Thalidomide for Recalcitrant Cutaneous Lupus Erythematosus
Monday, February 07, 2005
Recalcitrant cutaneous lupus erythematosus (CLE) causes patients
considerable discomfort and often leads to disfigurement. Although
the majority of CLE responds to the combination of sun protection,
local glucocorticoids, and antimalarials, some cases require more
aggressive therapy. Thalidomide (Thalomid® -
Celgene Corporation) is a powerful option for treating recalcitrant
CLE. Numerous clinical studies have demonstrated thalidomide's
value as monotherapy in treating all forms of cutaneous lupus. In
1975, Rubio and Gonzalez first used it in chronic cutaneous lupus
erythematosus (CCLE), and numerous subsequent studies corroborated
its prompt effectiveness in antimalarial-resistant and
topical-steroid-resistant lesions of CCLE.1 Further
studies have shown equal effectiveness in subacute cutaneous lupus
erythematosus (SCLE).2-4 In all of the aforementioned
studies, participating patients were refractory to previous
treatment (topical steroids and antimalarials, and often other
therapies as well), and, in nearly all, patients achieved responses
and were able to discontinue all medications previously required to
control their cutaneous disease. Doses ranged from 50 mg to 400 mg
daily, and maintenance doses ranged from 25 mg to 100 mg qd.
Clearly, except for oral glucocorticoids, few if any other
therapies offer such efficacy in treating CLE.
Why is such an effective treatment not utilized more frequently
by clinicians? Side effects of thalidomide treatment are common and
may be serious. Somnolence is perhaps the most common side effect
and a frequent cause of treatment discontinuation. Initially
marketed as a sedative, thalidomide has been reported to cause
drowsiness in anywhere from 50% to 100% of patients.5,6
The effect may be overcome by lowering the dosage, and tolerance
usually develops over time. Constipation and abdominal distention
are other frequent complaints. In their study of 23 patients with
cutaneous lupus, Atra and Sato noted constipation or abdominal
distention in 22% of their patients. However, lowering the drug's
dosage adequately controlled side effects. Other side effects less
commonly reported include dry mouth, urticaria, rash, mood changes,
circulatory changes, amenorrhea, edema, dizziness, and
Thalidomide's most serious side effects are peripheral
neuropathy and teratogenicity. Peripheral neuropathy is a common
side effect of thalidomide treatment and may be both severe and
irreversible. Although usually sensory, neuropathy may involve
motor roots as well. It usually appears after months of chronic use
of thalidomide. Although some studies have debated
this,7 several studies have linked it with cumulative
dose, citing 40 mg to 50 g as the dose after which neuropathy
usually becomes apparent.8-11 Incidence varies widely,
and may depend on the age of the patient (older patients seem to be
more prone to neuropathy), sex (females are more prone), the
presence of pre-existing neurologic disease, and the disease being
treated.12 Reported incidence varies from 1% to 70%.
Recovery may be slow or fail to occur: one study estimated that 4
to 6 years after treatment, 25% of patients had full recovery, 25%
had some improvement, and 50% had no change.10
The drug's most infamous side effect is its teratogenicity.
Phocomelia and death to the fetus are most common, although others
have been reported to occur concurrently, including deformities of
the internal organs.13 The incidence of birth defects is
highest during the critical period of pregnancy, from 35 to 50 days
after the last menstrual period, and even one 50 mg tablet ingested
during this period is sufficient to produce devastating effects.
Because of the seriousness of these effects, Celgene Corporation
has gone to great lengths, with the development of the System for
Thalidomide Education and Prescribing Safety (STEPS) program, to
ensure no woman becomes pregnant while taking this medication.
Physicians and pharmacies must be certified to prescribe this
medication, patients must use 2 methods of birth control, and serum
pregnancy tests must be performed biweekly to monthly. Such
stringent prescribing restrictions and regulations have caused some
clinicians to shy away from use of this medication.
