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American Academy of Dermatology 2015
At the American Academy of Dermatology’s 73rd Annual Meeting in San Francisco from March 20 to 24, 2015, more than 18,500 visitors from 99 countries attended nearly 400 presentations by more than 900 speakers from around the world. The meeting showcased the latest information and research on the diagnosis and treatment of hair, skin, and nail conditions.
Eczema Treatment: Beyond Topical Therapy
In the relatively near future, said Dr. Siegfried, there’s hope that children with severe atopic dermatitis (AD) may have new, more targeted treatment options. Recently, the Food and Drug Administration (FDA) recognized the importance of including children in clinical trials. “Because the adult pipeline is so robust, that paves the way to have more data in children,” she said.
Among more than two dozen topical, enteral, and parenteral candidates in development for eczema worldwide, the closest to FDA approval are the following, both in phase 3 testing:
- Dupilumab (Regeneron)—a subcutaneously administered interleukin (IL)-4 and IL-13 inhibitor for adult eczema
- AN2728 (Anacor)—a topical phosphodiesterase 4 inhibitor being studied in children older than 2 years of age
Dr. Siegfried said corticosteroids are the only drug class approved by the FDA for systemic use in children with eczema—not because high-level data support use, but because prednisone has been available and widely used since 1955. Despite corticosteroids’ FDA approval for childhood eczema, “published guidelines actually advise against this treatment.” 1 The lack of approved systemic options for children with severe eczema is unfortunate, she said, because systemic treatment of appropriate cases may improve patient adherence and outcomes.
The severity of a child’s eczema may exceed the benefits of topical therapy alone for many reasons. “One is the need for an excessive amount of topical medication,” she said. Due to a lack of randomized, controlled trials in children, “We don’t have a good definition of what’s too much or too long, especially with regard to moderate-to-high-potency topical corticosteroids. The only simple biomarker of excessive exposure to topical corticosteroids is morning serum cortisol, to screen for adrenal suppression.”
Dr. Siegfried considers systemic therapy in children who require long-term mid-to-high-potency topical corticosteroids: more than 15 days a month, and more than 60 g a month.
Optimizing topical treatment requires more education, understanding, time, and effort than some parents can manage, while children “dislike the texture of the medications or can’t tolerate burning or stinging. So in many ways, adherence to systemic treatment is easier,” she added.
As an alternative to corticosteroids, she said, abundant pediatric and adult safety data support use of methotrexate. “Methotrexate has been used for decades to treat children with cancer, intravenously at doses 300 times what we use for AD.” Methotrexate is also inexpensive and easy to use and monitor, she noted. Other systemic drugs used for pediatric AD—cyclosporine, azathioprine, and mycophenolate mofetil—are more immunosuppressive, said Dr. Siegfried, while methotrexate is an immunomodulator.
The methotrexate label includes 12 boxed warnings. However, she said, most involve risks associated with high doses used in cancer or when used in combination with other immunosuppressants. “I haven’t seen any significant adverse effects in well over 100 children I treated for up to five years,” she said. Available for more than 60 years, methotrexate has been widely used for long-term management of a variety of conditions in adults and children.
Dr. Siegfried generally starts with a dose of 0.5 mg/kg weekly, a bit higher than the dose used in published skin-disease studies. “After 12 weeks, about 60% of children respond very well. In the 40% who don’t, I’ll check a methotrexate polyglutamate level and raise the dose or try subcutaneous administration.”
She avoids daily long-term use of cyclosporine, which tastes terrible, must be given two or three times daily, and can cause nephrotoxicity. “But it’s very effective in the short term for patients with severe flares.” Hospitalization in a coordinated multispecialty program of the type Dr. Siegfried has implemented works equally well, she said.
While some children achieve long-term control with methotrexate, others—whose AD has been complicated by allergic contact dermatitis to complex topical products—benefit from switching to less allergenic topicals. Patients with microbial triggers—primary immune deficiency or persistent infections—require antimicrobial treatment. Laboratory evidence of immune deficiency may make them candidates for intravenous immunoglobulin (IVIG) or interferon gamma.
Infantile Hemangiomas May Require Early Care
For infantile hemangiomas (IH), Dr. Cohen said, oral propranolol (Hemangeol, Pierre Fabre Pharmaceuticals) has prompted the fastest standard-of-care change in pediatric dermatology in the last three or four decades. Early recognition of the condition helps children avoid potentially serious complications.
“For the first 25 years of my career, the standard of care for complex infantile hemangiomas was oral steroids,” which he generally avoids in young children. “But if a patient had an IH that was obstructing the airway, bleeding, ulcerated, or interfering with vision or hearing, we used relatively high doses of oral steroids, commonly for four to six months.”
Soon after the first publication about oral propranolol for IH appeared in 2008,2 Dr. Cohen said, many pediatric dermatologists—who are usually slow to adopt new treatments because of safety concerns—began embracing it. As a result, propranolol “has revolutionized the way we approach these lesions. And it’s quite safe compared to high-dose oral steroids.”
In the last three years, Dr. Cohen and two colleagues have treated approximately 1,000 children with the medication. One big problem is getting to children early in the disease course. At birth, a child might have a red streak or patch that clinicians mistake for a vascular malformation. But IH can activate quickly and grow extensively in weeks. A good history and frequent re-examination for new, growing, or changing lesions are important.
