Donald Rudikoff

The treatment of atopic dermatitis with systemic immunosuppressive agents.

Atopic dermatitis (AD) is a chronic, relapsing skin disease that typically occurs in individuals with a personal or family history of atopy ie, hay fever, asthma, or AD itself. Typically beginning in early childhood, the disease affects approximately 7 to 17% of the pediatric population. Although in many cases there is moderation of the disease with increasing age, it may persist into adulthood in up to 60% of patients. AD can be managed in many patients with topical therapies, sometimes supplemented by systemic antibiotics, but some individuals, typically those with widespread disease or recalcitrant local disease that interferes with the quality of life, require more aggressive treatment. Management should embrace measures to control environmental “flare factors” such as house dust mites or in young children, certain foods. In addition, coincident skin infection, emotional distress, xerosis from dry ambient air or excessive bathing, and high temperatures causing sweating-induced exacerbations should be addressed with allergen avoidance, antibiotic therapy, relaxation techniques, bathing and skin hydration, humidification, and air conditioning, respectively. If control of flare factors combined with aggressive topical therapy or phototherapy fail to control symptoms of AD, a number of systemic immunomodulatory agents may play a role in treatment (Table 1). Because these agents have significant side effects, utmost care should be exercised in their use. It is also crucial to realize, particularly when contemplating the use of these agents in children, that none of them is approved for the treatment of AD in the United States. Informed consent, preferably in writing, for off-label use in the treatment of AD, should be obtained. Patients should be given written documentation of possible adverse effects and the treatment regimen should be tailored to each patient to limit overall exposure to the systemic agent. Although an extensive discussion of immunopathogenesis (see Kang et al, this issue) is beyond the scope of this paper, a basic understanding of the role of various immune cells and mechanisms in the causation of AD helps to clarify the rationale for using these agents.

Cutaneous Paecilomyces lilacinus infection: Report of two novel cases

A 56-year-old white man had painful skin lesions on his left leg 10 months after a liver transplant. His medications included prednisone, tacrolimus, azathioprine, trimethoprim-sulfamethoxazole, acyclovir, and granulocyte-macrophage colony-stimulating factor. Examination revealed multiple crusted and violaceous papules, plaques and nodules extending from the dorsal aspect of the left foot to the left knee (Fig. 1). He had a leukocyte count of 2.8 xl03/g 1 and a hematocrit of 27.6%. A biopsy specimen revealed findings consistent with a deep fungal infection. Fungal cultures of bone marrow and blood were negative. The patient received a 2-week course of intravenous amphotericin B with subsequent oral itraconazole, 400 mg daily. About a year later, he was readmitted because of a cellulitis and persistent deep fungal infection of the left leg. The patient was treated with oral itraconazole, but the infection persisted. Lesions extended from the dorsal aspect of the left foot to the left upper thigh. A culture grew P. lilacinus. A biopsy specimen demonstrated granulomatous and suppurative dermatitis. A periodic acid-Schiff stain demonstrated fungal spores and hyphae within the dermal granuloma. Oral itraconazole was stopped and the patient was again given intravenous amphotericin B but experienced no improvement. With

p53 Mutations in Basal Cell Carcinomas Arising in Routine Users of Sunscreens

Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5–9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these pS3 exons. All of the mutations were located at dipyr‐imidine sites, five of the six were C ← T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P= 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53‐independent pathway. Alternatively, solar U V A wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/ or a tumor suppressor gene, other than p53, for these patients.

