Isotretinoin Monitoring Trends: A National Survey of Dermatologists.

BACKGROUND: Isotretinoin is an effective treatment for nodulocystic acne. Outside of required pregnancy testing, laboratory monitoring suggested by the manufacturers is vague. Dermatologists, therefore, monitor a variety of tests with variable frequency. Despite intense monitoring, the majority of patients do not have gross laboratory abnormalities that warrant changes in management.

OBJECTIVE: To survey US dermatologists regarding laboratory monitoring practices while prescribing isotretinoin.

METHODS: An online survey sent via e-mail to members of the American Academy of Dermatology.

RESULTS: 12,396 surveys were sent with a response rate of ~19%. At baseline >60% of responders check a CBC, LFTs, and a lipid panel. 74% check a monthly lipid panel and LFTs, while 57% check a monthly CBC. 75% report stopping isotretinoin when AST or ALT values reach 3 times normal; 89% report stopping at 4 times normal. When triglycerides reach 4 times normal, 72% stop the medication.

CONCLUSIONS: There is no consensus on isotretinoin monitoring tests and frequency, though the majority of dermatologists surveyed monitor a lipid panel and LFTs.

J Drugs Dermatol. 2017;16(6):557-564.

Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR-alpha receptor.

The oral rexinoid bexarotene (Targretin) is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell leukemia/lymphoma (ATLL) that responded rapidly to combination therapy of bexarotene and interferon (IFN)-alpha2b with complete clinical response. We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the retinoid X receptor (RXR) subunits, RXR-alpha and RXR-beta, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-alpha and RXR-beta by resistant cells. We assessed RXR-alpha and RXR-beta expression by Western blot analysis and found that resistant cells had significantly decreased RXR-alpha expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-alpha receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

IL-21 enhances antitumor responses without stimulating proliferation of malignant T cells of patients with Sézary syndrome.

IL-21, a common gamma-chain cytokine secreted by activated CD4+ T cells, influences both humoral and cell-mediated immune responses through the regulation of T, B, dendritic, and natural killer (NK) cells. Sézary syndrome is an advanced form of cutaneous T-cell lymphoma, a clonally derived malignancy of CD4+ T cells that is characterized by profound defects in host cellular immune function. As a modulator of both innate and adaptive immune responses, IL-21 could play an important role in augmenting cell-mediated immunity in these patients. Normal donor and Sézary syndrome patient peripheral blood mononuclear cells were cultured with IL-21 and tested for CD8+ T- and NK-cell activation, NK-cell cytotoxicity, and tumor cell proliferation and apoptosis. IL-21 resulted in a modest increase in CD8+ T- and NK-cell activation, associated with a marked increase in cytolytic activity against both K562 and malignant CD4+ T-cell targets. Although IL-21 failed to demonstrate pro-apoptotic effects on the malignant CD4+ T cells, it is noteworthy that it had no demonstrable proliferative effects on these cells. Thus, IL-21 may play an important role in enhancing the host immune response of Sézary syndrome patients through the increased cytolytic activity of T and NK cells.

Pathophysiology of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (LE; syn LE-specific skin disease) is an autoimmune disease with well-defined skin manifestations often accentuated in a photodistribution and frequently associated with specific autoantibodies. These clinical observations have led to numerous laboratory studies related to the role of ultraviolet light, as well as studies of the cascade of immunologic events involved in the pathogenesis of cutaneous LE. We discuss the epidemiologic, clinical, and laboratory findings of cutaneous LE, including the classification of disease subsets. We review the evidence for abnormal photoreactivity in LE with an overview of the cellular, molecular, and genetic factors that may underlie this abnormality. As there is yet no convincing animal model of cutaneous LE, many studies remain descriptive in nature. To arrive at an understanding of the potential mechanisms underlying the development of cutaneous lupus, we discuss the role of ultraviolet light-mediated induction of apoptosis, antigen presentation, genetic factors, and mediators of inflammation. In addition, we consider the role and importance of humoral and cellular factors, synthesizing the current understanding of the pathophysiology of cutaneous lupus.

Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine.

The malignant cells in Sezary syndrome express the skin trafficking molecules' cutaneous lymphocyte associated antigen (CLA) and chemokine receptor 4 (CCR4). High levels of the CCR4 ligand, thymus, and activation-regulated chemokine (TARC), have been reported in the blood and skin of patients. The rexinoid X-receptor specific retinoid, bexarotene, has contributed to the resolution of cutaneous disease among patients. To evaluate the effects of bexarotene on skin trafficking molecule expression and chemotaxis, peripheral blood mononuclear cells from Sezary syndrome patients and healthy controls were treated with bexarotene in vitro. CCR4 and CLA expression levels and chemotaxis in response to TARC (6.25 ng/ml) were evaluated among lymphocytes before and after treatment with bexarotene (10 microM). Flow cytometric analysis was performed to evaluate CD4, CD26, CLA, and CCR4 cell surface expression. Transwell migration assays were performed to evaluate chemotaxis to TARC. Prior to treatment, malignant cells exhibited higher CCR4 expression (45-90%) and greater than four times more chemotaxis to TARC compared with healthy controls. After treatment with bexarotene for 36-96 hr, a 28% reduction in CCR4 expression was noted (P < 0.05) among the malignant population with an associated 9% decrease in chemotaxis to TARC (P < 0.05). Our results show that bexarotene may inhibit malignant cell trafficking to the skin through an ability to suppress CCR4 expression among Sezary syndrome lymphocytes.

High clinical response rate with multimodality immunomodulatory therapy for Sézary syndrome.

PURPOSE: The goal of this study was to evaluate the clinical response rate of patients with Sézary syndrome (SS) to multimodality immunomodulatory therapy consisting of extracorporeal photopheresis in combination with >/= 2 systemic biologic response modifiers (interferon-, interferon-, retinoids, and/or sargramostim) and psoralen plus UV-A. PATIENTS AND METHODS: Twenty-eight patients who met established criteria for SS were treated with multimodality immunomodulatory therapy at the Hospital of the University of Pennsylvania between January 2000 and December 2002. All patients received > 6 cycles of extracorporeal photopheresis. Patients were categorized into groups based on their response to therapy. RESULTS: An overall clinical response of 89% was achieved with multimodality immunomodulatory therapy. Twenty-nine percent of patients exhibited a complete response, characterized by no evidence of cutaneous disease and a Sézary count 5%. Sixty-one percent exhibited a partial response. Eleven percent were nonresponders. CONCLUSION: Based on our experience, multimodality immunomodulatory therapy is an exceptionally effective treatment for SS. The durability of response and impact on overall survival remains to be determined; however, this approach offers an appealing alternative to treatments associated with higher morbidity rates.

Ultraviolet-B recruits mannose-binding lectin into skin from non-cutaneous sources.

Mannose-binding lectin (MBL) is an integral part of the innate immune system and functions as an opsonin by binding to pathogens and certain apoptotic cells to promote their uptake by phagocytes. We recently identified an association of low-producing MBL polymorphisms with adult dermatomyositis (DM). Our model is that MBL deficiency leads to a defect in the clearance of apoptotic debris in the skin, thereby predisposing to photosensitive autoimmune disease. In this study, we sought to determine whether MBL binds within the epidermis, and to determine its source, and potential function of this binding. We demonstrated that the MBL is present in irradiated, but not in non-irradiated skin, and in irradiated skin it is bound to apoptotic keratinocytes (KC). We found that MBL is not made by KC, showing indirectly that it comes from an exogenous source, despite the fact that other complement components are made by KC and upregulated by ultraviolet irradiation. Finally, we demonstrated that non-KC-derived MBL bound to apoptotic KC in vitro and increased the uptake of these cells by dendritic cells. We hypothesize that MBL may facilitate non-inflammatory clearance of apoptotic debris in patients with photosensitive forms of DM.