Housman TS, Jorizzo JL, McCarty MA, Grummer SE, Fleischer AB, Sutej PG. Low-Dose Thalidomide Therapy for Refractory Cutaneous Lesions of Lupus Erythematosus. Arch Dermatol. 2003;139(1):50-54. doi:10.1001/archderm.139.1.50
Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2003
Thalidomide is an anti-inflammatory agent and an immunomodulator that inhibits the production of tumor necrosis factor α. It has shown promise as a treatment option for the cutaneous manifestations of lupus erythematosus (LE).
To assess the degree of clinical response per subtype of cutaneous lupus, the duration of therapy before documented clinical improvement, and the incidence of adverse effects, including peripheral neuropathy, with low-dose thalidomide therapy at 100 mg daily in the treatment of refractory cutaneous lesions of LE.
This retrospective medical record review of patients with refractory cutaneous manifestations of LE is one of the largest modern series in the literature. There were 29 patients seen at the Department of Dermatology, Wake Forest University School of Medicine (Winston-Salem, NC), who were unresponsive to conventional agents including antimalarial agents, and who started treatment between 1998 and 2000. Twenty-three patients who took the drug for 1 month or more were included in the analysis. Clinical responses were assessed by the investigators based on statements of improvement listed in the clinic notes and were categorized as "no response," "partial response," and "complete response." Partial response was classified as either 75% or greater or less than 75% improvement. The incidence of adverse effects including peripheral neuropathy was determined.
Of the 23 patients, 17 (74%) demonstrated complete resolution of the cutaneous manifestations of LE, whereas 3 patients (13%) demonstrated 75% or greater partial improvement; 3 patients (13%) had less than 75% partial clinical improvement; and 21 patients (91%) who demonstrated a complete or partial response did so within 8 weeks of initiating thalidomide therapy.
Based on the results of this case series, we believe that thalidomide should be given prime consideration as a treatment for antimalarial drug–resistant interface lesions of LE. The design of prospective, randomized, double-blind, placebo-controlled trials for this indication is warranted.
CUTANEOUS manifestations of lupus erythematosus (LE) are chronic, disfiguring lesions that may be associated with systemic disease. These cutaneous lesions can be simply classified into 3 categories of lesions: (1) vascular lesions seen in systemic lupus erythematosus (SLE); (2) interface lesions seen in chronic cutaneous lupus erythematosus (CCLE), subacute cutaneous lupus erythematosus (SCLE), or SLE; or (3) special lesions as seen in LE profundus or in vesiculobullous lesions.1 There is potential for overlap between CCLE and SCLE, between CCLE and LE profundus, and between CCLE/SCLE and SLE.2
First-line therapy for cutaneous manifestations of LE has traditionally been antimalarial agents (hydroxychloroquine sulfate and/or quinacrine hydrochloride) along with sun protection.2,3 Other systemic treatments include dapsone, retinoids, clofazimine, and/or intralesional triamcinolone.2,4- 6 However, owing to the chronicity of this disease, patients may be unresponsive or become refractory to conventional treatment and/or may have lesional recurrences.2 Moreover, many patients with discoid lesions go on to develop destructive or deforming scarring and/or pigmentary disturbances.2,7 This need for effective treatment led to the use of thalidomide as an alternate therapeutic modality for cutaneous LE.
