American Experience with Low-Dose Thalidomide Therapy for Severe Cutaneous Lupus Erythematosus

OBSERVATION American Experience With Low-Dose Thalidomide Therapy for Severe Cutaneous Lupus Erythematosus

Daihung Jay Duong; G. Thomas Spigel, MD; Richard T. Moxley III, MD; Anthony A. Gaspari, MD

Background: There is a renewed interest in thalidomide effects were sedation, constipation, and weight gain. Two therapy after its surprising effectiveness in treating erythema patients reported experiencing intermittent shaking epi- nodosum leprosum was first published. Thalidomide has sodes, an adverse effect not previously reported in the subsequently been reported to be effective in treating a num- literature. Four patients reported symptoms of paresthe- ber of dermatoses, including cutaneous lupus erythema- sia, but none was found to be caused by thalidomide- tosus. We examined the efficacy and adverse effects of low- induced peripheral neuropathy. dose, long-term thalidomide monotherapy in 7 patients with various forms of cutaneous lupus erythematosus that were Conclusions: A low starting dose of thalidomide as a unresponsive to traditional systemic treatments. monotherapy with continued sun avoidance is a safe and effective treatment for the various cutaneous manifesta- Observations: Six of the 7 patients treated with tha- tions of lupus erythematosus after traditional therapeu- lidomide after discontinuation of other oral agents had tic options have failed to control disease. Our experi- complete or marked resolution of their previously treat- ence with low-dose, long-term thalidomide therapy ment-resistant cutaneous lesions, with an average re- suggests that peripheral neuropathy is not as common sponse time of 2.2 ± 0.8 months. Our cohort of 7 pa- as suggested by other studies (up to 50% of patients treated tients with cutaneous lupus erythematosus was treated with thalidomide in some series). with thalidomide therapy for an average of 2.4 ± 3.1 years (range, 1 month to 9 years). The most common adverse Arch Dermatol. 1999;135:1079-1087

HALIDOMIDE (␣-N-phthalyl- ministration for the treatment of ery- glutamic-acid-imide), a glu- thema nodosum leprosum. However, it re- tamic acid derivative, was mains an experimental treatment for a first synthesized in 1956 by variety of inflammatory skin disorders.18 Kunz and his coworkers in Among those reported included actinic West Germany.1,2 Thalidomide became prurigo,19,20 orogenital ulcerations,21-23 T 24 widely used as a sleeping aid but was re- Weber-Christian disease, graft-vs-host moved from the market after teratogenic disease,25-28 and chronic cutaneous lupus and neurologic effects were estab- erythematosus (CCLE).29,30 lished.3-12 Subsequently, thalidomide be- Many European studies have docu- came available only for experimental pur- mented that thalidomide is an effective poses. There was renewed interest in the treatment for various inflammatory der- clinical uses of thalidomide after She- matoses, such as cutaneous lupus ery- 13 From the Olean Medical Group, skin reported in 1965 the effectiveness thematosus (CLE), that are unresponsive 31 Olean, NY (Dr Spigel); and of thalidomide in treating erythema no- to standard therapy. Knop et al, in a study Departments of Neurology dosum leprosum. Sheskin, after giving of 60 cases of CCLE, reported that 90% of (Dr Moxley), Dermatology thalidomide to patients with leprosy for the patients had a complete or marked re- (Dr Gaspari), and sedative purposes, made a serendipitous sponse to treatment with thalidomide, 400 Microbiology/Immunology discovery that the treatment resulted in im- mg/d, and that 71% had relapses when tha- (Dr Gaspari) and Cancer mediate improvement in symptoms, and lidomide was withdrawn. Stevens et al32 Center (Dr Gaspari), that the patients’ cutaneous erythema- had similar findings with thalidomide, 50 University of Rochester School of Medicine and Dentistry, tous lesions resolved in as little as 3 days. to 100 mg/d, with various adjustments, if Rochester, NY. Mr Duong is a His findings were confirmed by other re- any, in the doses of other oral medica- 14-16 17 medical student at the ports and by his follow-up study. tions already being used to treat CLE. Im- University of Rochester School Recently, thalidomide therapy has provements were observed within 2 weeks of Medicine and Dentistry. been approved by the Food and Drug Ad- of treatment, and maximum benefits were

