Thalidomide:
An Old Drug with New Tricks
Heidi Jacobe, M.D.
From Lupus News Summer 2002
Vol. 22, N. 2
The history of thalidomide
How does thalidomide work?
Thalidomide and lupus
Side effects of thalidomide
Nuts and bolts of thalidomide
Summary
References
About the author
The history
of thalidomide
Thalidomide was developed as a non-barbiturate sedative
(non-addictive sleep aid) in Germany during the 1950s.
It was removed from the market in 1961 after it was
linked to major birth defects in children whose mothers
took thalidomide during pregnancy. This incident spurred
the extensive drug testing policies now in place all
over the world.
New therapeutic effects of thalidomide
were accidentally discovered in patients with leprosy
and a disorder called erythema nodosum leprosum, shortly
after the drug was withdrawn from the market.
Subsequent therapeutic trials revealed thalidomide
can benefit a number of other disorders, including:
-
lupus erythematosus of the skin
-
oral ulcers associated with HIV
infection or Behcet's disease
-
sarcoidosis
-
chronic graft versus host disease
-
and some internal cancers.
These discoveries paved the way for
thalidomide's approval by the Food and Drug Administration
in 1998 for use in erythema nodosum leprosum.
Although the FDA established very strict
control of thalidomide's use, its approval led to
greater availability and increased interest in the
drug. As a result, thalidomide is now a very useful
drug in the treatment of a large number of disorders
from cutaneous (skin) lupus to multiple myeloma (a
type of blood cancer).
Today, despite its many uses, thalidomide
remains the most strictly regulated drug in the world.
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How does thalidomide
work?
Although thalidomide was initially developed as a
sedative, it has a multitude of other effects that
were not evident when it first came to market. The
first discovery was its teratogenic (ability to cause
birth defects) effect when taken by pregnant women.
Despite continued research, it is still unclear how
thalidomide produces birth defects.
The accidental discovery of thalidomide's
effectiveness in treating a complication of leprosy,
an inflammatory disorder, was the first evidence that
it has effects completely separate from its sedating
properties. Its effectiveness in treating inflammatory
disorders proves that thalidomide modulates the immune
system (the immune system protects the body from infection;
when it is out of balance it produces inflammatory
and autoimmune disorders like lupus).
Although the way in which thalidomide
modulates the immune system is not fully understood,
recent research shows that thalidomide inhibits production
of Tumor Necrosis Factor Alpha (TNF ). TNF is associated
with the development and symptoms of many diseases.
Thalidomide also affects angiogenesis
(the growth of new blood vessels). Because cancers
need the growth of new blood vessels to survive, thalidomide
also is effective in the treatment of some types of
cancer.
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Thalidomide
and lupus
Thalidomide has been used in a fairly large number
of people with the type of lupus that affects their
skin (discoid lupus, subacute cutaneous lupus, lupus
profundus, tumid lupus). Although antimalarial drugs
are still the first choice in treatment of lupus skin
lesions, thalidomide has become an accepted second-line
treatment for those individuals who do not respond
to other therapy.
Thalidomide often is highly effective
in treating lupus-associated skin lesions. Studies
show that even people who are resistant to other types
of treatment (antimalarials, methotrexate, etc.) can
respond very well to thalidomide. On average, significant
improvement in skin lesions occurs in 75-90 percent
of those treated with thalidomide, and 54-75 percent
of these individuals have complete clearance of their
skin lesions.
Most people begin noting improvement
in their skin lesions within the first month of starting
therapy, with continued improvement over the next
three to six months. Relapses (recurrence of skin
lesions) usually occur within one to two months of
drug withdrawal, but frequently are less severe.
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Side effects of
thalidomide
Although thalidomide is highly effective for lupus-associated
skin disease, it has significant side effects that
must be considered before starting therapy.
1) Thalidomide is definitively linked
to severe birth defects.
-
Pregnant women or women considering
pregnancy in the near future may not take thalidomide.
-
If a woman on thalidomide is of
childbearing potential, she must use two forms of
birth control. Birth control also must be continued
for three months after the drug is stopped.
-
Finally, patients of childbearing
potential must have monthly pregnancy tests while
on thalidomide, or the drug cannot be refilled.
2) Thalidomide can cause severe and
irreversible neuropathy (nerve injury) which commonly
appears as numbness and tingling of toes and fingers.
-
Neuropathy occurs in 10-50 percent
of patients who take thalidomide.
-
There is some evidence that older
age and greater doses increase the risk of neuropathy.
-
Most physicians obtain a series
of nerve tests before patients start thalidomide
and while they are on the drug, to monitor for this
side effect.
3) Drowsiness is commonly associated
with thalidomide therapy, especially at higher doses.
-
Drowsiness is usually minimized
by taking the medication in the evening.
-
Most patients develop tolerance
to this side effect after one to three weeks.
-
Constipation is also associated
with thalidomide therapy, especially when high doses
are used.
-
Other common reactions include dizziness,
irregular menstrual bleeding, and headache.
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Nuts and bolts
of thalidomide
Persons interested in learning more about thalidomide
should see a rheumatologist or dermatologist who can
confirm that there is a skin disorder that might respond
to thalidomide, and can evaluate whether the patient
has been already adequately treated with first-line
medications.
Thalidomide is heavily regulated and
may only be obtained through approved physicians and
pharmacies registered in the System for Thalidomide
Education and Prescribing Safety Program (STEPS).
Therefore, if thalidomide is a reasonable option after
evaluation by a rheumatologist or dermatologist, the
patient should be referred to a physician registered
with the STEPS program.
The STEPS program also requires the
active participation of the patient. STEPS requires
that patients:
1) participate in a regular phone survey
2) are not supplied with more than 28 days of medication
without refills
3) fill prescriptions within 7 days
4) obtain a written prescription from a registered
physician.
Thalidomide is manufactured by Celgene
under the name Thalomid®. The company provides
information about the drug and the STEPS program,
and provides a list of registered physicians and pharmacies
through its website, www.celgene.com/thalomid/.
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Summary
Thalidomide, developed as a sleep aid in the 1950s,
is effective in treating a large number of inflammatory
and autoimmune disorders.
Although most dermatologists consider
antimalarials as first-line therapy for cutaneous
lupus, thalidomide has been increasingly accepted
as second-line therapy, producing marked improvement
even in patients who have not responded to numerous
other treatments.
Many dermatologists also feel that using
thalidomide to manage lupus skin disease is relatively
safer than other drugs used, such as prednisone, methotrexate,
or Imuran.
Despite the inconvenience of prescribing
and obtaining the drug-due to its known teratogenic
danger in a developing fetus-thalidomide's only significant
known "toxicity" in its use in cutaneous
disease is neuropathy (disease of the nervous system),
which can be minimized by appropriate monitoring,
and is not a life-threatening condition.
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References
Ordi-Ros J. Thalidomide in the treatment of cutaneous
lupus refractory to conventional therapy. J Rheumatol
2000 Jun: 27(6): 1429-33.
Duong DJ, Gaspari AA. American experience
with low-dose thalidomide therapy for severe cutaneous
lupus erythematosus. Arch Dermatol 1999 Sep; 135 (9):
1079-87
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About the Author
Dr. Heidi Jacobe is an Assistant Professor of Dermatology
at the University of North Carolina. Her professional
interests are autoimmune connective tissue disease
and the skin, atopic dermatitis, and psoriasis. She
received her medical degree at Baylor College of Medicine
in Houston, TX, where she also completed her Internship
in Internal Medicine, and served her Residency in
Dermatology at the University of Texas Southwestern
Medical Center in Dallas.
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July 30, 2003
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