http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/09546634.2014.906036
ORIGINAL ARTICLE
Thalidomide: Still an important second-line treatment in refractory cutaneous lupus erythematosus? Isabelle Baret and Petra De Haes
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Department of Dermatology, University Hospital Leuven, Leuven, Belgium
Abstract
Keywords
Background: Cutaneous lupus erythematosus (CLE) can be a severe disease, characterized by extensive, disfiguring lesions and a relapsing course. Thalidomide is known as an effective treatment for CLE, however, its use is restricted by its potential side-effects. Nevertheless, it remains a valuable option to consider. Therefore, it is important to report new clinical experiences. Methods: The data of 30 patients with refractory CLE, who were treated with thalidomide, were retrospectively analyzed. The response rate was categorized as complete, partial or no response. The relapse rate and the occurrence of side-effects were registered. Results: Six patients prematurely discontinued treatment because of side-effects. The response rate was 100% in the remaining 24 patients, including 20 patients (83%) with complete response and 4 (27%) with partial response. Clinical relapse was frequent (73%) and occurred between 3 and 24 weeks after withdrawal of thalidomide. Nine patients (30%) developed peripheral neuropathy. In the majority, there was no complete resolution of the neuropathyassociated symptoms after stopping thalidomide. One patient developed a thrombosis in an artery stent. Conclusion: Because of high risk of polyneuropathy, low-dose thalidomide should be used and long-term therapy should be avoided. Therefore, it should be recommended to combine thalidomide with other treatments for CLE.
Polyneuropathy, refractory cutaneous lupus erythematosus, thalidomide
Introduction Thalidomide is a drug with a notorious and complex history. It was first synthesized in the mid-1950s and initially marketed as an over-the-counter sedative and anti-emetic. It quickly grew into a worldwide popular remedy for morning sickness during pregnancy. However, after some years thalidomide was withdrawn from the market because of its association with more than 10 000 cases of rare congenital malformations such as phocomelia (1). In 1965, Israeli physician J. Sheskin fortuitously discovered that thalidomide was also effective in the treatment of the disfiguring lesions of erythema nodosum leprosus. Since then, thalidomide has been used successfully in some other dermatological conditions, especially lupus erythematosus (LE) (2). Although the skin lesions of LE are not life threatening, they can be extended and very itchy or painful. In addition, the discoid subtype can cause severe, disfiguring scars. Despite a better understanding of the pathophysiological mechanisms involved in the development of cutaneous lupus erythematosus (CLE), there has not been a great breakthrough in its treatment. Many patients with CLE can be managed with ‘‘standard’’ therapies, including sunscreens, protective clothing and topical corticosteroids with or
Correspondence: Petra De Haes, Department of Dermatology, University Hospital Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium. Tel: +3216337950. Fax: +3216337872. E-mail: [email protected]
History Received 27 January 2014 Accepted 11 March 2014 Published online 14 April 2014
without an oral antimalarial agent. Systemic corticosteroids are effective for the treatment of acute severe skin lesions, but only for short-term use (3). For refractory cases, there is no consensus algorithm about the other possible systemic treatments. Retinoids, methotrexate, dapsone, azathioprine or mycophenolate mofetil have all been described as potentially useful. If patients are resistant or intolerant to all these treatments and/or in cases of severe or extensive CLE, thalidomide appears to be a good therapeutic option with a high clinical efficacy (4,5).
Patients and methods Patients Thirty outpatients, all aged 18 years or over and followed at the hospital from the Catholic University of Leuven (Belgium), received thalidomide for refractory CLE from February 1998 to August 2013. Their medical records were retrospectively reviewed. The diagnosis and classification of CLE were based on clinical and histological criteria as well as on serological abnormalities according to the ‘‘Du¨sseldorf Classification 2004’’ (6). All patients had failed therapy with other drugs. They did not respond to at least two different treatments of the following medications: anti-malaria (hydroxychloroquine 400 mg/day or chloroquine 200 mg/day, and/or quinacrine 100 mg/day) for 42 months, systemic corticosteroids, acitretin, azathioprine, methotrexate or dapsone. Systemic disease was diagnosed according to the American College of Rheumatology classification criteria (7).
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Treatment protocol and evaluation Thalidomide risk management program (first according to Pharmion, later to Celgene) was followed in all patients. Women in childbearing years were required to use reliable contraception from 1 month before start till 1 month after stop of thalidomide. A monthly pregnancy test was performed before start and during the therapy. For men, it was necessary to use condoms as the contraceptive method. All patients signed the required informed consent. The risk of neuropathy and its symptoms were explained. All patients were examined at baseline with a neurological examination and an electromyography (EMG) of the upper and lower limbs. The EMG was repeated at least every year or earlier in the event of new neurological symptoms. Further, at baseline, measurements of full blood counts and immunological parameters [i.e. antinuclear antibodies (ANA) and subtyping, antiphospholipid antibodies] were performed. Thalidomide (first divided by Pharmion, and later by Celgene corporation), supplied on a ‘‘named patient’’ basis by the hospital pharmacy, was started at 50 mg daily at bedtime. If there was no response or in case of a severe extended CLE, the dose was increased to 100 mg daily but only when thalidomide was well tolerated. The dose was gradually tapered again once complete clinical improvement was achieved. The study population was regularly examined by the same two physicians of the department of dermatology, who are allowed to prescribe thalidomide in our center. At each visit, clinical response to therapy and occurrence of side effects, in particular peripheral neuropathy, were evaluated.
Clinical response was categorized as ‘‘complete response (CR)’’ (with improvement 75%), ‘‘partial response (PR)’’ (with improvement between 25% and 75%) and ‘‘no response (NR)’’ (with improvement 25%).