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 PATIENTS AND METHODS All 7 patients were treated according to the published guidelines for thalidomide use.39 All other systemic medications for controlling CLE were discon- We reviewed the medical records of 7 women with disfig- tinued. The patients returned every 3 months for follow- uring CLE who were treated with thalidomide in a 100- up, and the efficacy and adverse effects of their thalido- mg/d starting dose after exhausting the other therapeutic mide treatment were documented. Nerve conduction options, including glucocorticosteroids, antimalarials, studies, complete blood cell counts, 12-factor automated immunosuppressants, dapsone, clofazimine, and retinoids. blood chemistry studies, and thyroid studies (free thy- These patients continue to receive thalidomide therapy. roxine, thyrotropin) were done every 6 months or Candidates for thalidomide therapy were selected by the sooner as needed for baseline comparison. Any change presence of severe CLE that had previously been treated in blood cell count or results of serum chemistry studies with first- and second-line therapies.38 This treatment was was followed up closely to determine if it was thalido- offered on a compassionate basis by the Department of mide related. All patients were examined at baseline Dermatology, University of Rochester, Rochester, NY, for with a complete neurologic examination, with a focus on patients who had been referred by community dermatolo- clinical assessment of touch, scratch, vibratory, and gists. Table 1 lists their conditions and Table 2 position sensations. These examinations were repeated describes the therapeutic modalities that failed. Candidates at 6-month intervals during thalidomide therapy. Nerve were further selected by their ability to understand the conduction studies were done in all patients at baseline risks and benefits of thalidomide therapy. Further require- and at 6-month intervals to detect evidence of drug- ments included a willingness to comply with the monitor- induced sensory or motor loss in the extremities. The ing requirements, and to sign an informed consent (re- nerve conduction studies included unilateral examina- viewed and approved by the University of Rochester tion of the arm and leg. Standard techniques of percuta- Research Subjects Review Board). After a candidate for neous stimulation and surface recording were used. thalidomide therapy was identified, a single-patient inves- Motor conduction velocity, distal motor latency, and the tigational new drug application was submitted to the Food amplitude of the compound muscle action potential and Drug Administration. After this application was sub- were measured from the common peroneal, tibial, ulnar, mitted and approved (usually 3-6 months after submis- and/or median motor nerves. Sensory conduction veloc- sion), the Food and Drug Administration issued an inves- ity, sensory distal latency, and the amplitude (baseline to tigational new drug number (see Table 3). Contraception negative peak) of the sensory nerve action potential was initiated in women of childbearing age. A prescription (SNAP) were obtained from the sural, superficial pero- with payment and IND number were mailed to the sup- neal, ulnar, and/or median sensory nerves. The patients plier of thalidomide. This drug was then mailed to the pre- understood that they must stop taking thalidomide scribing physician, who dispensed the thalidomide to the should they begin to experience paresthesia. All patients patient. continued sun avoidance and use of sunscreen.

Table 1. Patient Histories*

Duration of Patient No./ Cutaneous 1982 ARA Sex/Age, y LE, y Lesion Sites Diagnosis Criteria for SLE Autoantibodies Contraception 1/F/46 25 Scalp CCLE ANA ANA Tubal ligation 2/F/48 7 Scalp, face, trunk, CCLE, SLE Malar rash, discoid rash, ND Tubal ligation extremities photosensitivity, ANA 3/F/49 33 Face, trunk, extremities SCLE, SLE Malar rash, discoid rash, ANA, anti-La Tubal ligation photosensitivity, ANA 4/F/28 11 Scalp, face, CCLE ND ND Oral, barrier 5/F/28 9 Scalp, face, trunk, CCLE, SLE Malar rash, discoid rash, ANA, anti-RNP, Oral, barrier extremities photosensitivity, anti-Ro arthritis, ANA, leukopenia 6/F/64 18 Face, mouth, trunk, Scleroderma with ANA ANA, anti-Ro None extremities LE, LP overlap (postmenopausal) 7/F/43 28 Face, mouth CCLE ND ND Hysterectomy

*LE indicates lupus erythematosus; ARA, American Rheumatism Association; SLE, systemic lupus erythematosus; CCLE, chronic cutaneous lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; LP, lichen planus; ANA, antinuclear antibody; ND, not determined; anti-La, Sjögren syndrome B antigen; anti-RNP, antiribonuclear proteins; and anti-Ro, Sjögren syndrome A antigen.

achieved within 16 weeks. Another study involving 11 in the cutaneous treatment of various forms of lupus ery- patients reported that a maintenance dose of 25 to 50 mg thematosus (LE).34-37 The reported adverse effects in these every night or every other night was necessary to pre- studies included paresthesia, drowsiness, abdominal dis- vent relapse.33 Other studies were also published con- turbances, dry mouth, urticaria, rash, mood changes, cir- firming the effectiveness of thalidomide, 100 to 400 mg/d, culatory changes, amenorrhea, and edema. Of these, par-