Early reports of thalidomide use for the treatment of cutaneous manifestations of LE were by Barba-Rubio and Franco-Gonzalez8 in 1975.8- 10 In 1983, Knop et al10 reported complete or marked benefit in 54 of 60 patients treated with a high thalidomide dosage (400 mg/d), which was then reduced to a minimum of 50 to 100 mg/d. Its anti-inflammatory and immunomodulatory properties that inhibit the production of tumor necrosis factor α are thought to contribute to its efficacy in cutaneous LE.11,12 In addition to treating SLE and cutaneous LE, thalidomide has been successfully used to treat chronic inflammatory diseases including prurigo nodularis, erythema nodosum leprosum, graft-vs-host disease, rheumatoid arthritis, aphthous stomatitis, and Behçet syndrome.11,12
Recent reports also confirm the efficacy of thalidomide for cutaneous LE in dosages ranging from 50 to 200 mg/d, with a complete response reported in 44% to 72% of patients and partial response reported in 28% to 37% of patients.9,13,14 Using 100-mg daily dose of thalidomide, a recent trial reported 12 (63%) of 19 patients with cutaneous lupus had complete improvement, 4 (21%) had partial improvement, and 3 (16%) had no response.15 The duration of thalidomide therapy needed for maximum benefit has been reported as anywhere from 12 to 16 weeks.13,15 In one series, thalidomide-induced sensory peripheral neuropathy, documented with a nerve conduction study, was reported in 21% of patients.16,17 Besides this and the significant risk of teratogenicity, other best documented adverse effects include paresthesias without associated clinical or electrophysiologic findings, drowsiness/fatigue, dizziness, weight gain, amenorrhea, constipation, headache, and nausea.9,10,13- 15,18,19
Patients treated with thalidomide between 1998 and 2000 at the Department of Dermatology at the Wake Forest University School of Medicine (Winston-Salem, NC) were identified. The medical records of all 29 patients with a clinicopathologic diagnosis of CCLE, SCLE, SLE, or LE profundus were retrospectively reviewed. Although overlap can exist between these diagnoses,2 the clinical criteria for confirmation of each diagnosis included the following: for SLE, patients met 4 of the 11 American Rheumatism Association criteria20; for CCLE, patients had discoid lesions and a negative finding on evaluation for SLE (pertinent laboratory findings may include a low positive antinuclear antibody titer, a positive anti-Ro/SSA antibody, and/or a negative anti–double-stranded DNA/anti-La/SSB antibody); for SCLE, patients had erythematous macules and papules that evolved into scaly, papulosquamous and/or annular, polycyclic plaques, especially in a photo distribution, with a positive anti-Ro/SSA or anti-La/SSB antibody2,21,22; for LE profundus, patients had deep, firm nodules and a negative workup for SLE (pertinent laboratory findings may include a positive antinuclear antibody titer and a negative anti–double-stranded DNA antibody).2 All clinical diagnoses were confirmed by histopathologic review of cutaneous lesional biopsy specimens.
Most (28 of 29) patients had failed standard therapy with antimalarial agents (hydroxychloroquine sulfate and/or quinacrine hydrochloride).2,3 Other failed systemic treatments included dapsone, retinoids, clofazimine, and/or intralesional triamcinolone.2,4- 6 In addition, some patients were treated by their rheumatologist for systemic manifestations of lupus and received more aggressive therapy, including oral prednisone, methotrexate, cyclosporine, and/or azathioprine (Table 1). In treating all 29 patients, we adhered to the System for Thalidomide Education and Prescribing Safety (STEPS) protocol,23 and patients were initially prescribed 100 mg of thalidomide by mouth at bedtime, which was tapered to 50 mg after complete clinical improvement.22 Nerve conduction studies along with neurologic examinations were performed by a neurologist at baseline, after 6 months of thalidomide therapy, and yearly thereafter. We were unable to obtain relapse rates beyond December 2000, since the medical record review was conducted within 1 to 2 months of the inclusion date end point of December 31, 2000.
1. Description. The Food and Drug Administration (FDA) has mandated that all patients prescribed thalidomide enroll in the STEPS program, which was developed to help ensure that fetal exposure to thalidomide does not occur. All prescribers and pharmacists must register with the pharmaceutical company to prescribe and dispense thalidomide.