Results Baseline patient characteristics Thirty patients with refractory or severe extended CLE were included. Both subtypes, discoid lupus erythematosus (DLE) (50%) and subacute cutaneous lupus erythematosus (SCLE) (46.7%), were approximately equally represented. Only one patient had an acute cutaneous lupus erythematosus (ACLE). Table 1 shows baseline clinical and serological data. There was a clear female predominance (83.3%). The mean age at the onset of thalidomide treatment was 49 ± 12 years (range 22–78). About 10 patients (33.3%) had an associated systemic disease. Two of them were diagnosed with a mixed connective tissue disease (MCTD), and the other eight patients fulfilled the criteria of SLE. Only one patient received thalidomide in monotherapy. In all other patients, thalidomide was combined with at least topical corticosteroids and/or (hydroxy)chloroquine. Clinical response Six patients (cases 7, 8, 10, 27, 28 and 30) were not further evaluated for clinical response because they prematurely stopped treatment due to disabling side-effects. Clinical response was observed in all of the remaining 24 patients (100%), of whom 20 (83%) achieved a CR and 4 patients
Table 1. Demographics and clinical characteristics of 30 patients treated with thalidomide for CLE. Patient no./sex/ age, years
CLE type
1/F/62 2/F/38 3/F/51 4/F/30 5/M/78 6/F/49 7/F/44 8/F/40 9/F/50 10/F/78 11/F/42 12/F/39 13/F/59 14/F/54 15/F/43 16/M/50 17/F/40 18/F/43 19/F/56 20/M/47 21/F/22 22/F/48 23/F/46 24/M/42 25/F/48 26/F/63 27/M/49 28/F/47 29/F/41 30/F/72
SCLE DLE ACLE DLE DLE SCLE SCLE DLE SCLE DLE DLE SCLE SCLE DLE DLE DLE DLE SCLE SCLE DLE SCLE DLE SCLE DLE DLE SCLE SCLE SCLE DLE SCLE
ANA (subtypes)
SLE
+ (SSA) + (dsDNA, U1-RNP, Sm)
(MCTD)
+ (SSA) + (SSA) + (SSA) + (SSA) + (SSA, SSB) + (SSA)
+ (SSA) + (SSA) + (dsDNA, U1-RNP) + (SSA, U1-RNP) + (SSA, SSB)
+ + +
+
(MCTD) +
+ (SSA, U1-RNP) + (SSA)
+
+ (SSA, SSB, U1-RNP, dsDNA)
+
+ (SSA)
+
Thalidomide monotherapy (other medications) Yes No (TCs, HCQ) No (TCs) No (HCQ) No (TCs) No (HCQ, OCs) No (HCQ, OCs) No (TCs, HCQ) No (TCs, HCQ) No (TCs) No (HCQ, OCs) No (TCs, HCQ) No (TCs, CQ) No (HCQ, OCs) No (HCQ) No (HCQ) No (TCs, HCQ) No (CQ) No (HCQ, OCs) No (TCs, HCQ) No (TCs, CQ) No (HCQ, OCs) No (HCQ, OCs) No (HCQ, OCs) No (OCs, AZA) No (TCs, HCQ) No (TCs, HCQ) No (HCS, OCs, AZA) No (HCS, OCs, AZA) No (TCs, HCQ)
F, female; M, male; CLE, cutaneous lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; ACLE, acute cutaneous lupus erythematosus; ANA, antinuclear antibody; SSA, anti-Ro/SSA antibody; dsDNA, anti-double-stranded DNA antibody; U1-RNP, anti-U1 ribonucleoprotein antibody; Sm, anti-Smith antibody; SSB, anti-La/SSB antibody; SLE, systemic lupus erythematosus; MCTD, mixed connective tissue disease; HCQ, hydroxychloroquine; CQ, chloroquine; Q, quinacrine; TCs, topical corticosteroids; OCs, oral corticosteroids; AZA, azathioprine.
Thalidomide for cutaneous lupus erythematosus
DOI: 10.3109/09546634.2014.906036
Table 2. Summary of the clinical response to thalidomide therapy. First response
Relapse
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During After stop Clinical (time to, dose outcome Patient Time to Cumulative weeks) no. (days) dose (mg) (after 3 months) reduction 1 2 3 4 5 6 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 29
10 19 23 21 33 14 14 19 35 29 38 26 10 65 14 37 61 32 54 28 35 25 31 48
500 950 1150 1050 1650 700 700 1200 2800 1450 1900 1300 500 5350 350 3650 4650 2850 4000 2450 1750 1250 1550 3200
CR CR PR PR CR CR CR CR CR CR PR CR CR CR CR CR PR CR CR CR CR CR CR CR
No No – – No No No Yes Yes No – No No No No No – Yes No No Yes No No Yes
Yes (6) No – – No Yes (24) Yes (8) – – Yes (12) – No Yes (6) Yes (24) Yes (3) Yes (5) – – Yes (9) No – Yes (4) Yes (24) –
CR, complete response; PR, partial response; NR, no response.
(27%) had a PR after 3 months of treatment (Table 2). The first improvement was seen at a mean of 4 weeks (range 1–9) and with a mean cumulative dose of 1.9 g (range 0.4–5.3). In the 20 patients, who achieved a CR, the thalidomide dose was gradually reduced. Fifteen patients were able to stop the treatment completely. The relapse rate after discontinuation of the drug in the latter patients was 73% (11 of the 15 patients) and relapse occurred between 3 and 24 weeks. In the remaining five patients (cases 11, 12, 21, 24 and 29), thalidomide could never be stopped completely due to flare-ups of cutaneous lesions when tapering the thalidomide dose. At the end of our observation period, 20 out of the 30 patients had permanently stopped the thalidomide therapy because of remission (4 patients) or due to side-effects (16 patients) (Table 3). The other 10 patients were still taking thalidomide with a maintenance dose varying between 50 mg daily and 50 mg twice a week. Side-effects As already stated, six patients had to stop thalidomide prematurely due to side-effects. Patient 7 developed a rash 2 weeks after start thalidomide. Three patients (cases 8, 10 and 28) stopped because of intolerable drowsiness and dizziness. Remarkably, two patients (cases 27 and 30) developed early EMG-confirmed sensory neuropathy after 42 and 45 days, respectively. In addition to those 6 patients, thalidomide was eventually withdrawn in another 10 patients (Table 3) because of disabling side-effects (i.e. neuropathy, drowsiness, concentration disorders and leukopenia). The most frequently reported side-effects were drowsiness (67%), neuropathy (30%), concentration disorders (20%) and constipation (13%) (Table 4). Only three patients tolerated the treatment well, without any side-effect. Paraesthesia, numbness and cramps in hands and/or feet and legs were reported by nine patients (30%), three males and six females. An EMG confirmed a sensory axonal neuropathy in eight
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Table 3. Evaluation at the end of observation period. Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Maintenance therapy of thalidomide (dose)
Stop due to side effects
Stop because of achieved remission + +
+ + (50 mg/2 days) + + (50 mg/day) + + + + + (50 mg/1–2 days) + (50 mg/1–2 days) + + + + + + (50 mg/1–2 days) + (50 mg, 3/week) + + (50 mg, 3/week) + + Yes (50 mg, 2/week) Yes (50 mg, 3/week) + + + Yes (50 mg, 5/week) +
Table 4. Patient-reported adverse effects.
