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NEW YORK -- Of all the things the skin does each day -- protecting the vital organs, muscles and skeleton, and controlling body temperature and fluids -- one of its most important functions is the ability to defend the body against viruses that can cause illness. In the past, treatment options were not advanced enough to use the skin's own immunity to assist in the resolution of both common and life-threatening conditions. However, recent understanding of the immunity of the skin has resulted in the development of treatments that use the body's immune system to fight illness and resolve common conditions, including many dermatologic skin conditions.
Speaking today at the American Academy of Dermatology's (AAD) Derm Update 2003, dermatologist Brian Berman, MD, PhD, professor of dermatology and internal medicine at the University of Miami School of Medicine in Miami, discussed the new agents that dermatologists are using to boost the skin's own immunity to safely and effectively treat some skin conditions.
"The benefit of these new therapies is that they use the body's own defenses to successfully control and potentially cure some of the most common skin conditions -- conditions that can be both physically and psychologically disruptive to patient's lives," said Berman. "These therapies can be used in two unique ways: to optimize and enhance the skin's immunity to resolve viral infections and skin cancers, or to control abnormally excessive immunity reactions that are common in skin conditions, such as psoriasis and atopic dermatitis."
One class of these topical agents is Immune Response Modifiers (IRMs), which enhance the skin's ability to identify and control, or destroy, infections, bacteria and other foreign objects in the body responsible for illness. IRMs work by stimulating cytokine production in the skin. Cytokines are naturally occurring proteins that are used by immune system cells to communicate with each other. When cytokines are stimulated by IRMs, they enhance cell immunity, a natural process to help the body control or eliminate virus-infected and tumor cells. Because IRMs assist the immune system as a whole -- rather than target specific viruses or tumors -- they have potential use in the treatment of a wide variety of dermatologic diseases.
One IRM -- imiquimod -- was approved by the Food and Drug Administration (FDA) for the treatment of genital warts caused by human papillomavirus (HPV) infections. Although they usually do not hurt or itch, genital warts can be unsightly and embarrassing, and are associated with the development of genital cancers. While current treatments involve destroying the visible warts by freezing, burning, or applying acids, the problem can recur after these treatments because the virus that causes the warts can persist in the skin.
The use of imiquimod prompts the body to fight off the virus that causes genital warts. In fact, a recent study showed that the use of imiquimod, in a 5 percent cream, increased the levels of cytokines in the skin enhancing the antiviral state. Over half of patients who applied imiquimod three times a week for up to 16 weeks completely cleared their genital warts.
"Before the approval of imiquimod, the only patients whose genital wart infections were truly cured were those whose immune system recognized and eliminated the virus. However, this was not a common occurrence," stated Berman. "This new treatment can assist many more patients by boosting the body's immunity to destroy this virus, reduce the need for surgery and destructive ablations."
Another potential use for IRMs is to treat keloids, the excessive scars that result from alteration in the normal wound healing process following skin injury, including surgery. These scars can occur in any individual but are most common in people with darker skin. Keloids form when alterations occur in the normal control of skin fibroblast cell function, which are the cells that make the structural fibers of the connective tissues in the skin. One of the naturally occurring immunomodulators, or anti-inflammatory agents, in the skin is interfreron which can normalize the skin's wound-healing function. The use of imiquimod has been shown to induce the production of interfreron to prevent the keloid from returning following surgery.
"These disfiguring scars are tender, can cause pain and burning, and can be psychologically challenging for the individuals affected by them," said Berman. "Current treatment involves removing the scars surgically, which more often than not causes the scars to recur, often larger than the original keloid removed. The use of IRMs to prevent keloids offers hope to those individuals who struggle with these scars."
IRMs also show promise for the treatment of skin cancer and actinic keratoses, the precursor to a form of skin cancer. Basal cell carcinoma (BCC) is the most common form of skin cancer, accounting for more than 80 percent of all skin cancers each year. If detected and treated early, BCC has a 95 percent cure rate. However, if left untreated, it can grow into nearby areas and invade the bones making successful treatment more difficult. Current treatment methods for BCC include invasive surgical removal and destruction.