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Patient No. Glucocorticosteroids Antimalarials Dapsone Clofazimine Isotretinoin Immunosuppressants 1 Class I topical and Hydroxychloroquine 50 mg/d for 8 wk; NU 1.0 mg/kg Azathioprine, 150 mg po intralesional injections sulfate, 200 mg po BID discontinued per day; BID for 6 mo; for 20 y; repeated alone or in because of lack discontinued discontinued because tapering courses of combination with of efficacy because of of lack of efficacy oral treatment at quinacrine lack of 0.5 mg/kg per day hydrochloride, efficacy over 2 y 100 mg/d for 5 y 2 Class I topical Hydroxychloroquine NU NU NU Azathioprine, 50 mg/d po administration over sulfate, 200 mg/d for 3 mo; discontinued 5 y; repeated tapering po for 2 mo; because of courses of oral discontinued because development of florid treatment at 0.5 mg/kg of severe pruritus; genital warts per day over 5 y chloroquine, 500 mg/d po for 4 wk, also caused pruritus 3 Class I-III topical Hydroxychloroquine NU NU NU Azathioprine, 75 mg po treatment during 20 y; sulfate, 200 mg po BID BID for 3 mo; repeated tapering for 3 mo; quinacrine discontinued because courses of oral drugs hydrochloride, of lack of efficacy at 0.5-1.0 mg/kg 100 mg/d for 4 mo; per day over 3 y discontinued because of lack of efficacy 4 Class I-lll topical drugs Hydroxychloroquine NU 100 mg/d NU Azathioprine, 100 mg po and intralesional sulfate, 200 mg po BID po for 4 mo; BID for 5 mo; injections over 18 y; for 3 y; quinacrine discontinued discontinued because repeated tapering hydrochloride, 100 because of of lack of efficacy and courses of oral drugs mg/d po over 4 y lack of nausea at 0.5-1.0 mg/kg per intermittently; efficacy and day over 4 mo chloroquine, 500 mg nausea twice a week po for 4 mo; discontinued because of lack of efficacy 5 Class l-III topical drugs; Hydroxychloroquine NU NU 1 mg/kg per day Azathioprine, 75 mg po repeated tapering sulfate, 200 mg po po for 4 wk; BID for 5 mo; courses of oral drugs, BID for 2 y; discontinued methotrexate, 20 0.5-1.0 mg/kg per day chloroquine, 500 mg/d because of mg/wk for 4 mo; over 6 y po for 4 mo; quinacrine pancreatitis cyclophosphamide, 50 hydrochloride, 100 mg/d po; discontinued mg/d for 7 mo; because of lack of discontinued because efficacy of lack of efficacy 6 Class I-II topical drugs; Hydroxychloroquine NU NU 1 mg/kg per day Azathioprine, 50 mg po repeated tapering sulfate, 200 mg po po for 4 mo; BID for 2 mo; courses of oral drugs, BID; quinacrine discontinued discontinued because 0.5-1.0 mg/kg per day hydrochloride, 100 because of of increase in liver over 14 y mg/d po alone and in lack of enzyme levels; combination for 2 y; efficacy cyclophosphamide, 50 discontinued because mg po BID for 1 mo; of lack of efficacy discontinued because of leukopenia 7 Class I topical treatment Hydroxychloroquine NU NU 1 mg/kg per day Azathioprine, 50 mg/d for 6 y; repeated sulfate, 200 mg po po for 8 wk; po for 2 wk; intralesional injections BID; quinacrine discontinued cyclophosphamide, 50 of triamcinolone hydrochloride, 100 because of mg/d po for 4 wk acetonide, 10 mg/mL; mg/d po alone and in lack of (both caused patient refused oral combination for 5 y efficacy leukopenia) glucocorticosteroids

*LE indicates lupus erythematosus; po, orally; BID, twice daily; and NU, not used.

esthesia, sedation, and constipation were the most cult to obtain. For these reasons, there are no random- common. ized trials that have proved the efficacy of thalidomide Although thalidomide is well recognized as an ef- as a second-line drug in CLE. Herein, we report our ex- fective agent for CLE through the studies done mainly perience in treating 7 patients with CLE during 9 years. in Europe, it is rarely used to treat this disorder in the Our experience confirms its remarkable efficacy and sur- United States because of its risks and because it is diffi- prising safety as monotherapy.

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Patient Duration of Response Able to No. FDA IND No. Thalidomide Treatment† Time, mo‡ Response Remission Taper Dose 1 35 285 9 y§࿣¶ 2 Partial No Yes 2 52 609 1.5 y§¶ 2 Complete No No 3 55 112 8 mo§¶ 3 Partial No No 4 51 037 2 y§¶ 1 Partial No No 5 56 022 4 mo§¶ 3 Complete No Yes 6 48 393 3 y§¶ 2 Partial# No Yes 7 39 882 1 mo¶** NA None NA NA

*FDA indicates Food and Drug Administration; IND, investigational new drug; and NA, not applicable. For all patients, thalidomide was given at a dose of 100 mg/d. †Average, 2.4 ± 3.1 years. ‡ Average, 2.2 ± 0.8 months. §Ongoing treatment. ࿣Source of thalidomide: GWL Hansen’s Disease Center, Baton Rouge, La. ¶Source of thalidomide: Pediatric Pharmaceuticals, Iselin, NJ. #Complete response for ulcers in hands, partial response for lesions in lower extremities. **Dropped out of treatment. It was not possible to determine whether this patient responded to thalidomide.

Table 4. Patient-Reported Adverse Effects

No. of No. in Whom Adverse Effect Patients Affected Successfully Dealt With Interventions Neurologic symptoms 4* 4 Discontinue, then reinstate thalidomide therapy (patient 2); in all 4 patients (2, 3, 5, 6) symptoms not linked to thalidomide-induced neuropathy Sedation 4 3 Take earlier at night; decrease dose Constipation 3 2 Laxatives; dietary changes (increase fluid intake and fiber in diet); exercise Weight gain 3 0 None (Ͻ10% increase in lean body mass) Weakness 1 0 None; monitor adverse effect† Muscle cramps 1 0 None; monitor adverse effect† Mood changes 1 0 None; monitor adverse effect† Shakes 2 1 None; monitor adverse effect†

*Neurologic evaluation and nerve conduction studies did not show thalidomide as cause of symptoms. †Laboratory testing did not disclose a hematological, biochemical, endocrinological, or neurological basis for these symptoms (data not shown).