Adverse effects Drowsiness Neuropathy symptoms Concentration disorder Constipation Dizziness Rash Skin dryness, itch Leukopenia Hypotension Impotence Gynecomastia
Number of patients affected (%)
Number of patients who stopped therapy
20 (67) 9 (30) 6 (20) 4 (13) 3 (10) 2 (6) 2 (6) 1 (3) 1 (3) 1 (3) 1 (3)
5 9 2 0 2 1 1 1 0 0 0
of the nine patients. The daily dose of thalidomide, at the moment of the first neurological symptom was 50 mg, with the exception of two patients with a daily dose of 100 mg. The duration of follow-up before appearance of first neurologic abnormality ranged from 1 to 55 months (average 15.5 ± 18 months). The mean cumulative dose at that moment was 26 g, varying from 1.9 to 68.9 g. Thalidomide was stopped in all patients with signs of sensory neuropathy, with or without EMG abnormalities. There was a complete resolution of the clinical neurological symptoms in seven patients (78%). Two patients (cases 3 and 14) had only a partial resolution. They still had some complaints of paraesthesia or numbness up to 7 and 2.5 years, respectively, after the interruption of thalidomide. One female patient (case 18), aged 45 years, developed an arterial thrombosis in a femoropopliteal artery stent during thalidomide therapy (50 mg daily, after 81 weeks of treatment with cumulative dose of 14.9 g). The patient had an associated SLE. She had no personal or familiar history of thrombosis and
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the antiphospholipid antibodies were negative. However, she had other prothrombotic risk factors, including smoking and a preceding episode of prolonged immobilization as result of a hip fracture. The patient stopped smoking, the dose of antiplatelet therapy (acetylsalicylic acid) was increased and thalidomide was stopped temporarily, but reintroduced 3 weeks after the event because of serious relapse of CLE. No recurrence of thrombotic episodes occurred during the remaining observation period while taking thalidomide 50 mg daily.
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Discussion Thalidomide is one of the few agents with good efficacy for refractory CLE according to several case reports and observational studies (8–20). However, it is still regarded as a second-line therapy because of its toxicity profile and the restricted availability. In accordance with previous reports, we observed a high rate of clinical response. After excluding six patients with disabling side-effects and premature stop, a total of 24 patients was included to evaluate the clinical efficacy. All patients experienced clinical improvement within 1–9 weeks after starting thalidomide. After 3 months of treatment, 20 (83.3%) of those patients achieved a CR. Initial reports studied thalidomide administered at doses up to 400 mg/day (8,9), whereas subsequent studies found a reduced starting dose of 50–100 mg/day to be effective as well (10–20). Cuadrado et al. (16) found in their study no significant correlation between the thalidomide daily dose (100, 50 or 25 mg) and the response rate. The time necessary to obtain clinical response, was also similar in the three dosage groups, ranging from 2 to 10 weeks. This is comparable to the data in our study. As described previously, thalidomide probably suppresses disease activity only as long as it is administered (8,9). Similar to other series, a high rate of relapse (73%) was observed in patients who stopped thalidomide and relapse occurred between 3 and 24 weeks. In five patients, thalidomide could never be stopped completely due to flare-ups of cutaneous lesions when tapering the thalidomide dose. In contrast to several previous studies (12,13,16), thalidomide was not given in monotherapy at our center. In the majority of patients, thalidomide was combined with topical corticosteroids and/or (hydroxy)chloroquine. In fact, all patients had already been treated with at least those medications, but because of inefficacy of treatment, thalidomide was finally associated. The observed clinical response (CR or PR) is therefore the difference in response before and after the association of thalidomide. We preferred to combine thalidomide with (hydroxy)chloroquine, unless the presence of side effects such as retinopathy, in order to keep the thalidomide therapy as short as possible and with the lowest necessary dose. Other systemic medications like oral corticosteroids and azathioprine, mostly needed in patients with SLE to control extracutaneous features, were not interrupted either. In some patients though, the dose of the systemic corticosteroids could be gradually tapered after the association of thalidomide. Thalidomide was not well tolerated in our study. About 16 of 30 patients (53%) eventually had to stop treatment because of side-effects. Similar to previous reports, drowsiness was the most reported adverse effect, consistent with its original prescription as a sedative (11,16,17). This effect can mostly be minimized by administration of thalidomide in the evening or by reducing the daily dose. Sometimes patients gradually habituate to the thalidomide sedative action (17). It was nevertheless the reason of discontinuation of the drug in six of our patients. With strict avoidance of thalidomide use during pregnancy, axonal sensory peripheral neuropathy (PN) has now become the most important
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and most feared side-effect, especially since this is potentially irreversible. The real incidence of thalidomide-induced neuropathy and its relationship to the administered dose is still a matter of debate. The reported incidence of PN in patients treated with thalidomide for dermatological indications ranges from 51% in patients with erythema nodosum leprosum to 470% in patients with prurigo nodularis (18). In the different series of CLE patients treated with thalidomide, the incidence rate of PN also varies greatly (range 18–71%) (16–20). Thirteen patients (43%) in our series developed neurological symptoms with a confirmed sensory axonal neuropathy by EMG in nine of them. Thalidomide treatment was interrupted immediately in all patients, with or without EMG abnormalities. The daily dose of thalidomide, at the moment of the first neurological symptoms was 50 mg, with the exception of two patients with a daily dose of 100 mg. This further confirms that neuropathy may also occur at low daily dose thalidomide (16). As described previously, no correlation was found with the duration of the therapy or with the thalidomide cumulative dose. The mean cumulative dose at the moment of first neurologic symptoms was 26 g, but varied from 1.9 to 68.9 g. Remarkably, two patients in our study developed early EMG-confirmed sensory neuropathy after 42 and 45 days, respectively, and with a daily dose of 50 mg. These data demonstrate that the occurrence of thalidomide-induced