Stephen E. Wolverton

Important Controversies Associated with Isotretinoin Therapy for Acne

Isotretinoin is a remarkably effective drug for severe, recalcitrant acne vulgaris. Soon after the drug’s release in the early 1980s, a number of important adverse effects were reported subsequently leading to a variety of medical and medicolegal controversies. Three of these controversies will be highlighted concerning the putative role of isotretinoin in (1) depression and suicide, (2) inflammatory bowel disease, and (3) iPledge and pregnancy prevention programs. It appears that a very small subset of patients receiving isotretinoin for acne are at risk for depression, which is very manageable provided there is adequate patient awareness of the possibility, maximum communication between the patient and physician, and cessation of therapy if clinically important depression occurs (after which the depression rapidly resolves in a week or less). Multiple controlled studies actually suggest a very favorable effect of isotretinoin on depression and anxiety common in the population requiring isotretinoin. With regard to inflammatory bowel disease, in just one study, only ulcerative colitis association with isotretinoin reached statistical significance. The actual incidence of this association is strikingly low. Finally, it is clear that even the most recent pregnancy prevention program (iPledge) is no more successful than prior programs; there will likely always be a small number of female patients becoming pregnant while receiving isotretinoin for acne vulgaris.

The Muir-Torre syndrome in a black patient with AIDS: Histopathology and molecular genetic studies

In 1981, a black man had adenocarcinoma of the colon. In 1986, he had a sebaceous adenoma and the diagnosis of the Muir‐Torre syndrome was established. The patient was found to be HIV seropositive in 1986, and 8 years later fulfilled the CDC criteria for AIDS. During 1989 to 1993 the CD4 count was >200 cells/ml and the patient had 2 sebaceous tumors, 1 basal cell carcinoma and 1 keratoacanthoma. In 1994 to 1996, the CD4 count was <200 cells/ml and the patient developed 18 sebaceous tumors and a poorly differentiated adenocarcinoma of the finger which metastasized to axillary lymph nodes. Microsatellite analysis of tumor DNA from a sebaceous adenoma and adenocarcinoma of the finger revealed widespread microsatellite instability. The interaction of AIDS with the behavior of the tumors in the Muir‐Torre syndrome has not previously been reported. Although our patient had an increase in the number of new sebaceous tumors at the same time he experienced deterioration of the immune system, he is doing well 15 years after resection of adenocarcinoma of the colon and 16 months after metastatic poorly differentiated adenocarcinoma of the skin. This follows the previously observed tendency for cancers of the Muir‐Torre syndrome, especially those displaying widespread microsatellite instability, to be less lethal than their histologically similar counterparts in people without Muir‐Torre syndrome.

Immunosuppression and sebaceous tumors: A confirmed diagnosis of Muir-Torre syndrome unmasked by immunosuppressive therapy

Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis caused by mutations in the DNA mismatch repair genes MLH1 and MSH2. This case describes a patient with an extensive family history of colon cancer who experienced the onset of multiple sebaceous adenomas and carcinomas after undergoing kidney transplantation and receiving immunosuppressive therapy. The finding of deficient MSH2 expression in the immunohistochemical analysis of a sebaceous carcinoma prompted genetic testing for a systemic mutation in the mismatch repair gene. A systemic mutation of the MSH2 gene was detected and, despite the absence of a visceral malignancy, the diagnosis of MTS was made. Immunosuppression has previously been thought to play a possible role in unmasking a latent MTS phenotype in transplant recipients, but systemic mutations have not previously been analyzed. The relationship between immunosuppression and sebaceous tumors with the possibility of unmasking a MTS phenotype in transplant recipients is discussed.