RESULTS paresthesia, sedation, constipation, and weight gain. Se- dation and constipation were for the most part well tol- Table 3 summarizes the course of each patient’s treat- erated by the patients. Most became accustomed to the ments; Table 4 describes their reported adverse effects. drug’s sedative effect, and 2 patients reported insomnia Six of the 7 patients responded to thalidomide treatment. when not taking thalidomide. Constipation was toler- One patient dropped out after 1 month of thalidomide treat- able after dietary changes and taking laxatives as needed. ment with concerns about the possible adverse effect of No treatment was recommended for weight gain, since neuropathy (this patient had not experienced any ad- this adverse effect was transient and not distressing to verse effects at the time of discontinuing thalidomide). Of any of the patients. There were no complaints of de- the 6 patients who responded to treatment, 2 had com- creased libido. plete resolution of their cutaneous lesions by the end of Nerve conduction studies did not demonstrate ab- the first year of treatment. The other 4 showed marked normalities that specifically related to treatment with tha- (80%) improvement in their skin, with scarring and hy- lidomide. The motor nerve conduction data were all perpigmentation remaining in the scalp or chest. One pa- within the normal range for distal motor latency (pero- tient had hair regrowth after 2 months of treatment, and neal, Ͻ5.8 milliseconds; tibial, Ͻ6.2 milliseconds; ul- this regrowth reached a plateau by the sixth month of treat- nar, Ͻ4.0 milliseconds; median, Ͻ4.2 milliseconds), for ment. Figure 1 summarizes the effects of thalidomide compound muscle action potential amplitudes (pero- therapy on the cutaneous lesions in patients 3 through 6. neal, Ͼ2.2 mV; tibial, Ͼ6.0 mV; ulnar, Ͼ4.0 mV; me- Figure 2 depicts the effects of thalidomide therapy on dian, Ͼ6.0 mV), and for motor conduction velocities (pe- the histological changes of CCLE in patient 5. roneal, Ͼ40 m/s; tibial, Ͼ38 m/s; ulnar, Ͼ52 m/s; median, Table 4 lists the adverse effects reported to us by the Ͼ50 m/s). Sensory nerve conduction was also within the patients. The most common adverse effects reported were normal range with the exception of 1 patient. This pa-

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C D

E F

G H

Figure 1. Clinical responses to thalidomide therapy. Patient 3 (subacute cutaneous lupus erythematosus) before thalidomide therapy (A) and after 8 weeks of thalidomide therapy at 100 mg/d (B). There was marked flattening of lesions and decrease in the severity of the erythema. Patient 4 (chronic cutaneous lupus erythematosus of scalp) before thalidomide therapy (C) and after 16 weeks of thalidomide therapy (D), which caused complete resolution of the associated erythema. Patient 5 (widespread chronic cutaneous lupus erythematosus) before therapy (E) and after 8 weeks of thalidomide therapy (F). Patient 6 (scleroderma with lupus erythematosus–lichen planus overlap syndrome) 8 weeks after temporarily discontinuing thalidomide therapy (G), resulting in a relapse of the inflammatory skin lesions (October 1996), and during thalidomide therapy, 100 mg/d (April 1997) (H).

tient developed a decline and loss of the SNAP signals sory nerve conduction data for the patients were within from her left sural and and left superficial peroneal nerves the normal ranges for the amplitudes of SNAPs (sural, in association with clinical and imaging findings of a com- Ͼ6 µV; superficial peroneal, Ͼ6 µV; ulnar, Ͼ17 µV; me- pressive left L5-S1 radiculopathy. Otherwise, the sen- dian, Ͼ20 µV) and for the sensory conduction veloci-

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Figure 2. Effect of thalidomide therapy on the histological changes of chronic cutaneous lupus erythematosus. A, Skin biopsy specimens were obtained from patient 5 before thalidomide therapy, which corresponds to the clinical lesions depicted in Figure 1, E. There was an inflammatory infiltrate and an active interface dermatitis around hair follicles and dermoepidermal junction (hematoxylin-eosin, original magnification ϫ20). B, After 8 weeks of thalidomide therapy, which corresponds to the clinical lesions depicted in Figure 1, F, there was resolution of the interface dermatitis, and the intensity of the inflammatory infiltrate had diminished considerably. There was considerable pigment incontinence (hematoxylin-eosin, original magnification ϫ20).