PN is unpredictable. It has been suggested that individual susceptibilities (female sex, advanced age) with a possible genetic predisposition might be more relevant than daily dose and duration of therapy (19). In our study, three males and six females developed PN, but there was also a clear female predominance in the whole observation group. The age of onset of PN ranged from 43 to 78 years. With 43% of patients developing PN, at variable time points after initiating thalidomide therapy and with a wide variety of cumulative doses, peripheral nerve function should always be monitored closely in patients taking thalidomide. EMG should be performed at baseline and every 6–12 months during therapy. Patients must be well informed about possible signs of peripheral sensory neuropathy. Thalidomide should be stopped immediately when clinical and/or EMG signs of PN occur. In addition, the issue of the reversibility of thalidomide-induced PN remains controversial too (18–21). Two patients of our study group continued to have complaints of paraesthesia or numbness up to 7 and 2.5 years, respectively, after the interruption of thalidomide. The chance of full recovery in those patients is probably very low. Thalidomide is also known to have pro-trombotic properties. Although this risk of thrombotic and trombo-embolic events has mainly been reported in patients with cancer and myeloma, rare associations with non-malignant dermatological disorders, including LE, have also been described (19,22–24). In our study, one female patient developed an arterial thrombosis in a femoropopliteal artery stent after 81 weeks of thalidomide treatment with a 50 mg daily dose. The patient had no personal or familiar history of thrombosis and biochemical screening for prothrombotic parameters was negative. However, she clearly had associated prothrombotic risk factors, including smoking and a preceding episode of prolonged immobilization due to a hip fracture. There is some controversy whether thalidomide treatment needs to be interrupted (permanently) in these cases. Limited evidence suggests that with the addition of warfarin or antiaggregant prophylaxis, the thalidomide therapy may be continued safely (19). Certainly, it is important to screen for thrombotic risk factors in patients before starting the treatment. Although thrombotic side-effects of thalidomide seem to be rare in patients treated for CLE, it is important to screen for other thrombotic risk factors before starting the treatment. It is, however, unclear whether thalidomide can be started or continued in patients with a history of, or other risk factors for, thrombosis. Limited evidence suggests
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DOI: 10.3109/09546634.2014.906036
that with the addition of warfarin or antiaggregant prophylaxis, thalidomide can be given safely (19). However, this should only be done in cases of severe CLE resistant to other therapeutic options with close monitoring of the patient. In the mid-1990s, a promising analogue of thalidomide, lenalidomide, was developed to improve the effectiveness and in particular the tolerance of thalidomide. Lenalidomide has mainly been studied in and has been approved for the treatment of multiple myeloma and other myelodysplastic syndromes. As structural analogues with immunomodulatory features, thalidomide and lenalidomide seem to have the same efficacy and relapse rates. However, in a retrospective review of serious adverse drug reactions of thalidomide and lenalidomid, interesting differences between their safety profile were observed (25). Nervous system and vascular disorders were more frequently reported with thalidomide-based regimens while hematologic, skin and infectious disorders and secondary primary cancers were seen more frequently with lenalidomide-based regimens. In recent years, three studies have been published in which lenalidomide was investigated specifically as a treatment for CLE. A similar therapeutic efficacy and relapse ratio was seen with lenalidomide compared to thalidomide, but lenalidomide seems to be better tolerated (26–28). However, Braunstein et al. (27) described an increased risk of developing a severe SLE flare in their small cohort of patients treated with lenalidomide, with one patient developing a renal flare. This possible side-effect of lenalidomide was not confirmed in the larger cohort study of Corte´s-Herna´ndez et al. (28). Further controlled clinical trials are required to confirm the possible role of lenalidomide as treatment for CLE and to investigate the potential risk of inducing a severe SLE flare.
Conclusions Based on this case series and previous studies, we believe that thalidomide can still be considered as a therapeutic option for CLE in two conditions: in cases of severe flare of CLE to achieve a relatively fast and effective clinical response, or in patients in whom other therapeutic options have already been omitted because of side-effects or ineffectiveness. However, one should be realistic that thalidomide is probably not suitable for long-term use because of the high risk of polyneuropathy.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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6. Kuhn A, Lehmann P, Ruzicka T. Cutaneous Lupus Erythematosus. Heidelberg: Springer-Verlag, 2004. p 53–8. 7. Tan EM, Cohen AS, Fries JF, et al. The 1982 revisited criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–7. 8. Knop J, Bonsmann G, Happle R, et al. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol. 1983;108:461–6. 9. Atra E, Sato EI. Treatment of the cutaneous lesions of systemic lupus erythematosus with thalidomide. Clin Exp Rheumatol. 1993; 11:487–93. 10. Stevens RJ, Andujar C, Edwards CJ, et al. Thalidomide in the treatment of the cutaneous manifestations of lupus erythematosus: experience in sixteen consecutive patients. Br J Rheumatol. 1997;36: 353–9. 11. Sato EI, Assis LS, Lourenzi VP, Andrade LE. Long-term thalidomide use in refractory cutaneous lesions of systemic lupus erythematosus. Rev Assoc Med Bras. 1998;44:289–93. 12. Duong DJ, Spiegel T, Moxley RT, Gaspari AA. American experience with low-dose thalidomide therapy of severe cutaneous lupus erythematosus. Arch Dermatol. 1999;135:1079–87. 13. Kyriakis KP, Kontochristopoulos GJ, Panteleos DN. Experience with low-dose thalidomide therapy in chronic discoid lupus erythematosus. Int J Dermatol. 2000;39:218–22. 14. Ordi-Ros J, Corte´s F, Cucurull E, et al. Thalidomide in the treatment of cutaneous lupus refractory to conventional therapy. J Rheumatol. 2000;27:1429–33. 15. Housman TS, Jorizzo JL, McCarty MA, et al. Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus. Arch Dermatol. 2003;139:50–4. 16. Cuadrado MJ, Karim Y, Sanna G, et al. Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens. Am J Med. 2005;118:246–50. 