2 Patient Requirements. All patients must be counseled regarding the benefits, the risk of birth defects, and other adverse effects and precautions associated with thalidomide therapy via booklets and/or videotapes. In addition to serial pregnancy tests, a woman of childbearing potential must use 2 kinds of birth control during treatment and for 4 weeks before and after therapy. A man must use a latex condom every time he has intercourse with a woman and for 4 weeks after concluding treatment. After patient and prescriber sign the consent form, 1 copy stays with the prescriber, 1 copy goes to the STEPS program coordinating center (Boston University School of Public Health), 1 copy is for the patient, and 1 copy is delivered to the pharmacy along with the prescription. Each patient must participate in a mandatory and confidential survey.
3. Drug Dosing. Thalidomide is prescribed at 100 mg by mouth each night, and prescriptions are written for 28 days only. At initiation of therapy, the dosage may be decreased to 50 mg for a few nights to decrease unwanted drowsiness. Those who do not respond within 1 month of therapy may be prescribed 150 mg at bedtime. A patient who responds with clearing and is stable at the prescribed dosage may have the prescription adjusted to the lowest effective dose.
4. Monitoring. All female patients must be followed up every 28 days with a pregnancy test, whereas all male patients must be seen every 3 months or less. All patients must have baseline nerve conduction tests, with repeat testing at 6 months, 1 year, and then yearly thereafter.24 Baseline laboratory testing includes a complete blood cell count, with a differential and platelet count to check for possible neutropenia, which is especially recommended for patients positive for human immunodeficiency virus, and may be obtained at baseline and at each visit. All patients are followed up regarding adverse effects and progression of disease.
In addition to demographic data, information collected from the dermatology clinic medical records included all cutaneous manifestations of lupus, results from histopathologic examination, diagnostic laboratory results, previous and/or failed therapies, laboratory results while receiving thalidomide therapy, and thalidomide dosing and response. Clinical response was assessed by the investigators based on statements of improvement listed in the clinic notes and was categorized as "no response," "partial response" (including percentage of improvement), and "complete response" and was temporally related to the initiation of thalidomide. The incidence of adverse effects, including peripheral neuropathy, was determined. The reason(s) for not initiating or discontinuing thalidomide treatment was also noted.
Of the total 29 patients, there were 6 men and 23 women. The mean ± SD age of men at the onset of thalidomide therapy was 48 ± 10.8 years, and of women, 41 ± 12.1 years. There were 7 African Americans (6 women and 1 man) and 22 whites (17 women and 5 men; Table 1). Patient 1 was lost to follow-up after the initiation of treatment. Five of 29 patients (patients 9, 10, 21, 23, and 26) discontinued thalidomide treatment within 1 month of initiating therapy, citing fear of using the drug or concerns about possible adverse effects as the reason; therefore, their clinical response was unknown (Table 2). These 6 patients were excluded from data analysis; thus, all results reported are per an evaluable patient analysis. The causes of death for patients 12 and 29 were confirmed with a review of inpatient records and death certificates. Therefore, there were 6 patients who took thalidomide for less than 1 month and whose clinical response was unknown (Table 2), and 23 patients took the drug for more than 1 month and were assessed (including patients 11 and 22; Table 3).
Of the 23 patients treated for longer than 1 month, 17 (74%) demonstrated complete resolution of the cutaneous manifestations of lupus, whereas 3 (13%) demonstrated 75% or greater partial improvement, and 3 (13%) had less than 75% partial clinical improvement. All 23 patients had some level of improvement with either a partial or complete response after initiation of thalidomide therapy, 15 (65%) exhibited a complete response, and 6 (26%) demonstrated a partial response in the first 2 months of starting thalidomide therapy (Table 3). The most common diagnosis of those with a complete response to thalidomide was SLE (9 patients [39%];Table 3).
Of the 23 patients who were followed up for longer than 1 month, 5 (22%) had documented sensory, axonal neuropathy via a nerve conduction study while receiving thalidomide treatment (all baseline nerve conduction study results were normal). The duration of thalidomide treatment before obtaining a positive nerve conduction study result ranged from 8 to 16 months, with a mean of 11.6 months (Table 2). The incidence rate of reported paresthesias, even those unrelated to thalidomide therapy, was 26% (6 of 23 patients), but only 2 of the 5 patients with a positive nerve conduction study result complained of paresthesias (Table 2). The incidence rate of drowsiness/fatigue was 17% (4 patients); of dizziness, 13% (3 patients); of nausea or headache, 9% (2 patients); and of weight gain or constipation, 4% (1 patient). There were no reports of amenorrhea or pregnancies during thalidomide therapy (Table 2).