Uncomplicated focal (round or oval) IH often resolves without treatment, Dr. Cohen said. However, larger segmental hemangiomas—with irregular patterns that generally follow lines of embryonic development—are more likely to cause complications ranging from functional impairment to severe disfigurement. Hemangiomas of the head and neck may be associated with vascular anomalies of the brain or eye. Hemangiomas on the lower face, neck, and upper chest may signal anomalies of the heart and major blood vessels. When a complex segmental hemangioma involves the face, scalp, or upper chest, the child may have posterior fossa defects, segmental hemangioma, arterial abnormalities, cardiac abnormalities, eye abnormalities, and sternal defects (PHACES) syndrome.
“Evaluating these children early—sometimes in the first few weeks of life—is critical. It appears we can avoid many of the complications that may be associated with these more complex hemangiomas if we see and evaluate them early,” he said.
Some evidence indicates that propranolol’s mechanism of action in IH may involve shutting down vascular endothelial growth factor. “It’s amazing—sometimes with the first dose, you’ll see a visible change as the hemangioma turns gray and flattens slightly,” Dr. Cohen said. Treatment lasts six to nine months, on average, and can resume if the hemangioma recurs.
The most common side effects Dr. Cohen sees are sleep disturbances, diarrhea, and constipation. To minimize them, his clinic decreases FDA-recommended doses of 3 mg/kg per day to 2 mg/kg per day (still divided into two doses). Along with systemic therapy, his clinic often uses pulsed-dye and neodymium-doped yttrium aluminium garnet laser treatments for vascular changes that remain after propranolol treatment.
Vaccines Need Careful Attention
In the last decade, Dr. Mutizwa said, vaccines have become more relevant in dermatology because some have dermatologic indications and because dermatologists are using more immunosuppressive medications to treat inflammatory skin disease.
Ignoring vaccine guidelines can carry serious consequences. “Dermatologists should be taking primary responsibility for educating their patients about vaccines with skin-related indications,” he said, but many dermatologists don’t know what they should tell patients. “So we need to educate providers much better, and subsequently to disseminate that information to our patients effectively.”
For instance, dermatologists should do a better job telling patients who should receive the human papillomavirus (HPV) and herpes zoster vaccines. Dermatologists should consider offering these vaccinations themselves. Only 20% of U.S. patients for whom the herpes zoster vaccine is recommended (mainly adults older than 60 years of age) have received it.
A new HPV vaccine (Gardasil 9, Merck) protects against nine HPV strains that cause 90% of HPV-related cancers, versus about 70% cancer protection with the previously available quadrivalent vaccine. In people with known HPV disease, data suggest it’s still worthwhile to undergo HPV vaccination, which may protect them against further disease that could occur if they encounter additional HPV strains the vaccine covers.3
Dr. Mutizwa said dermatologists can cause harm by not providing age-appropriate vaccines before delivering immunosuppressive medications, and by not informing patients about restrictions—particularly for live vaccines—after they’re on immunosuppression. “Taking more than 20 mg daily of prednisone for more than two weeks is a contraindication for live vaccines,” he added. “That needs to be a standard part of our consent process when we’re putting patients on systemic steroids.”
Live vaccines also are contraindicated in patients taking tumor necrosis factor (TNF) blockers for psoriasis and other conditions, he said. “If you know someone is going to go on a TNF agent, you can vaccinate them two to four weeks prior to starting the TNF agent.” If such a patient needs a live vaccine while on immunosuppression, to maximize safety he suggested waiting until the patient has been off the drug for one to three months, depending on the medication’s half-life, before vaccinating.
Dermatologists increasingly use rituximab to treat pemphigus vulgaris, Dr. Mutizwa said. “Because rituximab reduces the body’s capability of generating new antibodies, do not give either live or inactivated vaccines while patients are on rituximab.” In general, providers should wait at least six months after treatment, and four weeks before the next dose, if they’re going to vaccinate a patient receiving rituximab.
With cyclosporine, cyclophosphamide, and mycophenolate mofetil, Dr. Mutizwa said, patients shouldn’t receive live vaccinations at any dose. However, per current guidelines, providers can consider giving the zoster vaccine to patients receiving methotrexate doses of less than 0.4 mg/kg weekly or azathioprine doses of less than 3 mg/kg daily.4
Avoid the measles-mumps-rubella (MMR) and varicella vaccines for a year after IVIG therapy, he advised. IVIG consists of pooled immunoglobulins from the general population. “The high levels of neutralizing antibodies to both MMR and varicella present in the general population would mean patients receiving these vaccines after a recent IVIG infusion would likely have a suboptimal protective immunologic response.”
Patients with HIV can receive any inactivated vaccine that’s indicated at any time. For patients with very low CD4 counts, consider revaccination once CD4 counts rise to 200 to 500 cells/mm3. Additionally, he said, live vaccines should not be given to HIV patients with CD4 counts of less than 200 cells/mm3. Patients with higher CD4 counts should get the MMR and varicella vaccines if they don’t have prior immunity.
- Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol 2014;71(2):327–349.
- Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358(24):2649–2651.
- Joura EA, Garland SM, Paavonen J, et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012;344:e1401.
- Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58(3):e44–e100.