17. Coelho A, Souto MI, Cardoso CR, et al. Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a 65 series of Brazilian patients. Lupus. 2005;14:434–9. 18. Briani C, Zara G, Rondinone R, et al. Thalidomide neurotoxicity: prospective study in patients with lupus erythematosus. Neurology. 2004;62:2288–90. 19. Corte´s-Herna´ndez J, Torres-Salido M, Castro-Marrero J, et al. Thalidomide in the treatment of refractory cutaneous lupus erythematosus prognostic factors of clinical outcome. Br J Dermatol. 2012; 166:616–23. 20. Frankel HC, Sharon VR, Vleugels RA, et al. Lower-dose thalidomide therapy effectively treats cutaneous lupus erythematosus but is limited by neuropathic toxicity. Int J Dermatol. 2013;52:1407–9. 21. Zara G, Ermani M, Rondinone R, et al. Thalidomide and sensory neurotoxicity: a neurophysiological study. J Neurol Neurosurg Psychiatry. 2008;79:1258–61. 22. Flageul B, Wallach D, Cavelier-Balloy B, et al. Thalidomide and thrombosis. Ann Dermatol Venereol. 2000;127:171–4. 23. Llambrich A, Romero D, Iranzo P, et al. Acute myocardial infarction in a patient with cutaneous lupus erythematosus treated with thalidomide. J Eur Acad Dermatol Venerol. 2007;21:136–7. 24. Piette JC, Sbai A, France`s C. Warning: thalidomide-related trombotic risk potentially concerns patients with lupus. Lupus. 2002;11:67–70. 25. Olivier-Abbal P, Teisseyre A-C, Motastruc J-L. Comparison of serious adverse reactions between thalidomide and lenalidomide: analysis in the French Pharmacovigilance database. Med Oncol. 2013;30:733–41. 26. Shah A, Albrecht J, Bonilla-Martinez Z, et al. Lenalidomide for the treatment of resistant discoid lupus erythematosus. Arch Dermatol. 2009;145:303–6. 27. Braunstein I, Goodman NG, Rosenbach M, et al. Lenalidomide therapy in treatment refractory cutaneous lupus erythematosus: histologic and circulating leukocyte profile and potential risk of a systemic lupus flare. J Am Acad Dermatol. 2012;66:571–82. ´ vila G, Vilardell-Tarre´s M, Ordi-Ros J. 28. Corte´s-Herna´ndez J, A Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus. Arthritis Res Ther. 2012;14:R265.
ORIGINAL ARTICLE
Thalidomide: Still an important second-line treatment in refractory cutaneous lupus erythematosus? Isabelle Baret and Petra De Haes
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Department of Dermatology, University Hospital Leuven, Leuven, Belgium
Abstract
Keywords
Background: Cutaneous lupus erythematosus (CLE) can be a severe disease, characterized by extensive, disfiguring lesions and a relapsing course. Thalidomide is known as an effective treatment for CLE, however, its use is restricted by its potential side-effects. Nevertheless, it remains a valuable option to consider. Therefore, it is important to report new clinical experiences. Methods: The data of 30 patients with refractory CLE, who were treated with thalidomide, were retrospectively analyzed. The response rate was categorized as complete, partial or no response. The relapse rate and the occurrence of side-effects were registered. Results: Six patients prematurely discontinued treatment because of side-effects. The response rate was 100% in the remaining 24 patients, including 20 patients (83%) with complete response and 4 (27%) with partial response. Clinical relapse was frequent (73%) and occurred between 3 and 24 weeks after withdrawal of thalidomide. Nine patients (30%) developed peripheral neuropathy. In the majority, there was no complete resolution of the neuropathyassociated symptoms after stopping thalidomide. One patient developed a thrombosis in an artery stent. Conclusion: Because of high risk of polyneuropathy, low-dose thalidomide should be used and long-term therapy should be avoided. Therefore, it should be recommended to combine thalidomide with other treatments for CLE.
Polyneuropathy, refractory cutaneous lupus erythematosus, thalidomide
Introduction Thalidomide is a drug with a notorious and complex history. It was first synthesized in the mid-1950s and initially marketed as an over-the-counter sedative and anti-emetic. It quickly grew into a worldwide popular remedy for morning sickness during pregnancy. However, after some years thalidomide was withdrawn from the market because of its association with more than 10 000 cases of rare congenital malformations such as phocomelia (1). In 1965, Israeli physician J. Sheskin fortuitously discovered that thalidomide was also effective in the treatment of the disfiguring lesions of erythema nodosum leprosus. Since then, thalidomide has been used successfully in some other dermatological conditions, especially lupus erythematosus (LE) (2). Although the skin lesions of LE are not life threatening, they can be extended and very itchy or painful. In addition, the discoid subtype can cause severe, disfiguring scars. Despite a better understanding of the pathophysiological mechanisms involved in the development of cutaneous lupus erythematosus (CLE), there has not been a great breakthrough in its treatment. Many patients with CLE can be managed with ‘‘standard’’ therapies, including sunscreens, protective clothing and topical corticosteroids with or
Correspondence: Petra De Haes, Department of Dermatology, University Hospital Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium. Tel: +3216337950. Fax: +3216337872. E-mail: [email protected]
History Received 27 January 2014 Accepted 11 March 2014 Published online 14 April 2014
without an oral antimalarial agent. Systemic corticosteroids are effective for the treatment of acute severe skin lesions, but only for short-term use (3). For refractory cases, there is no consensus algorithm about the other possible systemic treatments. Retinoids, methotrexate, dapsone, azathioprine or mycophenolate mofetil have all been described as potentially useful. If patients are resistant or intolerant to all these treatments and/or in cases of severe or extensive CLE, thalidomide appears to be a good therapeutic option with a high clinical efficacy (4,5).
Patients and methods Patients Thirty outpatients, all aged 18 years or over and followed at the hospital from the Catholic University of Leuven (Belgium), received thalidomide for refractory CLE from February 1998 to August 2013. Their medical records were retrospectively reviewed. The diagnosis and classification of CLE were based on clinical and histological criteria as well as on serological abnormalities according to the ‘‘Du¨sseldorf Classification 2004’’ (6). All patients had failed therapy with other drugs. They did not respond to at least two different treatments of the following medications: anti-malaria (hydroxychloroquine 400 mg/day or chloroquine 200 mg/day, and/or quinacrine 100 mg/day) for 42 months, systemic corticosteroids, acitretin, azathioprine, methotrexate or dapsone. Systemic disease was diagnosed according to the American College of Rheumatology classification criteria (7).
