Original article
Lenalidomide therapy in treatment-refractory cutaneous lupus erythematosus: Histologic and circulating leukocyte profile and potential risk of a systemic lupus flare

Presented in part at the Society of Investigative Dermatology Montreal, Canada, May 7, 2009 Annual Meeting and American College of Rheumatology Philadelphia, PA, October 20, 2009 Annual Meeting.
https://doi.org/10.1016/j.jaad.2011.01.015Get rights and content

Background

Lenalidomide is a thalidomide analogue that may serve as an adjunctive therapy for treatment-refractory cutaneous lupus erythematosus (CLE).

Objectives

We evaluate the use of lenalidomide in CLE and describe the skin and circulating leukocyte profile of treatment-refractory patients before and after treatment.

Methods

Five subjects were treated with lenalidomide in an unblinded open-label study. Immunohistochemistry of skin was performed for T-cell markers, glycosaminoglycans, and CXCL10, an interferon-inducible chemokine, before and after treatment. Immunophenotyping and measurement of interferon-inducible genes from peripheral blood mononuclear cells was also performed before and after treatment.

Results

Four subjects demonstrated clinical improvement of their skin, however one of these responders subsequently developed symptoms of systemic lupus erythematosus. Small changes in rare circulating leukocyte subsets, plasmacytoid dendritic cells, and regulatory T cells were observed with treatment and may correlate with clinical response. Treatment was associated with increased circulating HLA-DR expression and decreased markers of interferon-mediated pathways, regardless of clinical response.

Limitations

Our results are limited by small sample size and the measurement of rare populations of circulating cell subsets.

Conclusions

Lenalidomide may have usefulness as therapy for severe, treatment-refractory CLE. However, our preliminary data suggest that lenalidomide may activate T cells and trigger systemic disease in some patients with CLE. We also saw a different histologic and circulating leukocyte phenotype in the nonresponding subject. Further characterization of the skin and circulating leukocyte profile of treatment-refractory patients will improve our understanding of CLE.

Section snippets

Patients

Five patients were enrolled according to the following inclusion criteria: (1) DLE or SCLE diagnosis, (2) no response to 3 months of hydroxychloroquine, and (3) participation in RevAssist, a distribution program run by the manufacturers of lenalidomide.26 Patients with SLE (by American College of Rheumatology criteria); who were pregnant; had thrombocytopenia, lymphopenia, or neutropenia; or a history of deep venous thrombosis or pulmonary embolism were excluded. Informed consent was obtained.

Results

We present the clinical response to lenalidomide in 5 subjects and describe the histologic features and circulating leukocyte profile before and after treatment. Expression levels of IFN-inducible genes in blood before and after treatment are shown as a measure of systemic IFN-mediated signaling.

Discussion

Four of 5 patients with treatment-refractory CLE had a clinically satisfactory response to lenalidomide. Two of the responders (subjects 1 and 3) and the nonresponder previously failed thalidomide therapy. Lesional biopsy specimens showed histologic features of CLE including CD3+ infiltrate and GAG accumulation. Two subjects had a CD4 predominant infiltrate, in keeping with prior reports.9, 10 Recent investigation suggests CD4 predominance better characterizes SCLE and TLE, whereas CD8

References (38)

  • V. Kotla et al.

    Mechanism of action of lenalidomide in hematological malignancies

    J Hematol Oncol

    (2009)
  • S. Meller et al.

    Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus

    Arthritis Rheum

    (2005)
  • J. Wenzel et al.

    Enhanced type I interferon signaling promotes Th1-biased inflammation in cutaneous lupus erythematosus

    J Pathol

    (2005)
  • J. Wenzel et al.

    The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets

    Br J Dermatol

    (2007)
  • J. Flier et al.

    Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation

    J Pathol

    (2001)
  • B. Tebbe et al.

    Immunohistochemical analysis of chronic discoid and subacute cutaneous lupus erythematosus–relation to immunopathological mechanisms

    Br J Dermatol

    (1995)
  • J. Wenzel et al.

    Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA

    Br J Dermatol

    (2005)
  • C.M. Magro et al.

    Cutaneous lymphocyte antigen expression in benign and neoplastic cutaneous B- and T-cell lymphoid infiltrates

    J Cutan Pathol

    (2008)
  • B. Franz et al.

    Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

    Arthritis Rheum

    (2007)
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    Supported in part by the Alliance for Lupus Research, a Merit Review Grant from the Department of Veterans Affairs Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, and by the National Institutes of Health (K24-AR 02207) to Dr Werth. Celgene Corporation provided the drug free of charge.

    Conflicts of interest: None declared.

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