Major adverse effects from systemic drugs: Defining the risks

This review covers the most important adverse effects from systemic drugs prescribed by dermatologists. The emphasis is on major adverse effects from these drugs that are either life-threatening or more commonly may lead to significant, irreversible morbidity. In descending order of relative risk for a fatal outcome or persistent morbidity, the major adverse effects discussed are dapsone agranulocytosis, methotrexate pancytopenia, retinoid teratogenicity, corticosteroid osteonecrosis, immunosuppression carcinogenesis, methotrexate hepatotoxicity, cyclosporine nephrotoxicity, azathioprine agranulocytosis and pancytopenia, corticosteroid osteoporosis, retinoid bone toxicity, corticosteroid hypothalamic—pituitary—adrenal axis suppression, and corticosteroid growth suppression. The great majority of these adverse effects are preventable, are diagnosable at an early, reversible stage, or can be readily managed should the complication occur. Furthermore, after carefully reviewing reports on the occasional fatal outcomes from the adverse effects discussed in this review, I believe virtually all deaths could have been prevented with careful attention to definable risk factors and with proper monitoring measures. Overall, the goal of this review is to bring clinicians to a proper level of concern regarding the risks from these drugs, while allowing safe use of potentially risky systemic drugs to the benefit of patients with serious and important skin conditions.

Can short courses of systemic corticosteroids truly cause osteonecrosis

One of the most feared complications of long‐term corticosteroid therapy is osteonecrosis (avascular necrosis, aseptic necrosis). There is, no doubt, a causal role for systemic corticosteroids inducing osteonecrosis with such chronic therapy. The controversy involves whether short‐term (<1 month) courses of systemic corticosteroids can truly induce osteonecrosis. This article presents both the biologic basis and statistical support for why such short‐term courses of systemic corticosteroids rarely, if ever, truly induce osteonecrosis. Data from two very large populations (renal transplantation and systemic lupus erythematosus) with overall increased risk for osteonecrosis are carefully examined in view of the aforementioned controversy.

Medical Malpractice in Dermatology-Part I: Reducing the Risks of a Lawsuit.

Malpractice risk is a common source of concern for the practicing physician. Dermatologists experience fewer lawsuits than most other specialists in medicine, but the risk is not negligible. All physicians should familiarize themselves with areas of potential risk and avoid medico-legal pitfalls. We present Part I of a two-part series addressing medico-legal questions common to most practitioners that cause a great deal of anxiety. Part I will focus upon risk management and prevention of future malpractice lawsuits, and Part II deals with suggestions and guidance once a lawsuit occurs. Herein, we discuss the primary sources of malpractice lawsuits delivered against healthcare practitioners including issues with informed consent, patient noncompliance, medical negligence, and inappropriate documentation, including use of electronic medical records. The overall goal is to effectively avoid these common sources of litigation. The risk management strategies discussed in this paper are relevant to the everyday practitioner and may offer physicians some degree of protection from potential liability.

Drug-Induced Acneiform Eruptions

Acne vulgaris is a polymorphic inflammatory skin disease, clinically characterized by mixture of comedones, superficial and deep inflamed papules, pustules, and nodules. It is a chronic inflammation of the pilosebaceous unit. Acneiform drug eruptions are a monomorphic inflammatory skin disease lacking comedones with lesions typically in the same stage. This type of drug eruption has an abrupt onset and is often associated with various medications (Table 54.1). The pathogenesis of acneiform drug eruptions is poorly understood; documented evidence when available will be presented under the specific drug categories in this chapter.

Traditional immune-modulating drugs

The subject of traditional immune modulating drugs is potentially vast. However, only a small number of these drugs are commonly used by dermatologists. This chapter addresses the key mechanisms of how the majority of inflammatory skin diseases are treated, and discusses six systemic drugs from four drugs groups: (1) calcineurin inhibitors: cyclosporine; (2) antimetabolites/purine analogues: azathioprine and mycophenolate mofetil; (3) antimetabolites/folate antagonists: methotrexate and dapsone; (4) alkylating agents: cyclophosphamide; and (5) lysosomotropic agents: hydroxychloroquine. This classification scheme is a reasonable way to categorize the drugs, although it should be noted that several of these drugs have additional mechanisms of action that differ from the above categories. Furthermore, it is not realistic to discuss all available immune-modulating drugs; several notable drug groups not covered in this chapter include retinoids and interferons.