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Treatment protocol and evaluation Thalidomide risk management program (first according to Pharmion, later to Celgene) was followed in all patients. Women in childbearing years were required to use reliable contraception from 1 month before start till 1 month after stop of thalidomide. A monthly pregnancy test was performed before start and during the therapy. For men, it was necessary to use condoms as the contraceptive method. All patients signed the required informed consent. The risk of neuropathy and its symptoms were explained. All patients were examined at baseline with a neurological examination and an electromyography (EMG) of the upper and lower limbs. The EMG was repeated at least every year or earlier in the event of new neurological symptoms. Further, at baseline, measurements of full blood counts and immunological parameters [i.e. antinuclear antibodies (ANA) and subtyping, antiphospholipid antibodies] were performed. Thalidomide (first divided by Pharmion, and later by Celgene corporation), supplied on a ‘‘named patient’’ basis by the hospital pharmacy, was started at 50 mg daily at bedtime. If there was no response or in case of a severe extended CLE, the dose was increased to 100 mg daily but only when thalidomide was well tolerated. The dose was gradually tapered again once complete clinical improvement was achieved. The study population was regularly examined by the same two physicians of the department of dermatology, who are allowed to prescribe thalidomide in our center. At each visit, clinical response to therapy and occurrence of side effects, in particular peripheral neuropathy, were evaluated.
Clinical response was categorized as ‘‘complete response (CR)’’ (with improvement 75%), ‘‘partial response (PR)’’ (with improvement between 25% and 75%) and ‘‘no response (NR)’’ (with improvement 25%).
Results Baseline patient characteristics Thirty patients with refractory or severe extended CLE were included. Both subtypes, discoid lupus erythematosus (DLE) (50%) and subacute cutaneous lupus erythematosus (SCLE) (46.7%), were approximately equally represented. Only one patient had an acute cutaneous lupus erythematosus (ACLE). Table 1 shows baseline clinical and serological data. There was a clear female predominance (83.3%). The mean age at the onset of thalidomide treatment was 49 ± 12 years (range 22–78). About 10 patients (33.3%) had an associated systemic disease. Two of them were diagnosed with a mixed connective tissue disease (MCTD), and the other eight patients fulfilled the criteria of SLE. Only one patient received thalidomide in monotherapy. In all other patients, thalidomide was combined with at least topical corticosteroids and/or (hydroxy)chloroquine. Clinical response Six patients (cases 7, 8, 10, 27, 28 and 30) were not further evaluated for clinical response because they prematurely stopped treatment due to disabling side-effects. Clinical response was observed in all of the remaining 24 patients (100%), of whom 20 (83%) achieved a CR and 4 patients
Table 1. Demographics and clinical characteristics of 30 patients treated with thalidomide for CLE. Patient no./sex/ age, years
CLE type
1/F/62 2/F/38 3/F/51 4/F/30 5/M/78 6/F/49 7/F/44 8/F/40 9/F/50 10/F/78 11/F/42 12/F/39 13/F/59 14/F/54 15/F/43 16/M/50 17/F/40 18/F/43 19/F/56 20/M/47 21/F/22 22/F/48 23/F/46 24/M/42 25/F/48 26/F/63 27/M/49 28/F/47 29/F/41 30/F/72
SCLE DLE ACLE DLE DLE SCLE SCLE DLE SCLE DLE DLE SCLE SCLE DLE DLE DLE DLE SCLE SCLE DLE SCLE DLE SCLE DLE DLE SCLE SCLE SCLE DLE SCLE
ANA (subtypes)
SLE
+ (SSA) + (dsDNA, U1-RNP, Sm)
(MCTD)
+ (SSA) + (SSA) + (SSA) + (SSA) + (SSA, SSB) + (SSA)
+ (SSA) + (SSA) + (dsDNA, U1-RNP) + (SSA, U1-RNP) + (SSA, SSB)
+ + +
+
(MCTD) +
+ (SSA, U1-RNP) + (SSA)
+
+ (SSA, SSB, U1-RNP, dsDNA)
+
+ (SSA)
+
Thalidomide monotherapy (other medications) Yes No (TCs, HCQ) No (TCs) No (HCQ) No (TCs) No (HCQ, OCs) No (HCQ, OCs) No (TCs, HCQ) No (TCs, HCQ) No (TCs) No (HCQ, OCs) No (TCs, HCQ) No (TCs, CQ) No (HCQ, OCs) No (HCQ) No (HCQ) No (TCs, HCQ) No (CQ) No (HCQ, OCs) No (TCs, HCQ) No (TCs, CQ) No (HCQ, OCs) No (HCQ, OCs) No (HCQ, OCs) No (OCs, AZA) No (TCs, HCQ) No (TCs, HCQ) No (HCS, OCs, AZA) No (HCS, OCs, AZA) No (TCs, HCQ)
F, female; M, male; CLE, cutaneous lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; ACLE, acute cutaneous lupus erythematosus; ANA, antinuclear antibody; SSA, anti-Ro/SSA antibody; dsDNA, anti-double-stranded DNA antibody; U1-RNP, anti-U1 ribonucleoprotein antibody; Sm, anti-Smith antibody; SSB, anti-La/SSB antibody; SLE, systemic lupus erythematosus; MCTD, mixed connective tissue disease; HCQ, hydroxychloroquine; CQ, chloroquine; Q, quinacrine; TCs, topical corticosteroids; OCs, oral corticosteroids; AZA, azathioprine.
Thalidomide for cutaneous lupus erythematosus
DOI: 10.3109/09546634.2014.906036
Table 2. Summary of the clinical response to thalidomide therapy. First response
Relapse
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During After stop Clinical (time to, dose outcome Patient Time to Cumulative weeks) no. (days) dose (mg) (after 3 months) reduction 1 2 3 4 5 6 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 29
10 19 23 21 33 14 14 19 35 29 38 26 10 65 14 37 61 32 54 28 35 25 31 48
500 950 1150 1050 1650 700 700 1200 2800 1450 1900 1300 500 5350 350 3650 4650 2850 4000 2450 1750 1250 1550 3200
CR CR PR PR CR CR CR CR CR CR PR CR CR CR CR CR PR CR CR CR CR CR CR CR
No No – – No No No Yes Yes No – No No No No No – Yes No No Yes No No Yes
Yes (6) No – – No Yes (24) Yes (8) – – Yes (12) – No Yes (6) Yes (24) Yes (3) Yes (5) – – Yes (9) No – Yes (4) Yes (24) –
CR, complete response; PR, partial response; NR, no response.
