Thalidomide for the treatment of resistant cutaneous lupus: Efficacy and safety of different therapeutic regimens

doi:10.1016/j.amjmed.2004.04.030

The American Journal of Medicine

Volume 118, Issue 3, March 2005, Pages 246-250

https://doi.org/10.1016/j.amjmed.2004.04.030 Get rights and content

Purpose

Thalidomide is effective for the treatment of severe cutaneous lupus. Our aim was to study the safety and efficacy of different doses of thalidomide in this condition.

Methods

We studied patients with severe cutaneous lupus that was unresponsive to antimalarials, prednisolone, methotrexate, azathioprine, and cyclosporin A. Starting doses of 100 mg daily (n = 16 patients), 50 mg daily (n = 17), or 50 mg on alternate days (n = 15) were compared. The response to thalidomide was categorized as complete remission, partial remission, or no visible improvement. All patients received a baseline electromyogram (EMG) followed by repeat EMG every 3 to 6 months, or sooner if neuropathic symptoms developed.

Results

Forty-eight patients (46 female; mean [± SD] age, 44 ± 12 years; range, 22 to 71 years) with discoid lupus (n = 18), subacute cutaneous lupus (n = 6), or systemic lupus erythematosus with skin involvement (n = 24) were included. The response rate was 81%, including 29 patients (60%) in complete remission and 10 (21%) in partial remission. Nine patients (19%) failed to respond. Thirteen patients (27%) developed peripheral neuropathy, which was EMG-proven in 11, including 4 patients in the 50-mg alternate-day group. Other side effects included drowsiness, constipation or abdominal pain, and amenorrhea. The relapse rate after stopping thalidomide was 67% (26/39). There was no association between a positive response to the drug and either starting doses or cumulative dose. Similarly, no association was found between peripheral neuropathy and the starting or cumulative dose.

Conclusion

Thalidomide is effective for the treatment of severe cutaneous lupus. There were no clear dose-dependent effects. However, the high incidence of neurotoxicity, even at low doses, suggests that it may be most useful as a remission-inducing drug.

Section snippets

Methods

Patients were treated according to clinical need, with prior written informed consent. Female patients were required to have a negative pregnancy test. The diagnosis (biopsy-proven) was discoid lupus erythematosus in 18 patients, subacute cutaneous lupus in 4, and lupus profundus in 2 (for the purposes of analysis, patients with lupus profundus were included in the subacute cutaneous lupus group). Twenty-four patients had SLE with cutaneous disease and fulfilled at least 4 standard diagnostic

Results

All but 2 of the 48 patients were women; their ages ranged from 22 to 71 years (Table 1). The overall clinical response rate was 81% (n = 39 patients), with 29 patients (60%) in complete cutaneous remission and 10 (21%) showing partial remission. There was no significant association between thalidomide dose and response rate (Table 1). When complete and partial remission were considered together, the response rate was greater in those with SLE (92% [22/24]) than in those with subacute cutaneous

Discussion

The efficacy of thalidomide in cutaneous lupus is well established, but there is variation in the literature about its toxicity, possibly because of differences in the patients who were studied or the doses of thalidomide that were used. We examined the efficacy and safety of thalidomide at different doses, in three well-defined patient subgroups of patients. Our response rate (81%) is similar to previous reports, which range from 66%¹¹ to 100%.17, 18 This response rate is quite remarkable,