Recent reports in the oncology literature have definitively
shown an association between thalidomide use and thromboembolic
events, including deep vein thrombosis and pulmonary embolism. It
appears that this dangerous side effect may not be limited to
cancer patients treated with thalidomide. In our practice, 6 of 29
patients (20.7%) developed significant thromboembolic events while
on thalidomide therapy for cutaneous lupus (4 patients) or Behçet's
disease (2 patients) (unpublished data). Although these diseases
both have a higher background incidence of thrombosis, our
experience appears to confirm that thrombosis should be added to
the list of potentially worrisome side effects caused by
thalidomide. Care should be taken to avoid other risk factors for
thrombosis in patients who are treated with thalidomide (eg,
smoking, estrogen use).
The obvious dilemma is how to safely utilize this extremely
efficacious medication yet minimize risk of toxicity. The answer is
by using as low a dose for as short a time as is possible. We
routinely treat patients with recalcitrant CLE with short "pulse"
courses of low-dose thalidomide as induction therapy. A typical
patient begins treatment with 50 mg to 100 mg nightly. If the
patient is not already on combination antimalarial therapy with
hydroxychloroquine and quinacrine, these drugs are started
concomitantly. The thalidomide dose is halved as soon as the
patient shows a good response (typically between 2 weeks and 2
months) and is discontinued as soon as the skin is clear (typically
2 months to 5 months). It is imperative that the patient remain on
antimalarials as maintenance therapy, since up to 75% of patients
relapse following discontinuation of thalidomide when it is used as
monotherapy.4-6 It is possible to perform additional
pulses if relapses recur (ie, each summer, after substantial sun
In summary, thalidomide is an extremely efficacious drug, yet a
healthy respect for its potential adverse events is required. We
have found that short courses of thalidomide added to patients'
previous treatment regimens induce rapid, complete, and
long-lasting remissions while minimizing patients' risk of
dangerous side effects.
- Rubio JB, Gonzalez FF. Lupus eritematoso discoide y talidomida.
Dermatol Rev Mex. 1975;19:131-139.
- Duong DJ, Spigel GT, Moxley RT III, Gaspari AA. American
experience with low-dose thalidomide therapy for severe cutaneous
lupus erythematosus. Arch Dermatol.
- Scolari F, Harms M, Gilardi S. Thalidomide in the treatment of
chronic lupus erythematosus [in French]. Dermatologica.
- Hasper MF. Chronic cutaneous lupus erythematosus: thalidomide
treatment of 11 patients. Arch Dermatol.
- Knop J, Bonsmann G, Happle R, et al. Thalidomide in the
treatment of sixty cases of chronic discoid lupus erythematosus.
Br J Dermatol. 1983;108:461-466.
- Atra E, Sato EI. Treatment of the cutaneous lesions of systemic
lupus erythematosus with thalidomide. Clin Exp Rheumatol.
- Molloy FM, Floeter MK, Syed NA, et al. Thalidomide neuropathy
in patients treated for metastatic prostate cancer. Muscle
- Fullerton PM, O'Sullivan DJ. Thalidomide neuropathy: a
clinical, electrophysiological, and histological follow-up study.
J Neurol Neurosurg Psychiatry. 1968;31:543-551.
- Chaudhry V, Cornblath D, Corse A. Thalidomide-induced
neuropathy: clinical and electrophysiological features.
Neurology. 1996;46:S283. Abstract S27.003.
- de Iongh RU. A quantitative ultrastructural study of motor and
sensory lumbrosacral nerve roots in the thalidomide-treated rabbit
fetus. J Neuropathol Exp Neurol. 1990;49:564-581.
- Clemmensen OJ, Olsen PZ, Andersen KE. Thalidomide
neurotoxicity. Arch Dermatol. 1984;120:338-341.
- 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.
- Manson JM. Teratogenicity. In: Cassarett and Doull's
Toxicology: The Basic Science of Poisons. 3rd ed. New York,
NY: Macmillan Publishing Co; 1986:195-220.