(27%) had a PR after 3 months of treatment (Table 2). The first improvement was seen at a mean of 4 weeks (range 1–9) and with a mean cumulative dose of 1.9 g (range 0.4–5.3). In the 20 patients, who achieved a CR, the thalidomide dose was gradually reduced. Fifteen patients were able to stop the treatment completely. The relapse rate after discontinuation of the drug in the latter patients was 73% (11 of the 15 patients) and relapse occurred between 3 and 24 weeks. In the remaining five patients (cases 11, 12, 21, 24 and 29), thalidomide could never be stopped completely due to flare-ups of cutaneous lesions when tapering the thalidomide dose. At the end of our observation period, 20 out of the 30 patients had permanently stopped the thalidomide therapy because of remission (4 patients) or due to side-effects (16 patients) (Table 3). The other 10 patients were still taking thalidomide with a maintenance dose varying between 50 mg daily and 50 mg twice a week. Side-effects As already stated, six patients had to stop thalidomide prematurely due to side-effects. Patient 7 developed a rash 2 weeks after start thalidomide. Three patients (cases 8, 10 and 28) stopped because of intolerable drowsiness and dizziness. Remarkably, two patients (cases 27 and 30) developed early EMG-confirmed sensory neuropathy after 42 and 45 days, respectively. In addition to those 6 patients, thalidomide was eventually withdrawn in another 10 patients (Table 3) because of disabling side-effects (i.e. neuropathy, drowsiness, concentration disorders and leukopenia). The most frequently reported side-effects were drowsiness (67%), neuropathy (30%), concentration disorders (20%) and constipation (13%) (Table 4). Only three patients tolerated the treatment well, without any side-effect. Paraesthesia, numbness and cramps in hands and/or feet and legs were reported by nine patients (30%), three males and six females. An EMG confirmed a sensory axonal neuropathy in eight
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Table 3. Evaluation at the end of observation period. Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Maintenance therapy of thalidomide (dose)
Stop due to side effects
Stop because of achieved remission + +
+ + (50 mg/2 days) + + (50 mg/day) + + + + + (50 mg/1–2 days) + (50 mg/1–2 days) + + + + + + (50 mg/1–2 days) + (50 mg, 3/week) + + (50 mg, 3/week) + + Yes (50 mg, 2/week) Yes (50 mg, 3/week) + + + Yes (50 mg, 5/week) +
Table 4. Patient-reported adverse effects.
Adverse effects Drowsiness Neuropathy symptoms Concentration disorder Constipation Dizziness Rash Skin dryness, itch Leukopenia Hypotension Impotence Gynecomastia
Number of patients affected (%)
Number of patients who stopped therapy
20 (67) 9 (30) 6 (20) 4 (13) 3 (10) 2 (6) 2 (6) 1 (3) 1 (3) 1 (3) 1 (3)
5 9 2 0 2 1 1 1 0 0 0
of the nine patients. The daily dose of thalidomide, at the moment of the first neurological symptom was 50 mg, with the exception of two patients with a daily dose of 100 mg. The duration of follow-up before appearance of first neurologic abnormality ranged from 1 to 55 months (average 15.5 ± 18 months). The mean cumulative dose at that moment was 26 g, varying from 1.9 to 68.9 g. Thalidomide was stopped in all patients with signs of sensory neuropathy, with or without EMG abnormalities. There was a complete resolution of the clinical neurological symptoms in seven patients (78%). Two patients (cases 3 and 14) had only a partial resolution. They still had some complaints of paraesthesia or numbness up to 7 and 2.5 years, respectively, after the interruption of thalidomide. One female patient (case 18), aged 45 years, developed an arterial thrombosis in a femoropopliteal artery stent during thalidomide therapy (50 mg daily, after 81 weeks of treatment with cumulative dose of 14.9 g). The patient had an associated SLE. She had no personal or familiar history of thrombosis and
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the antiphospholipid antibodies were negative. However, she had other prothrombotic risk factors, including smoking and a preceding episode of prolonged immobilization as result of a hip fracture. The patient stopped smoking, the dose of antiplatelet therapy (acetylsalicylic acid) was increased and thalidomide was stopped temporarily, but reintroduced 3 weeks after the event because of serious relapse of CLE. No recurrence of thrombotic episodes occurred during the remaining observation period while taking thalidomide 50 mg daily.