HIV-Associated Pruritus

With the advent of highly active antiretroviral therapy (HAART), life-threatening opportunistic infection has become less common in patients with HIV infection and longevity has increased dramatically. With increased longevity, the problems of living with a chronic disease have become more prominent in this patient population. Disorders such as fat redistribution and metabolic abnormalities can result from antiviral medications and from HIV disease itself. Pruritus is one of the most common symptoms encountered in patients with HIV.The spectrum of skin diseases in such patients encompasses dermatoses of diverse etiologies; a few are peculiar to patients with HIV while others are not. Some of these conditions may cause severe and sometimes intractable pruritus that provokes scratching, picking, disfigurement, sleep loss, and significant psychological stress. Moreover, the expense of ongoing medical treatments can be daunting. Skin rash can sometimes be the initial presentation of HIV infection or serve as a harbinger of disease progression.Causes of pruritus include skin infections, infestations, papulosquamous disorders, photodermatitis, xerosis, drug reactions, and occasionally lymphoproliferative disorders. Drug eruptions are particularly common in patients who are HIV positive, presumably as a result of immune dysregulation, altered drug metabolism, and polypharmacy. Itching can also result from systemic diseases such as chronic renal failure, liver disease, or systemic lymphoma.Workup of pruritus should include a careful examination of the skin, hair, nails, and mucous membranes to establish a primary dermatologic diagnosis. If no dermatologic cause is found, a systemic cause or medicationrelated etiology should be sought. Idiopathic HIV pruritus is a diagnosis of exclusion and should only be considered when a specific diagnosis cannot be established.The management of HIV-associated pruritus should be directed at the underlying condition. Phototherapy has been found to be useful in the treatment of several HIV-associated dermatoses and idiopathic pruritus as well. Unfortunately, some of the treatments that have been suggested for patients with HIV are anecdotal or based on small uncontrolled studies. The last decade has seen a surge in the utilization of HAART which, to some degree, reconstitutes the immune system and ameliorates some dermatologic diseases. On the other hand, some skin diseases flare temporarily when HAART is started. Unless frank drug allergy is suspected, HAART does not need to be stopped.

A spotlight on smallpox

Naturally occurring smallpox was eradicated in the late 1970s after a carefully organized worldwide public health initiative coordinated by the World Health Organization (WHO). In what might be the most momentous public health achievement of the twentieth century, a virus that had killed more people than any other pathogen in the history of mankind, was relegated to the test tube. Although some authorities have considered it to be an unlikely candidate for a biologic weapon, recent hypothetical scenarios such as the “Dark Winter” exercises have revealed the profound vulnerability of the United States civilian population to smallpox attack.1–3 Moreover, the events of September 11, 2001 and subsequent spread of weaponized anthrax spores through the U.S. Mail have heightened anxiety among civilians and increased concern among public health officials over our lack of preparedness against future acts of bioterrorism. Smallpox is especially worrisome because it is highly contagious via droplet infection, causes a painful and disabling febrile illness, and has a case-fatality rate of up to 30%.4,5 The famous British historian Macaulay referred to it as, “the most terrible of all the ministers of death.” The majority of smallpox survivors were left with disfiguring scars and blindness occurred in up to ten percent of cases. With the eradication of smallpox, routine vaccination of civilians and international travelers was abandoned.6,7 Consequently, the great majority of the U.S. population, even those previously vaccinated, are now considered vulnerable to infection. The loss of widespread immunity in a population, ie, so called “herd immunity”, allows a higher proportion of primary contacts of an infected individual to contract a disease. Each primary contact can then infect a greater percentage of secondary contacts, etc. This permits exponential spread of the disease in a population. Our vulnerability is further heightened by increased population density and mobility and the likelihood of delayed recognition of new index cases by two generations of physicians who have no experience with variola. A recent mathematical model suggested that if 100 individuals in the U.S. population were initially infected, quarantine and vaccination would eventually control the outbreak but there would be 4200 cases and an entire year would be required to stop the outbreak. One can only speculate as to what effect such an outbreak would have on the national psyche, the economy, tourism, etc.8 After the eradication of variola, remaining viral stocks were sequestered at 2 laboratories, one at the U.S. Center for Disease control (CDC) in Atlanta and the other in the former Soviet Union. Although the WHO Committee has advocated destruction of remaining viral stocks, it has been repeatedly postponed so these stocks are still in existence.9 The disquieting possibility that clandestine stockpiles might exist and anecdotal reports that the former Soviet Union probably produced large quantities of smallpox virus are cause for concern.9,10 Dr. Kanatjan Alibekov, former First Deputy Director of Biopreparat, the former Soviet Union’s biologic weapons program, from 1988 to 1992, defected to the U.S. in 1992. He alleges that the former Soviet Union successfully bioengineered a number of biologic weapons including smallpox, plague, anthrax, Venezuelan equine encephalitis, tularemia, brucellosis and was working on several hemorrhagic fevers.11 It has also been proposed that smallpox virus could potentially be genetically altered or recombined with other pathogens such as Ebola to produce even more dangerous bioweapons; as if smallpox itself were not a great enough threat. During the 1991 Gulf War, stocks of camelpox virus, which is very similar to smallpox virus, were discovered in Iraq and allegedly were intended for biologic warfare use.12 Moreover, outbreaks of monkey pox, another orthopox virus, have been reported in Africa with case fatality rates of about 10%. Although humanto-human contagion of this agent is thought to be too limited to sustain significant epidemic spread, genetic manipulation of this virus could conceivably increase its transmissibility.13 A team in Australia recently reported the inadvertent creation of an unusually deadly form of mousepox.14 They had been trying to create a contraceptive vaccine, using a benign mousepox virus to express genes for proteins carried on mouse eggs. To boost the antibody response against these proteins they added the gene for interleukin 4 (IL-4). The augmented IL-4 expression down regulated cell-mediated immuFrom the Department of Dermatology, Mount Sinai School of Medicine, New York, New York. Address all correspondence to: Donald Rudikoff, MD, Box 1048, 1 Gustave L. Levy Place, New York, NY 10029. Email: RNAhybrid@aol.com.