ties (sural, Ͼ40 m/s; superficial peroneal, Ͼ40 m/s; ul- receiving thalidomide. Since complete neurologic ex- nar, Ͼ49 m/s; median, Ͼ48 m/s). Amplitudes of the aminations did not show any abnormalities, magnetic SNAPs varied in the same nerve on different studies, but resonance imaging of the brain was not performed. there was no consistent trend in the values to indicate a No significant changes in blood cell count were noted significant decline in amplitudes. Coexisting clinical con- in any of the patients after initiation of thalidomide treat- ditions rather than the treatment with thalidomide caused ment. One patient had a history of slightly depressed white neurologic symptoms. blood cell count that did not change after thalidomide Four patients reported experiencing paresthesia, but was started. No electrolyte disturbances were noted, and sensory nerve conduction studies did not disclose any the serum urea nitrogen and serum creatinine levels in drug-induced abnormalities. None of the 4 cases could the patients with systemic LE remained stable at base- be linked to thalidomide by neurologic evaluation and line. None of these patients developed abnormalities in nerve conduction studies (see Table 4). In 1 patient, peri- thyroid function tests (data not shown). oral paresthesia resolved when thalidomide treatment was In patients who had circulating autoantibodies at withdrawn for 2 weeks and did not recur when treat- baseline (patients 1, 3, 5, and 6), thalidomide therapy did ment was restarted. The second patient had improve- not decrease these circulating antibodies, despite its ben- ment in neurologic symptoms while still receiving tha- eficial effects on their dermatologic disease (data not lidomide; nerve conduction studies showed abnormalities shown). This suggests that the thalidomide may be work- consistent with her underlying connective tissue dis- ing by an anti-inflammatory mechanism, rather than the ease but not with thalidomide neuropathy. The third pa- immunomodulation of a pathogenic immune response. tient was found to have paresthesia caused by a C6 compression of a nerve root. The last patient recently developed paresthesia after 9 years of thalidomide treat- COMMENT ment. Nerve conduction studies did not show a thalidomide neuropathy. It is of interest that 2 patients reported similar Cutaneous lesions secondary to systemic LE, subacute adverse effects of intermittent “shaking” episodes since CLE, or CCLE in the 6 patients who took thalidomide, starting thalidomide treatment. These shaking episodes 100 mg/d, for more than 1 month all showed marked im- were described as being similar to tremors and chills. They provement. The average response time was 2.2 ± 0.8 were preceded by thoughts of impending shakes by the months. The patients’ conditions remained stable even whole body. These symptoms initially occurred in the after discontinuing other treatment modalities, includ- mornings, progressed to occur all day, and then gradu- ing oral, injected, or topical glucocorticosteroids, and other ally resolved. No hematologic, biochemical, or nerve con- immunosuppressive or modulating pharmacologic agents duction abnormalities were found that could explain this (Table 2). In addition to the resolution of the clinical signs phenomenon. There were no abnormalities in body tem- and symptoms associated with CLE (Figure 1), thalido- perature associated with these shaking episodes. In 1 pa- mide also resulted in the resolution of the histological tient, this symptom resolved while the patient was still changes associated with CLE (Figure 2). The patients with