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Discussion Thalidomide is one of the few agents with good efficacy for refractory CLE according to several case reports and observational studies (8–20). However, it is still regarded as a second-line therapy because of its toxicity profile and the restricted availability. In accordance with previous reports, we observed a high rate of clinical response. After excluding six patients with disabling side-effects and premature stop, a total of 24 patients was included to evaluate the clinical efficacy. All patients experienced clinical improvement within 1–9 weeks after starting thalidomide. After 3 months of treatment, 20 (83.3%) of those patients achieved a CR. Initial reports studied thalidomide administered at doses up to 400 mg/day (8,9), whereas subsequent studies found a reduced starting dose of 50–100 mg/day to be effective as well (10–20). Cuadrado et al. (16) found in their study no significant correlation between the thalidomide daily dose (100, 50 or 25 mg) and the response rate. The time necessary to obtain clinical response, was also similar in the three dosage groups, ranging from 2 to 10 weeks. This is comparable to the data in our study. As described previously, thalidomide probably suppresses disease activity only as long as it is administered (8,9). Similar to other series, a high rate of relapse (73%) was observed in patients who stopped thalidomide and relapse occurred between 3 and 24 weeks. In five patients, thalidomide could never be stopped completely due to flare-ups of cutaneous lesions when tapering the thalidomide dose. In contrast to several previous studies (12,13,16), thalidomide was not given in monotherapy at our center. In the majority of patients, thalidomide was combined with topical corticosteroids and/or (hydroxy)chloroquine. In fact, all patients had already been treated with at least those medications, but because of inefficacy of treatment, thalidomide was finally associated. The observed clinical response (CR or PR) is therefore the difference in response before and after the association of thalidomide. We preferred to combine thalidomide with (hydroxy)chloroquine, unless the presence of side effects such as retinopathy, in order to keep the thalidomide therapy as short as possible and with the lowest necessary dose. Other systemic medications like oral corticosteroids and azathioprine, mostly needed in patients with SLE to control extracutaneous features, were not interrupted either. In some patients though, the dose of the systemic corticosteroids could be gradually tapered after the association of thalidomide. Thalidomide was not well tolerated in our study. About 16 of 30 patients (53%) eventually had to stop treatment because of side-effects. Similar to previous reports, drowsiness was the most reported adverse effect, consistent with its original prescription as a sedative (11,16,17). This effect can mostly be minimized by administration of thalidomide in the evening or by reducing the daily dose. Sometimes patients gradually habituate to the thalidomide sedative action (17). It was nevertheless the reason of discontinuation of the drug in six of our patients. With strict avoidance of thalidomide use during pregnancy, axonal sensory peripheral neuropathy (PN) has now become the most important
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and most feared side-effect, especially since this is potentially irreversible. The real incidence of thalidomide-induced neuropathy and its relationship to the administered dose is still a matter of debate. The reported incidence of PN in patients treated with thalidomide for dermatological indications ranges from 51% in patients with erythema nodosum leprosum to 470% in patients with prurigo nodularis (18). In the different series of CLE patients treated with thalidomide, the incidence rate of PN also varies greatly (range 18–71%) (16–20). Thirteen patients (43%) in our series developed neurological symptoms with a confirmed sensory axonal neuropathy by EMG in nine of them. Thalidomide treatment was interrupted immediately in all patients, with or without EMG abnormalities. The daily dose of thalidomide, at the moment of the first neurological symptoms was 50 mg, with the exception of two patients with a daily dose of 100 mg. This further confirms that neuropathy may also occur at low daily dose thalidomide (16). As described previously, no correlation was found with the duration of the therapy or with the thalidomide cumulative dose. The mean cumulative dose at the moment of first neurologic symptoms was 26 g, but varied from 1.9 to 68.9 g. Remarkably, two patients in our study developed early EMG-confirmed sensory neuropathy after 42 and 45 days, respectively, and with a daily dose of 50 mg. These data demonstrate that the occurrence of thalidomide-induced PN is unpredictable. It has been suggested that individual susceptibilities (female sex, advanced age) with a possible genetic predisposition might be more relevant than daily dose and duration of therapy (19). In our study, three males and six females developed PN, but there was also a clear female predominance in the whole observation group. The age of onset of PN ranged from 43 to 78 years. With 43% of patients developing PN, at variable time points after initiating thalidomide therapy and with a wide variety of cumulative doses, peripheral nerve function should always be monitored closely in patients taking thalidomide. EMG should be performed at baseline and every 6–12 months during therapy. Patients must be well informed about possible signs of peripheral sensory neuropathy. Thalidomide should be stopped immediately when clinical and/or EMG signs of PN occur. In addition, the issue of the reversibility of thalidomide-induced PN remains controversial too (18–21). Two patients of our study group continued to have complaints of paraesthesia or numbness up to 7 and 2.5 years, respectively, after the interruption of thalidomide. The chance of full recovery in those patients is probably very low. Thalidomide is also known to have pro-trombotic properties. Although this risk of thrombotic and trombo-embolic events has mainly been reported in patients with cancer and myeloma, rare associations with non-malignant dermatological disorders, including LE, have also been described (19,22–24). In our study, one female patient developed an arterial thrombosis in a femoropopliteal artery stent after 81 weeks of thalidomide treatment with a 50 mg daily dose. The patient had no personal or familiar history of thrombosis and biochemical screening for prothrombotic parameters was negative. However, she clearly had associated prothrombotic risk factors, including smoking and a preceding episode of prolonged immobilization due to a hip fracture. There is some controversy whether thalidomide treatment needs to be interrupted (permanently) in these cases. Limited evidence suggests that with the addition of warfarin or antiaggregant prophylaxis, the thalidomide therapy may be continued safely (19). Certainly, it is important to screen for thrombotic risk factors in patients before starting the treatment. Although thrombotic side-effects of thalidomide seem to be rare in patients treated for CLE, it is important to screen for other thrombotic risk factors before starting the treatment. It is, however, unclear whether thalidomide can be started or continued in patients with a history of, or other risk factors for, thrombosis. Limited evidence suggests
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DOI: 10.3109/09546634.2014.906036
that with the addition of warfarin or antiaggregant prophylaxis, thalidomide can be given safely (19). However, this should only be done in cases of severe CLE resistant to other therapeutic options with close monitoring of the patient. In the mid-1990s, a promising analogue of thalidomide, lenalidomide, was developed to improve the effectiveness and in particular the tolerance of thalidomide. Lenalidomide has mainly been studied in and has been approved for the treatment of multiple myeloma and other myelodysplastic syndromes. As structural analogues with immunomodulatory features, thalidomide and lenalidomide seem to have the same efficacy and relapse rates. However, in a retrospective review of serious adverse drug reactions of thalidomide and lenalidomid, interesting differences between their safety profile were observed (25). Nervous system and vascular disorders were more frequently reported with thalidomide-based regimens while hematologic, skin and infectious disorders and secondary primary cancers were seen more frequently with lenalidomide-based regimens. In recent years, three studies have been published in which lenalidomide was investigated specifically as a treatment for CLE. A similar therapeutic efficacy and relapse ratio was seen with lenalidomide compared to thalidomide, but lenalidomide seems to be better tolerated (26–28). However, Braunstein et al. (27) described an increased risk of developing a severe SLE flare in their small cohort of patients treated with lenalidomide, with one patient developing a renal flare. This possible side-effect of lenalidomide was not confirmed in the larger cohort study of Corte´s-Herna´ndez et al. (28). Further controlled clinical trials are required to confirm the possible role of lenalidomide as treatment for CLE and to investigate the potential risk of inducing a severe SLE flare.
Conclusions Based on this case series and previous studies, we believe that thalidomide can still be considered as a therapeutic option for CLE in two conditions: in cases of severe flare of CLE to achieve a relatively fast and effective clinical response, or in patients in whom other therapeutic options have already been omitted because of side-effects or ineffectiveness. However, one should be realistic that thalidomide is probably not suitable for long-term use because of the high risk of polyneuropathy.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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