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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Dermatol. Author manuscript; available in PMC Sep 7, 2009.
Published in final edited form as:
PMCID: PMC2739109
NIHMSID: NIHMS82299

Lenalidomide for the Treatment of Resistant Discoid Lupus Erythematosus

Abstract

Background

Discoid Lupus Erthematosus (DLE) is a chronic, disfiguring disease characterized by scaly, erythematous disk-shaped patches and plaques followed by atrophy, scarring, and dyspigmentation. A small population of patients suffer from disease that is refractory to standard therapies. We investigated the use of lenalidomide, a thalidomide analogue, as a novel alternative therapy on two cases of refractory DLE and report our results.

Observations

Two patients with chronic, severe DLE were treated with low dose lenalidomide. One patient demonstrated improvement within 1 month on 5 mg and was maintained for 10 months before her dose was doubled to 10 mg for 12 months because of a slight worsening of symptoms. Clinical improvement was demonstrated by a sustained reduction in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score with no change in the CLASI damage score. Within five months, the patient was tapered off of oral prednisone 60 mg daily; however, she was restarted and maintained on a low dose of prednisone 5 mg daily for management of SLE symptoms. Of note, the patient experienced mild neutropenia after being on 10 mg. Lenalidomide carries a black box warning of neutropenia, and it is recommended to monitor complete blood cell count (CBC) weekly for the first 2 months and then monthly. The second patient failed to show clinical improvement and lenalidomide was discontinued after six months.

Conclusions

Lenalidomide is a potential alternative or adjunctive treatment for patients with severe, chronic DLE that is refractory to standard therapies. A larger study is needed to clarify its role in the treatment of DLE and other forms of cutaneous lupus.

INTRODUCTION

Discoid Lupus Erythematosus (DLE) is a clinical subtype of cutaneous lupus erythematosus (CLE) that typically presents as scaly, erythematous disk-shaped patches and plaques that are followed by atrophy, scarring, and dyspigmentation (1). These are chronic, disfiguring lesions and are sometimes refractory to treatment. Approximately 25% of cases fail to respond to standard first line systemic therapy with antimalarials (2). Among the alternative systemic therapies, thalidomide is an accepted treatment and has demonstrated clinical efficacy in up to 90% of recalcitrant cases in some studies (3). Its primary efficacy in CLE is thought to be related to suppression of inflammatory mediators, including tumor necrosis factor-alpha (TNF-α), and inhibition of antigen presentation (4,5). Unfortunately, thalidomide is difficult to use chronically because of its notorious side effect profile, including teratogenicity and peripheral neuropathy (6). Given thalidomide’s vast clinical potential to treat inflammatory and neoplastic conditions, efforts have led to the development of a promising thalidomide analogue, lenalidomide (CC-5013 or Revlimid) in the mid 1990s. It is currently FDA-approved for the treatment of multiple myeloma and myelodysplastic syndrome and in clinical trials for the treatment of solid malignancies. Its potent anti-inflammatory and immunomodulatory properties may be via the inhibition of proinflammatory cytokine secretion such as TNF-alpha, T cell co-stimulation, and antiangiogenic activity (7). In comparison to thalidomide, it is a 2000-fold more potent inhibitor of TNF-α (8,9). It has a lower frequency of many of the common side effects of thalidomide (sedation, constipation, neuropathy), and preclinical studies have failed to show teratogenicity or mutagenesis in animals. One of the major adverse effects is myelosuppression (neutropenia, thrombocytopenia) which has led to a black box warning, and may occur at doses (5-10 mg daily) needed for treatment of cutaneous lupus. We initiated treatment at 5 mg daily, observed results for at least 6 weeks and then increased to maximum dose of 10 mg daily, if necessary. An additional known side effect of lenalidomide is increased risk of deep venous thrombosis, and patients should be provided with antimalarials or anticoagulants such as aspirin, which may decrease the risk of such events (10).

Thus, lenalidomide may be a potential alternative therapy for patients with CLE. Herein we describe the treatment of two patients with severe recalcitrant generalized DLE with lenalidomide through a compassionate study. The study was begun prior to marketing of the drug in the US, where the drug is now available with safety monitoring and restrictions similar to its analogue, thalidomide. Two individual treatment INDs based on a detailed treatment protocol were requested from the FDA in addition to IRB approval. Both patients were selected from the patient population under the care of the senior author. The first patient was chosen based on her previous success on thalidomide, which needed to be discontinued due to neuropathy. The second patient was offered the treatment due to the failure of most other treatments, including thalidomide. This was done approximately 6 months into the successful therapy of the first patient. Both patients gave written informed consent to the treatment.

CASE REPORT

Case 1

A 43-year-old African American female presented with a 9-year history of refractory, generalized DLE and 10 year history of SLE with lesions characterized by erythematous and dyspigmented macules and papules, some with erosions and scale, on her face, scalp, back, and bilateral upper and lower extremities. The diagnosis of DLE was confirmed by skin biopsies. The symptoms of her SLE included persistent polyarthritis as well as intermittent fevers, abdominal pain, serositis, and mildly elevated liver function tests (AST/ALT). Baseline laboratory examination demonstrated a positive antinuclear antibody (ANA) (1:320) with a nucleolar and speckled pattern, anti-double stranded DNA antibody, and antiSSA antibody. Over the years, her DLE had failed to respond to several therapies, including topical corticosteroids, antimalarials (hydroxychloroquine, quinacrine, and/or chloroquine), dapsone, methotrexate, mycophenolate mofetil, rituximab, IVIG, azathioprine. Although she had some response to thalidomide, it had to be stopped due to peripheral neuropathy. Her concomitant medications for her DLE/SLE during this compassionate study included hydroxychloroquine, quinacrine, oral prednisone, and neurontin.