Multiple indurated papules on penis and scrotum.

Background: Sarcoidosis is a chronic disease with involvement of multiple organs. Cutaneous lesions may appear as the only manifestation or may be accompanied by systemic disease. Objective: To learn that genital sarcoidosis is a rare entity that should be included in the differential diagnosis of genital papules and nodules. Methods and Results: A 31-year-old African-American man presented with cutaneous lesions on his penis and scrotum existing for 2 years. The genital lesions were so prominent as to interfere with his sexual life. Sarcoidosis was demonstrated on biopsy. Conclusions: Sarcoid lesions may affect any skin area, but are rarely described on the genitalia. Dermatologists should be aware that genital sarcoidosis is a rare entity that should be included in the differential diagnosis of genital papules and nodules. Additionally, genital sarcoidosis may cause urinary problems and may represent a therapeutic challenge.

Frequency of culture-proven dermatophyte infection in patients with suspected tinea pedis.

Background: This study examined the incidence of culture‐proven tinea pedis in patients who presented with a foot rash clinically suspected to be tinea pedis. Methods: Cultures were taken from 874 patients in 4 dermatology clinics across the country. The incidence of patients with positively cultured tinea pedis was compared with the total number of patients in the study. Results: The surprisingly low percentage of patients correctly diagnosed with tinea pedis was determined to be 32%. The remaining 68% of patients either had a nonfungal foot dermatitis or tinea pedis with false‐negative cultures. Conclusions: This study demonstrates the need for fungal cultures when patients present with scaling feet as well as the importance of a broad differential diagnosis to ensure timely and appropriate therapy.

Color atlas: eczema

Atopic dermatitis is a chronic relapsing skin disorder often presenting in infancy and early childhood and characterized by an age-dependent distribution. Lesions may be acute, subacute, or chronic. The cardinal feature of atopic dermatitis is pruritus, and many of the lesions of atopic dermatitis result from rubbing and scratching persuant to this symptom. Patients with atopic dermatitis have alterations in cutaneous immunity and barrier function that may cause them to be more susceptible to skin infection including viruses, certain bacteria and dermatophytic fungi. Should smallpox vaccination be reinstituted in the U.S., patients with eczema or household contacts of patients with eczema should not be vaccinated because of the risk of eczema vaccinatum.

Cutaneous mucormycosis of the upper extremity: a series of patients and review of the literature

We present our experience with three cases of cutaneous mucormycosis involving the upper extremity. One patient was on long-term steroid therapy for polymyalgia rheumatica and myelodysplastic syndrome. A second patient had an advanced HIV infection. The third patient presented following a renal transplantation for which he was on immunosuppressive therapy.All three patients had wide local excision of the eschar and skin graft as immediate coverage or as a delayed reconstruction. Systemic Amphotericin B treatment was given for varying durations according to the recommendation of the infectious disease service. All skin grafts healed with full resolution of the infectious process, but one patient died of pneumonia.