrawn from the market. A single dose of 100mg of thalidomide in the mother was enough to produce typical malformations in the baby, which include phocomelia of the arms and legs (hands and feet attached close to the body, resembling the flippers of a seal), amelia (absence of leg or arm), and other internal malformations of the urogenital, respiratory, and gastrointestinal tract.[1]

Thalidomide affects the central nervous system. Drowsiness, dizziness, decreased libido and mood changes can occur. Thalidomide also causes neurological problems which can limit its use. The peripheral nerves go to the fingers and toes. Thalidomide can damage peripheral nerves (peripheral neuropathy) resulting in burning of fingers and toes, impaired temperature sensitivity, and difficulty with finger movements. These symptoms may or may not go away after thalidomide is discontinued. Most cases of neuropathy occurred in patients who had received a high dose for longer than 6 months and usually after several years (dose dependent). Recovery is less likely if thalidomide is not stopped right away when symptoms occur, or if muscle weakness problems are present. Peripheral neuropathy is a common problem for HIV-positive persons, occuring in 15 to 50%. These people should not receive the drug. Also, the combination with other drugs_such as ddC and ddI which can cause peripheral neuropathy_should be avoided. Thalidomide may also produce a severe hypersensitivity reaction( rash, fever, and a fast heart rate).[1,11]

Case reports using thalidomide in HIV-positive individuals with major and minor apthous ulcers who failed the usual treatments have shown responses to thalidomide at doses ranging from 100mg a day to 400 mg a day. The ulcer pain seemed to resolve within 2 to 4 days. The dose in most case reports was then decreased to 50mg a day, with most ulcers healing within 2 weeks. Follow ups 4 to 6 months after treatment of 2 to 8 weeks with thalidomide revealed no recurrences.[5,6,7,8,9,10] Of course, these case reports are of treatment successes. A review article by Gunzler in 1992 stated that half of HIV-positive persons who used thalidomide had long-standing remission, and others experienced temporary remission lasting up to several months.[1] A crossover study of thalidomide vs placebo by Revus involving 73 participants (HIV status unknown) who had minor or major apthous ulcers present for more than 6 months was conducted in France in 1987. Patients were randomized to receive thalidomide (100mg) first or placebo tablets (with identical taste and shape) for the first 2 months and were then switched for another period of 2 months without interruption. 45% [17] of 38 persons treated with thalidomide and only 3% [1] of 35 people treated with placebo showed complete clearing of all ulcers within 1 month of treatment and maintenance of this during the second month. Thirteen of 17 individuals in remission who then received placebo had a relapse. Most people went about 20 days before relapsing. More than 50% of the participants in this trial chose to continue treatment at the end of the study. Daily doses were then tailored to individuals and some people intially treated with 100mg a day were free of apthous ulcers with 50 mg twice each week.[12]

The use of thalidomide over short periods may prove to be an alternative therapy for HIV-positive people suffering from apthous ulcerations resistant to other forms of therapy. Clearly, women of child-bearing age must be aware of the history of this drug and the high risk of birth defects, and anyone with a peripheral neuropathy needs to be aware that the problem may be made worse with thalidomide. Randomized placebo-controlled, double-blinded studies are needed to evaluate the efficacy of thalidomide in HIV-positive persons with apthous ulcers. The AIDS Clinical Trials Unit is doing a six month study comparing thalidomide to placebo for treatment of apthous ulcers of mouth and esophagus.

For further information contact the AIDS Clincal Trial Unit at (206) 223-3184 or 1-800-874-2572.

References:

1. Gunzler, Thalidomide in Human Immunodeficiency Virus Patients. Drug Safety 7(2): 116-134, 1992.

2. Muzyka, Major aphthous ulcers in patients with HIV disease. Oral Surgery Oral Medicine Oral Pathology. Vol 77, No. 2 February 1994.

3. Glick, Alternative Therapies for Major Aphthous Ulcers in AIDS Patients. JADA, Vol. 123, July 1992.

4. Makonkawkeyoon, Thalidomide inhibits the repication of HIV type 1. Proc.Natl. Acad. Sci.USA Vol 90, pp. 5974-5978, July 1993.

5. Reyes-Teran, Major recurrent oral ulcers in AIDS: report of three cases. J Oral Pathol Med 1992; 21: 409-411.

6. Nicolau, Thalidomide: Treatment of Severe Recurrent Aphthous Stomatitis in Patients with AIDS. DICP, The Annals of Pharmacotherapy. 1990 November, Volume 2, 1054-1056.

7. Gorin, Thalidomide in hyperalgic pharyngeal ulceration of AIDS. Lancet, Vol 335, June 1990.

8. Phelan, Major aphthous-like ulcers in patients with AIDS. Oral Surg, January 1991, 68-72)

9. Strazzi, Apthous ulcers in HIV-infected patients, genitourinary Medicine, Dec. 1992, Vol 68 (6), 424-5.

10. Ghigliotti, Thalidomide: Treatment of choice for aphthous ulcers in patients seropositive for HIV. JAADermatology, Volume 28, Number 2, Part 1, 271-272.

11. Williams, Thalidomide hypersensitivity in AIDS. Lancet, 337: Feb 16, 1991, 437.

12. Revus, Crossover Study of Thalidomide vs Placebo in Severe Recurrent Aphthous Stomatitis. Arch Dermatol. Vol 126, July 1990. 923-927.

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