She had a good clinical response within 1 month of starting lenalidomide therapy at 5 mg and was maintained at this dose for 10 months. Between month two and five, she was successfully tapered off oral prednisone 60 mg daily; however, she was restarted and maintained on a low dose of prednisone 5 mg daily for intermittent management of her SLE symptoms. At 10 months, her DLE activity increased slightly and her dose was doubled to 10 mg daily; the patient was maintained on this dose for an additional 12 months (Figure 1). At 22 months, her dose was decreased to 5 mg daily due to sustained neutropenia that developed while on 10 mg daily. Of note, the patient had a history of neutropenia and lymphopenia in 2002 prior to use of this drug. Thus, the neutropenia may have been secondary to SLE flares as well as lenalidomide.

Figure 1
CLASI shows a reduction of the CLASI activity score and no change in the CLASI damage score over 22 months. The rapid initial improvement in the CLASI activity score was followed by some worsening of skin disease, although not back to the level seen prior ...

For the 22 months duration on this drug, her clinical response was assessed as partial improvement based on the following measures: physical exam, general impression assessments on a visual analog scale of 0-10 by physician and patient (data not shown), and an objective assessment of therapeutic response using the recently validated scoring system, the “Cutaneous Lupus Erythematosus Disease Area and Severity Index” (CLASI) (11). The CLASI has two separate scores: the “activity” score reflects erythema and scaling while the “damage” score documents scarring and permanent dyspigmentation. There was a sustained reduction in the CLASI activity score with no change in the CLASI damage score (Figure 1). Photography demonstrates the improvement in her skin lesions (Figure 2). Although the study has ended, the patient has continued to have diminished activity of her DLE at this maintenance dose. However, the rapid initial improvement was followed by some worsening of skin disease, although not back to the level seen prior to starting the drug.

Figure 2
A, B: Facial erythema in discoid lupus lesions at baseline.

Pregnancy testing, routine biochemistry tests (complete blood count with differential, comprehensive metabolic panel, liver function tests, urinalysis), and electrocardiograms were performed at regular intervals for safety monitoring and were within normal limits with the exception of neutropenia as noted above and intermittent hypokalemia, which had been present at baseline. Nerve conduction studies were abnormal at baseline but remained unchanged during the study while her thalidomide-induced peripheral neuropathy symptoms resolved while on the study drug. There were no serious adverse events thought to be secondary to the study drug.

Case 2

The second patient was a 40-year old African American female with a 10-year history of severe refractory generalized DLE and SLE. Her lesions were characterized by erythema, scale, dyspigmentation and scarring of her face, scalp, back, and extremities. Baseline laboratory examination demonstrated positive ANA (1:160), anti-double stranded DNA antibody, and low C4. The SLE manifested itself with recurrent flares of pleuritis, arthritis, and nephropathy. Her DLE had failed to respond to several therapies, including antimalarials (hydroxychloroquine, chloroquine, and/or quinacrine), thalidomide, oral prednisone, dapsone, rituximab, methotrexate, azathioprine, and cyclosporine. Her concomitant medications during the study included chloroquine, quinacrine, methotrexate, azathioprine, and oral steroids. She was started on 5 mg of lenalidomide and maintained on that dose for 6 months. She failed to show clinical improvement and experienced adverse events of unclear attribution, which precluded dose escalation. The events included mild leukopenia which was likely related to SLE flares, mildly elevated liver function tests, cellulitis of the leg, and vasculitis. The patient was discontinued from lenalidomide at six months because of a lack of response of her cutaneous LE.

COMMENT

We report the use of lenalidomide as an alternative therapy for discoid lupus erythematosus (DLE) in two African American patients. The partial improvement of one of the patients suggests this may be useful as an alternative or adjunctive systemic therapy for patients with severe recalcitrant DLE with minimal or no systemic involvement, or patients who are not able to tolerate thalidomide. A larger case series or prospective study is needed to further evaluate the clinical effectiveness, biologic activity, and tolerability of this immunomodulator for DLE and other forms of cutaneous lupus erythematosus, which we hope to do in the future.

Acknowledgments

Funding/Support: This study was supported in part by a V.A. Merit Review grant and National Institutes of Health (NIH K24-AR 02207) and Celgene Corporation, who provided the patients with lenalidomide.

Footnotes

Author Contributions: Dr. Werth had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Werth. Acquisition of data: Werth, Bonilla-Martinez, Okawa, Rose. Analysis and interpretation of data: Shah, Albrecht, Bonilla-Martinez, Rosenbach, Werth, Drafting of the manuscript: Shah, Werth, Critical revision of the manuscript for important intellectual content: Albrecht, Bonilla-Martinez, Rosenbach, Statistical analysis: Albrecht, Werth, Obtained funding: Werth, Administrative, technical, or material support: Celgene Corporation. Study supervision: Werth.

Role of the Sponsor: The sponsor had no role in the design and conduct of the study; in the collection, analysis and interpretation of data; or in the preparation, review, or approval of the manuscript.

Financial Disclosure: Dr. Werth serves as a consultant to Celgene Corporation.

All other Financial Relationships: Dr. Werth serves as a consultant to Astion Pharmaceuticals, Centocor, Aegis, and Kemia. Dr Werth has received research funding from TolerRx, Inc. and Celgene Corporation for unrelated projects.

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