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 systemic LE have not shown signs of their systemic dis- ment has not been necessary. One patient elected to disease since starting thalidomide and discontinuing other continue because of concerns about the potential ad- treatments. The use of sunscreens and sun avoidance verse effect of neuropathy. remains a must, since most of these patients have histo- Some studies of thalidomide neuropathies associ- ries of photosensitivity. ated with the treatment of dermatologic diseases have suggested that the occurrence of neuropathy may be related to cumulative thalidomide dose (emerging after Ͼ40- HERE IS a general lack of agreement on the to 50-g total dose), whereas other reports have indi- effective starting dose and treatment sched- cated that the cumulative dose was not important.12,46 ule of thalidomide. In our experience, 100 There is a suggestion that host-related factors (female sex mg daily in the evening is an adequate and advanced age) may be critical risk factors in pa- starting dose. We have been successful in tients who develop neuropathy in the first few months Ttapering the dose of thalidomide in 3 patients (patients of treatment.5,47,48 In our series of 7 female patients, 4 have 1, 5, and 6) (from daily dosing to alternate-day or every- taken a cumulative dose of thalidomide greater than 50 third-day dosing with 100 mg of thalidomide). In the other g without a detectable neuropathy. Three of these pa- patients (patients 2 through 4), our attempts to taper the tients were younger than 50 years. It is likely that the small dose of thalidomide resulted in a prompt exacerbation sample size, the relatively young age of our patients, the of their condition, which necessitated the continuation brief duration of thalidomide therapy, the low doses used, of a daily dosing regimen. and an absence of preexisting neurologic disease were Complete discontinuation of thalidomide therapy all factors responsible for a lack of thalidomide neuro- has not been possible in any of our patients, because of toxic effects in this series. relapses in their dermatologic disease. This is in con- Careful serial clinical examinations with detailed test- trast to what has been suggested by other clinicians, that ing of peripheral nerve function appear to offer the most the dose be gradually decreased until treatment can be suitable approach to detect early signs related to thalido- discontinued altogether.33 The induction of long-term re- mide-induced neuropathy. The occurrence of neuro- mission by thalidomide has not been reported, and this pathic complaints may vary depending on the disorder has been our experience as well. This suggests that a requiring thalidomide treatment, and genetic as well as maintenance dose is necessary for long-term control of other predisposing factors may influence the likelihood disease. that neuropathy will develop.49 The use of electrodiag- One of the patients with CCLE (patient 1) was ini- nostic testing to identify thalidomide-induced neuropa- tally treated with thalidomide provided by a Hansen dis- thy is also not as reliable as one might hope. The ampli- ease treatment center (Table 3). This source of thalido- tudes of SNAP are quite variable on reproducibility mide was interrupted because of a drug shortage, which testing.49-51 Some investigators have grouped the SNAP necessitated obtaining thalidomide from a different sup- measurements to adjust to this variability in the method.49 plier (Pediatric Pharmaceuticals, Iselin, NJ). Although we Most of the disorders that require thalidomide therapy have no information about the relative bioavailabilities have an increased likelihood of other causes of neuropa- of thalidomide from the 2 suppliers, this patient main- thy, including compression neuropathy, such as carpal tained an excellent clinical response to thalidomide pro- tunnel syndrome, which by itself can cause a decline in vided by a different supplier. There are 3 American phar- the SNAP. This increased tendency toward various types maceutical companies that manufacture and distribute of neuropathy emphasizes the need for clinical exami- thalidomide, but relative bioavailabilities of thalido- nation and judgment to establish whether the symp- mide from these sources is not known. This is a poten- toms are caused by toxic effects of thalidomide or an- tially important issue that warrants study. other process. For example, one study reported the The mechanism of action of thalidomide remains incidence of thalidomide neuropathy to be 21% to 50% unknown, but the drug is known to possess certain in patients with various dermatoses, without significant anti-inflammatory and immunomodulatory properties. difference in incidence between the different condi- The actions of thalidomide include the inhibition of mono- tions.49,52 It is interesting that the sensory nerve evalua- cyte tumor necrosis factor ␣ production,40 inhibition of tion in these reports used the SNAP amplitudes for su- polymorphonuclear leukocyte chemotaxis41 and phago- ral and median nerves. The median nerve is particularly cytosis,42 inhibition of lymphocyte proliferation in re- prone to compression neuropathy. Perhaps the varia- sponse to mitogenic or allogenic stimulation,43 inhibition in incidence of neuropathy observed in these pre- tion of helper T-cell type 1 cytokine production while vious reports partly results from factors other than toxic enhancing helper T-cell type 2 cytokine production,44 and effects of thalidomide. Hafstrom48 reported that de- inhibition of angiogenesis.45 One or more of these mecha- creased SNAPs with normal conduction velocities, a char- nisms may explain thalidomide’s effectiveness in con- acteristic finding in drug-induced neuropathy, can also trolling the cutaneous manifestations of LE. be seen in asymptomatic patients. In our patients who The most serious adverse effects of thalidomide treat- have not reported paresthesia, repeated nerve conduc- ment are teratogenicity and neuropathy. Therefore, strict tion studies have not shown any sensory or motor loss. contraceptive measures and close monitoring of neuro- Continued monitoring of patient 3, who has a history logic symptoms are necessary. In our patients, no seri- of carpal tunnel syndrome, is necessary, since underly- ous adverse effects have