This case series further confirms thalidomide's efficacy in treating refractory cutaneous interface manifestations of LE. However, it is reserved as a secondary line of therapy because of its cost to the patient (approximately $567 for a 28-day course at 100 mg/d); the degree of monitoring by the STEPS protocol; its teratogenicity and adverse effects including peripheral neuropathy; and the availability of antimalarial therapy.2,23 System to Manage Accutane-Related Teratogenicity (SMART) program monitoring requirements for isotretinoin have prepared dermatology office staff for STEPS, and new biologic tumor necrosis factor α inhibitors that are being promoted for use in psoriasis cost 3 times what thalidomide costs. It is our observation that dermatologists are currently more likely to refer patients who are candidates for thalidomide therapy. The STEPS protocol has been enhanced as of July 30, 2001.25
Lupus erythematosus is an autoimmune disorder in which the etiology may be a combination of environmental, hormonal, and genetic factors that lead to polyclonal B-cell activation.2 One major environmental factor is UV light, which can precipitate cutaneous lesions in patients with CCLE, SLE, and SCLE,2,26- 30 especially in patients producing anti-Ro/SSA autoantibodies.2,31 Therefore, for patients with interface lesions with a high potential for scarring or disfigurement, thalidomide may be a good choice for spring and summer seasonal therapy. Moreover, patients are more likely to tolerate the monitoring of thalidomide if they are treated for a finite period of time, thus decreasing the inconvenience and the risk of adverse effects.
The present study again confirms the efficacy of low-dose thalidomide at 100 mg by mouth each night for the cutaneous manifestations of LE. Previous studies suggested that 12 to 16 weeks of thalidomide therapy were needed for maximum benefit13,15; however, our data illustrate that 21 (91%) of 23 patients who demonstrated a complete or partial response did so within 8 weeks of initiating thalidomide therapy. Physicians may be more likely to use thalidomide knowing that if the patient responds, he or she will usually do so within 2 months of initiating therapy, thus controlling cost and saving time spent on monitoring and education. Of note, patients may demonstrate a response within 2 weeks of initiating thalidomide therapy, but since our follow-up visits are 1 month after baseline per STEPS, the first opportunity to assess improvement is not usually less than 4 weeks.
The incidence of both treatment-related and unrelated paresthesias (26%) in this case series is consistent with that reported in previous studies.10 However, one series reported 35 to 37 months of therapy prior to developing a documented sensory, axonal neuropathy, whereas we note a range of 8 to 16 months.16 Although drowsiness/fatigue or dizziness were the 2 most frequently reported adverse effects, only 2 of 6 patients discontinued therapy as a result.
The STEPS protocol has limited the use of this efficacious drug and may have made physicians less motivated to prescribe thalidomide. New developments in dermatology including the introduction of the SMART Program monitoring requirements for isotretinoin and the acceptance of newer, most costly biologic tumor necrosis factor α inhibitors into dermatologic practice should obviate those limitations to thalidomide use. Using thalidomide in a seasonal fashion (from spring to fall) increases the likelihood of compliance and usage by both physicians and patients. Based on this case series, we believe that low-dose thalidomide should be given prime consideration in the treatment of antimalarial drug–resistant interface lesions of LE and has earned a niche on the therapeutic ladder in the management of these lesions.
Corresponding author: Joseph L. Jorizzo, MD, Department of Dermatology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1071 (e-mail: firstname.lastname@example.org).
Accepted for publication January 4, 2002.
Dr Jorizzo has spoken previously regarding the use of thalidomide in dermatology practice and has received honoraria for this on several occasions. There were no outside sources of support for this study.