Sirolimus: a therapeutic advance for dermatologic disease.

Sirolimus, also known as rapamycin (SRL, Rapamune®), was approved in 1999 by the US Food and Drug Administration to prevent graft rejection in renal transplantation. As a member of the mammalian target of rapamycin (mTOR) inhibitor class, its potent immunosuppressant, anti-angiogenic and anti-proliferative properties are well recognized. When compared to other immunosuppressants, SRL has a lower risk of renal, neurologic and lymphoproliferative complications. It has become a promising treatment modality for angiofibromas, Kaposi's sarcoma and other inflammatory and malignant disorders of the skin. With the recent discovery that mTOR inhibitors extend the lifespan of mice, sirolimus and other rapamycin analogs (rapalogs) are emerging as therapeutic targets for the treatment and prevention of age-related diseases.

Systemic retinoids: chemoprevention of skin cancer in transplant recipients.

Solid organ transplant recipients (OTRs) have an increased incidence of skin cancer, resulting in significant morbidity and mortality post-transplantation. Chemoprevention strategies are focused on reducing and delaying the development of skin cancer in these patients. Although systemic retinoids are widely used in OTRs, few randomized controlled trials have been performed. Limited data suggest that acitretin may have a beneficial role in high-risk OTRs. Since rebound flares occur upon discontinuation of retinoids, chemoprevention should be viewed as a lifelong therapy. Further studies are required to establish the efficacy and long-term safety of systemic retinoids as chemopreventive agents for high-risk transplant recipients.

Advances in pemphigus therapy.

The pemphigus variants represent a group of potentially life-threatening autoimmune mucocutaneous blistering diseases. Though systemic corticosteroids have dramatically reduced the rate of disease mortality, current therapeutic options are limited by their toxicity profiles. Advancements in our understanding of the molecular mechanisms involved in the pathogenesis of pemphigus have translated into the development of novel therapies. However, few treatments have been subject to randomized controlled trials to firmly establish therapeutic efficacy. Herein, we focus on the new and emerging therapies in the management of pemphigus.

Rituximab: a B-cell depletion therapy for dermatologic disease.

Rituximab (Rituxan, Genentech/ Biogen Idec) is a genetically engineered chimeric murine/human monoclonal antibody directed against CD20, a B lymphocyte-specific antigen. Initially approved for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL), rituximab has been increasingly used to treat a variety of immune-mediated and autoimmune diseases. While anecdotal case reports recommend its "off-label" use in dermatology, randomized clinical trials are required to firmly establish the safety and efficacy of this emerging biologic therapy.

Mycophenolate mofetil: a dermatologic perspective.

Introduced in the 1970s as a treatment for psoriasis, mycophenolic acid has since been reformulated as mycophenolate mofetil (MMF). With an improved side-effect profile and enhanced bioavailability, MMF is a promising drug for immune-mediated skin disease. Currently approved for the prevention of organ rejection, its list of "off-label" dermatologic indications continues to grow. As a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), MMF inhibits de novo purine synthesis. Its relative lack of hepatonephrotoxicity and seemingly low risk of carcinogenicity offer important therapeutic advantages. While case reports and case series dominate the dermatologic literature, preliminary results are sufficiently promising to warrant larger, randomized clinical trials with this emerging therapy.

Intravenous immunoglobulin: use in dermatology.

A manufactured blood product derived from fractionated human plasma, intravenous immunoglobulin (i.v.Ig) contains supra-physiologic levels of IgG. i.v.Ig is currently used in the treatment of immunodeficiency syndromes, inflammatory disorders and infections diseases. Uncontrolled clinical studies and anecdotal case reports recommend its use in dermatology, but randomized clinical trials are lacking. In selecting the most appropriate i.v.Ig for the patient, convenience, efficacy, safety and tolerability of the different products should be considered. With several measures in place to ensure its safety, i.v.Ig offers new hope for the treatment of many severe dermatologic conditions.

Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case.

The risk of azathioprine-induced myelosuppression can be predicted by detecting patients with intermediate or low thiopurine methyltransferase (TPMT) activity. Population studies have shown that 89% of whites have high TPMT activity, 11% have intermediate TPMT activity, and 0.3% have low TPMT activity. Three specific mutations in the TPMT gene that cause decreased TPMT activity have recently been identified. Patients homozygous for the TPMT mutations have low TPMT activity, and patients heterozygous for TPMT mutations have intermediate TPMT activity. This has led to the development of a technique for TPMT genotype analysis that will identify patients at risk of azathioprine-induced myelosuppression. We report a case of a patient with bullous pemphigoid who experienced azathioprine-induced myelosuppression and who was later found to be homozygous for TPMT mutant alleles. Using the cost of treatment required for this patient and the estimated population prevalence of TPMT mutations, we examined the cost impact of screening for TPMT mutations in all patients being considered for azathioprine therapy. We calculated that screening is cost-neutral assuming patients homozygous for TPMT mutations experience myelosuppression, and that it is cost-beneficial assuming patients heterozygous for TPMT mutations also experience myelosuppression while receiving azathioprine. Screening patients for TPMT mutations will reduce the risk of azathioprine-induced myelosuppression, and our study suggests that it may also be a cost-attractive strategy.