been observed, even in those ing carpal tunnel syndrome may be a risk factor for treated for longer than 1 year, and discontinuation of treat- thalidomide-induced peripheral neuropathy.53 In sum-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 The minor adverse effects have been tolerable to the Table 5. Guidelines for Prescribing Thalidomide* patients. We continue to monitor the symptom of shaking. This phenomenon has not been previously re- For Female Patients ported, and we have not been able to link it to thalidomide- 1. Establish appropriateness of thalidomide therapy vs therapeutic alternatives induced biochemical, hematological, or neurologic 2. Provide comprehensive counseling on risks and benefits of abnormalities. This symptom has not been a dose- thalidomide therapy limiting toxic effect. In one patient, the symptom has re- 3. Determine if patient has childbearing potential solved without interrupting treatment; in the other pa- • Two forms of contraception, beginning at least 4 wk before tient, this symptom has persisted but has not been dose therapy, all during therapy, and at least 4 wk after stopping limiting. therapy with thalidomide • Contraceptive methods must include at least 1 highly effective Overall, the patients who have shown improve- method (eg, intrauterine device [IUD], hormonal [birth control ment have been pleased with the results of thalidomide pills, injections, or implants], tubal ligation, or partner’s therapy. The patients have perceived a benefit in arrest- vasectomy) and 1 additional effective method (eg, latex condom, ing the progression of their chronic, previously unre- diaphragm, or cervical cap) lenting dermatologic disease. The minor adverse effects • If hormonal or IUD contraception is medically contraindicated, another highly effective method or 2 barrier methods must be of thalidomide have been tolerable in all patients, since used at same time all of them have been afflicted with their dermatoses for • Use patient education materials provided many years (Table 1). 4. Continue selected birth control options for at least 4 wk before Various studies, mainly in Europe, have reported the initiating thalidomide therapy safety and effectiveness of various doses of thalidomide 5. Initiating therapy • Repeat patient counseling in the treatment of the CLE. In our experience, a low start- • Perform pregnancy test, even if continuous abstinence is the ing dose of thalidomide has been a safe and effective chosen method of birth control monotherapy for CLE after traditional therapeutic op- • Administer thalidomide patient quiz tions have been exhausted. Minor adverse effects are com- • Complete informed consent form mon but tolerable. The dispensing of thalidomide is tightly • Complete mandatory and confidential survey enrollment form regulated in the United States, given the drug’s infa- • Provide prescription 6. Patient monitoring during first 4 wk of therapy mous history. Even so, thalidomide is a promising treat- • Repeat patient counseling ment option for clinicians to consider, but caution and • Perform pregnancy tests every week for first 4 wk of therapy familiarity with the prescribing guidelines cannot be over- • If pregnancy test is negative, provide prescription for 1-wk supply emphasized (Table 5). of thalidomide 7. Subsequent patient visits (after first 4-wk period) • Repeat patient counseling Accepted for publication April 21, 1999. • Perform pregnancy tests every 4 wk if patient’s menstrual cycles This study was supported in part by grant 1R01AH/ are regular, every 2 wk if cycles are irregular OH4108-01 from the National Institutes of Health, Bethesda, • Complete follow-up survey form Md (Dr Gaspari), and by a grant from the Lupus Founda- • If pregnancy test is negative, provide prescription for 4-wk supply tion, Genessee Valley Chapter, Rochester, NY (Mr Duong). of thalidomide Reprints: Anthony A. Gaspari, MD, Department of Der- For Male Patients matology and Cancer Center, University of Rochester School 1. Establish appropriateness of thalidomide therapy of Medicine and Dentistry, Rochester, NY 14642 (e-mail: 2. Provide comprehensive counseling on risks and benefits of thalidomide therapy [email protected]). 3. Provide contraceptive counseling, including counseling on emergency contraception REFERENCES • Male patients must be instructed to use a latex condom every time they have sexual intercourse with a woman, even if they have had vasectomy 1. Burley DM, Dennison TC, Harrison W. Clinical experience with a new sedative • Use patient education materials drug. Practitioner. 1959;183:57-61. 4. Administer thalidomide patient quiz 2. Koch HP. Thalidomide and congeners as anti-inflammatory agents. Prog Med 5. Complete informed consent Chem. 1985;22:165-242. 6. Complete mandatory and confidential survey enrollment form 3. Taussig HB. A study of the German outbreak of phocomelia: the thalidomide syn- 7. Provide prescription drome. JAMA. 1962;180:1106-1114. 8. Subsequent visits 4. Burgio GR. The thalidomide disaster briefly revisited. Eur J Pediatr. 1981;136: • Repeat patient counseling 229-230. • Complete follow-up survey 5. Mellin GW. The saga of thalidomide. N Engl J Med. 1962;267:1184-1193. • Provide prescription for 4-wk supply 6. Lenz W. Thalidomide and congenital abnormalities [letter]. Lancet. 1962;1:45. 7. MellinGW.Thesagaofthalidomide(concluded).NEnglJMed.1962;267:1238-1244. 8. Florence AL. Is thalidomide to blame [letter]? BMJ. 1960;2:1954. *Modified from System for Thalidomide Education and Prescribing Safety 9. Kuenssberg EV, Simpson JA, Stanton JB. Is thalidomide to blame [letter]? BMJ. (STEPS). Warren, NJ: Celgene Corp; 1998 [educational material]. 1961;1:291. 10. Burley D. Is thalidomide to blame [letter]? BMJ. 1961;1:130. 11. Fullerton PM, Kremer M. Neuropathy after intake of thalidomide (Distaval). BMJ. mary, careful, serial neurologic evaluations of patients 1961;2:855-858. receiving thalidomide provides the single most effective 12. Fullerton PM, O’Sullivan DJ. Thalidomide neuropathy: a clinical, electrophysi- ological, and histological follow-up study. J Neurol Neurosurg Psychiatry. 1968; means to detect the early development of neuropathy. 31:543-551. Nerve conduction testing is a useful adjunct to the 13. Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther. clinical assessment. 1965;6:303-306.

