Vorinostat for the Treatment of Bullous Pemphigoid in the Setting of Advanced, Refractory Cutaneous T-Cell Lymphoma

Abstract

Histone deacetylase (HDAC) inhibitors represent a novel class of medication that is being targeted for use in the treatment of cancer. A member of this class, vorinostat, has recently been approved for the therapy of cutaneous T-cell lymphoma. Importantly, emerging data from animal studies have indicated that HDAC inhibitors may have the capacity to potently suppress the development of autoimmune disease. In this report, we describe a patient with advanced cutaneous T-cell lymphoma who developed refractory bullous pemphigoid (BP) and then experienced the rapid resolution of the BP following initiation of treatment with vorinostat. This observation may be broadly applicable to the treatment of other autoimmune skin diseases. REPORT OF A CASEOur patient, a 59-year-old woman, was diagnosed in 1996 as having mycosis fungoides/cutaneous T-cell lymphoma (MF/CTCL), stage IB, with a medical history of varicella zoster, gastritis, and osteopenia. She also had a history of sulfa allergy. Despite multiple treatments including psoralen-UV-A phototherapy, topical chemotherapy, topical corticosteroids, oral bexarotene, chemotherapy, autologous stem cell transplant, denileukin diftitox, and interferon gamma, she experienced disease progression to stage IVA with skin tumors, nodal involvement with large cell transformation, and peripheral blood involvement (6% CD4 ϩ CD7 − cells and a discrete population of 38% CD4 ϩ CD26 − cells). She subsequently underwent total skin electron beam radiation (TSEB) therapy and started treatment with extracorporeal photopheresis (ECP) in conjunction with interferon gamma.Three months later, she was admitted to the Hospital of the University of Pennsylvania, Philadelphia, with a 2-month history of progressive skin pain, itching, blisters on her buttocks and feet, oral and vaginal erosions, odynophagia, and lower extremity edema for which she was prescribed furosemide at an outside hospital. Initially, the concern was for radiation dermatitis vs disseminated herpetic infection. Despite aggressive skin care, pain control, and negative results from tests for herpes simplex and varicella zoster virus, her skin condition progressed to erythroderma, erosions, and tense bullae over her arms, abdomen, chest, back, legs, and mouth (sparing the eyes), raising the possibility of Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) or bullous drug hypersensitivity reaction. However, findings from multiple skin biopsy specimens were inconclusive for TEN. Hematoxylin-eosin staining demonstrated a subepidermal blistering disorder; although findings were consistent with BP, other diagnoses could not be completely ruled out based on histologic results at that time, including radiation recall dermatitis, drug-induced blistering reaction, and erythema multiforme. The inflammatory infiltrate was especially sparse in biopsied bulla, suggesting that the CTCL was not playing a role in the bullous process. Direct immunofluorescence at that time was inconclusive, although repeated biopsies of specimens of both skin a...

The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T‐cell lymphoma patients

“…Furthermore, HDACis have been shown to downregulate proinflammatory cytokines in mouse models of autoimmune diseases such as, arthritis, asthma, colitis, graft versus host disease, and systemic lupus erythematosus [29, 30, 49–53]. Similar effects have been observed in humans and we previously reported the resolution of the autoimmune blistering disease bullous pemphigoid in a CTCL patient treated with an HDACi [28]. There are also case reports associating the reactivation of latent herpes viruses with HDACi treatment suggesting that HDACis suppress antiviral immunity [25, 26].…”

“…In vitro experiments have also shown that HDACis enhance human regulatory T‐cell (Treg) suppressive function and increase the proportion of CTLA4 hi Tregs in suppression assays [27]. Consistent with these findings, HDACis have shown therapeutic benefit in animal models of autoimmune diseases and we previously reported the rapid resolution of an autoimmune blistering disorder in a CTCL patient treated with the HDACi vorinostat [28–32].…”

Mycosis fungoides bullosa associated with bullous pemphigoid

“…studied the incidence of internal malignancy in 1113 cases of BP in Japan, they did not observe an association between BP and MF. Thus far, only three reports describe the association of MF with BP and report the treatment of blistering skin lesions of BP that developed after MF with a regimen including ultraviolet phototherapy . To our knowledge, this is the first case of MF bullosa with the occurrence of BP.…”

Cleavage Isn't Everything

“…Vorinostat has been effective in treating the autoimmune blistering disease bullous pemphigoid. 22 There is also anecdotal support for the use of nicotinamide, either topical or oral, as an adjunctive therapy for pemphigus. [23][24][25] Future studies may further delineate the specific protein targets of the different histone deacetylase inhibitors, leading to more effective and potentially safer therapies for these life-threatening skin diseases.…”