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Cutaneous lupus erythematosus (CLE) is an inflammatory, autoimmune disease encompassing a broad spectrum of subtypes including acute, subacute, chronic and intermittent CLE. Among these, chronic CLE can be further classified into several subclasses of lupus erythematosus (LE) such as discoid LE, verrucous LE, LE profundus, chilblain LE and Blaschko linear LE. To provide all dermatologists and rheumatologists with a practical guideline for the diagnosis, treatment and long-term management of CLE, this evidence- and consensus-based guideline was developed following the checklist established by the international Reporting Items for Practice Guidelines in Healthcare (RIGHT) Working Group and was registered at the International Practice Guideline Registry Platform. With the joint efforts of the Asian Dermatological Association (ADA), the Asian Academy of Dermatology and Venereology (AADV) and the Lupus Erythematosus Research Center of Chinese Society of Dermatology (CSD), a total of 25 dermatologists, 7 rheumatologists, one research scientist on lupus and 2 methodologists, from 16 countries/regions in Asia, America and Europe, participated in the development of this guideline. All recommendations were agreed on by at least 80% of the 32 voting physicians. As a consensus, diagnosis of CLE is mainly based on the evaluation of clinical and histopathological manifestations, with an exclusion of SLE by assessment of systemic involvement. For localized CLE lesions, topical corticosteroids and topical calcineurin inhibitors are first-line treatment. For widespread or severe CLE lesions and (or) cases resistant to topical treatment, systemic treatment including antimalarials and (or) short-term corticosteroids can be added. Notably, antimalarials are the first-line systemic treatment for all types of CLE, and can also be used in pregnant patients and pediatric patients. Second-line choices include thalidomide, retinoids, dapsone and MTX, whereas MMF is third-line treatment. Finally, pulsed-dye laser or surgery can be added as fourth-line treatment for localized, refractory lesions of CCLE in cosmetically unacceptable areas, whereas belimumab may be used as fourth-line treatment for widespread CLE lesions in patients with active SLE, or recurrence of ACLE during tapering of corticosteroids. As for management of the disease, patient education and a long-term follow-up are necessary. Disease activity, damage of skin and other organs, quality of life, comorbidities and possible adverse events are suggested to be assessed in every follow-up visit, when appropriate.
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Citation Excerpt :
Of the 17 studies investigating thalidomide therapy [60–73,110,111], four non-controlled trials [60–62,111] showed high rates of response (98–100%) in patients with mixed subtypes of CLE [60,62] and DLE [61]. Similarly, high response rates were found in data from observational studies and case series (67–100%) [63–73,110]. However, studies tended to show a high risk of relapse on cessation of treatment [60–63,67,68].
Cutaneous lupus erythematosus (CLE), occurring with or without systemic lupus erythematosus (SLE), is a group of inflammatory skin diseases that can be very debilitating, causing significant psychological distress, and sometimes scarring.
We sought to comprehensively present the evidence for different treatment modalities in patients with cutaneous manifestations of lupus erythematosus (LE).
Medline, Embase, Scopus and Cochrane CENTRAL were searched electronically from 1990 to March 2019, using keywords related to cutaneous lupus and synonyms and treatment. Articles retrieved were screened for relevance, including reference lists of retrieved reviews. We included clinical trials, observational studies or case series with ≥5 patients focussing on treatment of CLE, with or without SLE.
The search identified 6637 studies, of which 107 were included. Each study commonly included a heterogeneous mixture of CLE subtypes, with or without SLE. The 107 included studies investigated 11 different categories of treatment in 7343 patients. Treatments included topical calcineurin inhibitors (13 studies), sun protection (5 studies), R-salbutamol cream (2 studies), antimalarials (22 studies), synthetic DMARDs (10 studies), retinoids (2 studies), thalidomide/lenalidomide (22 studies), biologic therapies (15 studies), intravenous immune globulin (3 studies), laser (6 studies) and other therapies (7 studies). General measures to be considered include smoking cessation, sun protection measures and optimisation of vitamin D levels. Moderate evidence exists for benefit with topical CNIs, particularly as a steroid sparing agent in areas at high risk of steroid complications (e.g. facial skin). There is moderate evidence for hydroxychloroquine, which is first-line in SLE patients, limited evidence to support other synthetic DMARDs, and moderate evidence supporting thalidomide but with significant risk of toxicity. Of biologic therapies, there are moderate data to support belimumab. Limited evidence exists for other therapies.
Many management options are available for CLE, including topical, systemic and biologic therapies, with a variable balance of efficacy and toxicity. There is a paucity of high-quality clinical trial data. Further trials are required to better understand optimal management of CLE, particularly in specific subgroups.
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Clinical research studyThalidomide for the treatment of resistant cutaneous lupus: Efficacy and safety of different therapeutic regimens

Purpose

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

J Am Acad Dermatol

The saga of thalidomideneuropathy to embryopathy, with case reports and congenital abnormalities

N Engl J Med

Thalidomide has 37 year history

JAMA

Thalidomide in the treatment of lepra reactions

Clin Pharmacol Ther

Treatment of rheumatoid arthritisthe thalidomide experience

J Rheumatol

Thalidomide in the treatment of the mucocutaneous lesions of Behcet’s syndromea randomised, double-blind, placebo controlled trial

Ann Intern Med

Marked anti-tumor effect from anti-angiogenesis (AA) therapy with thalidomide (T) in high risk refractory multiple myeloma

Blood

Effects of thalidomide on HIV-associated wasting syndromea randomised, double-blind, placebo-controlled clinical trial

AIDS

Thalidomide for the treatment of chronic graft-versus-host disease

N Engl J Med

Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus

Br J Dermatol

Update on therapy—thalidomide in the treatment of lupus

Lupus

Low-dose thalidomide is an effective second-line treatment in cutaneous lupus erythematosus

J Dermatol Treat

American experience with low-dose thalidomide therapy for severe cutaneous lupus erythematosus

Arch Dermatol

Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus

Arch Dermatol

Thromboembolism in patients on thalidomide for myeloma

Hematology

The 1982 revised criteria for the classification of systemic lupus erythematosus

Arthritis Rheum

Thalidomide in the treatment of the cutaneous manifestations of lupus erythematosusexperience in sixteen consecutive patients

Br J Rheumatol

Clinical research study
Thalidomide for the treatment of resistant cutaneous lupus: Efficacy and safety of different therapeutic regimens