ARCH DERMATOL / VOL 135, SEP 1999 1086

©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 14. Parikh DA, Maniar JK, Ganapati R. Thalidomide in leprosy and some dermato- 34. Naafs B, Bakkers JM, Flinterman J, Faber WR. Thalidomide treatment of sub- logical conditions: a review. Indian J Lepr. 1985;57:862-867. acute cutaneous lupus erythematosus. Br J Dermatol. 1982;107:83-86. 15. Hastings RC, Trautman JR, Enna CD, Jacobson RR. Thalidomide in the treat- 35. Holm AL, Bowers KE, McMeekin TO, Gaspari AA. Chronic cutaneous lupus ery- ment of erythema nodosum leprosum. Clin Pharmacol Ther. 1970;11:481-487. thematosus treated with thalidomide. Arch Dermatol. 1993;129:1548-1550. 16. Hendler SS, McCarty MF. Thalidomide for autoimmune disease. Med Hypoth- 36. Atra E, Sato EI. Treatment of the cutaneous lesions of systemic lupus erythem- eses. 1983;10:437-443. atosus with thalidomide. Clin Exp Rheumatol. 1993;11:487-493. 17. Sheskin J. The treatment of lepra reaction in lepromatous leprosy. Int J Derma- 37. Bessis D, Guillot B, Monpoint S, Dandurand M, Guilhou JJ. Thalidomide for sys- tol. 1980;19:318-322. temic lupus erythematosus. Lancet. 1992;339:549-550. 18. Grosshans E, Illy G. Thalidomide therapy for inflammatory dermatoses. Int J Der- 38. Drake L, Dinehart S, Farmer E, et al. Guidelines of care for cutaneous lupus ery- matol. 1984;23:598-602. thematosus. J Am Acad Dermatol. 1996;34:830-836. 19. London˜o F. Thalidomide in the treatment of actinic prurigo. Int J Dermatol. 1973; 39. Powell RJ, Gardner-Medwin JMM. Guideline for the clinical use and dispensing 12:326-328. of thalidomide. Postgrad Med J. 1994;70:901-904. 20. Lovell CR, Hawk JLM, Calnan CD, Magnus IA. Thalidomide in actinic prurigo. Br 40. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively J Dermatol. 1983;108:467-471. inhibits tumor necrosis factor ␣ production by stimulated human monocytes. 21. Gardner-Medwin JMM, Smith NJ, Powell RJ. Clinical experience with thalido- J Exp Med. 1991;173:699-703. mide in the management of severe oral and genital ulceration in conditions such 41. Faure M, Thivolet J, Gaucherand M. Inhibition of PMN leukocytes chemotaxis as Behc¸et’s disease: use of neurophysiological studies to detect thalidomide neu- by thalidomide. Arch Dermatol Res. 1980;269:275-280. ropathy. Ann Rheum Dis. 1994;53:828-832. 42. Barnhill RL, Doll NJ, Millikan LE, Hastings RC. Studies on the anti-inflammatory 22. Mascaro JM, Lecha M, Torras H. Thalidomide in the treatment of recurrent, ne- properties of thalidomide: effects on polymorphonuclear leukocytes and mono- crotic, and giant mucocutaneous aphthae and aphthosis. Arch Dermatol. 1979; cytes. J Am Acad Dermatol. 1984;11:814-819. 115:636-637. 43. Keenan RJ, Eiras G, Burckart GJ, et al. Inhibition of in vitro lymphocyte prolif- 23. Revuz J, Guillaume JC, Janier M, et al. Crossover study of thalidomide vs pla- eration alone and in combination with cyclosporine or FK506. Transplantation. cebo in severe recurrent aphthous stomatitis. Arch Dermatol. 1990;126:923- 1991;52:908-910. 927. 44. McHugh SM, Rifkin IR, Deighton J, Wilson AB, Lachmann PJ, Lockwood CM. 24. Eravelly J, Waters MFR. Thalidomide in Weber-Christian disease [letter]. Lan- The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and cet. 1977;1:251. concomitantly inhibits Th1 cytokine production in mitogen- and antigen- 25. Vogelsang GB, Santos GW, Colvin OM, Chen T. Thalidomide for graft-versus- stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immu- host disease [letter]. Lancet. 1988;1:827. nol. 1995;99:160-167. 26. McCarthy DM, Kanfer E, Taylor J, Barrett AJ. Thalidomide for graft-versus-host 45. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of disease [letter]. Lancet. 1988;2:1135. angiogenesis. Proc Natl Acad SciUSA. 1994;91:4082-4085. 27. Heney D, Lewis IJ, Bailey CC. Thalidomide for graft-versus-host disease in chil- 46. Wulff CH, Hoyer H, Asboe-Hansen G, Brodthaden H. Development of polyneu- dren [letter]. Lancet. 1988;2:1317. ropathy during thalidomide therapy. Br J Dermatol. 1985;112:475-480. 28. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic 47. Cohen S. Thalidomide polyneuropathy [letter]. N Engl J Med. 1962;266:1208. graft-versus-host disease. N Engl J Med. 1992;326:1055-1058. 48. Hafstrom T. Polyneuropathy after Neurosedyn (thalidomide) and its prognosis. 29. Knop J, Happle R, Bonsmann G, Vakilzadeh F, Macher E. Treatment of chronic Acta Neurol Scand. 1967;43(suppl 32):1-41. cutaneous discoid lupus erythematosus with thalidomide. Arch Dermatol Res. 49. Ochonisky S, Verroust J, Bastuji-Garin S, Gherardi R, Revuz J. Thalidomide neu- 1981;271:165-170. ropathy incidence and clinico-electrophysiologic findings in 42 patients. Arch Der- 30. Hasper M, Klokke AH. Thalidomide in the treatment of chronic discoid lupus ery- matol. 1994;130:66-69. thematosus. Acta Derm Venereol. 1982;62:321-324. 50. Chaudhry V, Cornblath DR, Mellitis ED, et al. Inter- and intra-examiner reliability 31. Knop J, Bonsmann G, Happle R, et al. Thalidomide in the treatment of sixty cases of nerve conduction measurements in normal subjects. Ann Neurol. 1991;30: of chronic discoid lupus erythematosus. Br J Dermatol. 1983;108:461-466. 841-843. 32. Stevens RJ, Andujar C, Edwards CJ, et al. Thalidomide in the treatment of the 51. Bleasel AF, Tuck RR. Variability of repeated nerve conduction studies. Electro- cutaneous manifestations of lupus erythematosus: experience in sixteen con- encephalogr Clin Neurophysiol. 1991;81:417-420. secutive patients. Br J Rheumatol. 1997;36:353-359. 52. Ochonisky S, Revuz J. Thalidomide use in dermatology. Eur J Dermatol. 1994;4:9-15. 33. Hasper MF. Chronic cutaneous lupus erythematosus: thalidomide treatment of 53. Clemmensen OJ, Olsen PZ, Andersen KE. Thalidomide neurotoxicity. Arch Der- 11 patients. Arch Dermatol. 1983;119:812-815. matol. 1984;120:338-341.

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