However, a recent study of the IRM imiquimod showed an excellent tumor-clearance rate in patients with BCC. Patients were treated five times a week for six weeks with the IRM before undergoing tumor excision. Following their surgery, eighty-two percent of those who were treated with imiquimod were found to have no additional evidence of the tumor.
Actinic keratoses (AKs) are common small, scaly spots that develop on parts of the body that have been exposed to the sun and that if left untreated, have the potential to progress to squamous cell carcinoma, the second leading cause of skin cancer deaths in the United States. While current therapies to treat AKs include cryosurgery, surgical removal and biopsy, topical chemotherapy, and photodynamic therapy, IRMs have been recently successful in treating AKs. In fact, a recent study showed an 83 percent median clearance rate of AKs when patients applied imiquimod twice a week to the affected area.
"The incidence of skin cancer is increasing at an alarming rate in the United States and these new options are showing promise in treating skin cancers and actinic keratoses safely and effectively with minimum downtime for patients and excellent cosmetic outcomes," said Berman.
There are many diseases that result from abnormally excessive immune responses, such as atopic dermatitis or eczema. For over a decade, potent systemic immunomodulators have been used for the treatment of eczema, a chronic skin condition characterized by itchy, inflamed skin -- typically on the insides of the elbows, backs of the knees and the face. But in the past two years, these medications have been incorporated into topical preparations called topical immunomodulators (TIMs) that exert their powerful anti- inflammatory effects on the activation of T-cells, a type of white blood cell in the body responsible for triggering immune responses. These treatments also target the skin without hampering the immune system's ability to defend itself from bacteria, viruses, and other diseases. Two TIMs, tacrolimus ointment and pimecrolimus cream, have been approved by the FDA for the treatment of atopic eczema.
"TIMs have been shown to effectively treat eczema and common skin disorders," stated Berman. "Because they are steroid-free they do not have the traditional side effects such as thinning of the skin, formation of dilated blood vessels, stretch marks, and infection."
Treatment of psoriasis, a recurring, non-contagious skin disorder that is characterized by raised, thickened patches of red skin covered with silvery- white scales, has recently benefited from the development of biologic agents. Biologic therapies block T-cell activation, which in psoriasis release cytokines to tell skin cells to reproduce and proliferate at an accelerated rate, thereby setting off other reactions that lead to psoriatic lesions forming on the skin.
The first biologic to be approved by the FDA for the treatment of psoriasis is alefacept which works by destroying activated T-cells, thereby stopping the early cycle of psoriasis. In a recent study, after patients received a 12-week course of alefacept, which is given intravenously or through injection, more than 30 percent of patients saw a very significant improvement in their psoriasis, including a reduction on the PASI (Psoriasis Activity and Severity Index) of greater than 75 percent. In addition, the level of improvement patients saw continued long after the course of treatment was finished, averaging eight months or longer, depending on the length of treatment.
Another biologic that is FDA approved for the treatment of psoriatic arthritis and is currently in phase III trials for the treatment of psoriasis is etanercept, which blocks Tumor Necrosis Factor (TNF), a primary cytokine, from initiating the skin cells to reproduce excessively. Other biologics for the treatment of psoriasis are in various stages of FDA approval including efalizumab, infliximab and adalimumab. Efalizumab interferes with the migration of T-cells to the skin and their activation in tissue, possibly reducing the numbers of memory T-cells that may result in fewer disease recurrences. Infliximab, which is partially mouse protein, and adalimumab, which is humanized, also blocks TNF, preventing the psoriasis cycle from beginning.
"These new immune response modifiers, topical immunomodulators and biologics are the future in treating common dermatologic viruses and conditions and offer new opportunities for dermatology and other specialties," said Berman. "These treatments have already positively affected patients' quality of life."
Source: American Academy of Dermatology