59th Annual Meeting of the American Academy of Dermatology - March 2-7,
2001; Washington, DC
What percentage of rosacea patients have some degree of ocular rosacea?
Imiquimod May Prevent Recurrence of Keloid Scars After Surgery
Tacrolimus Ointment Now Available for Atopic Dermatitis
Ascomycin Cream Promising in Inflammatory Dermatoses
Oral Ascomycin Shows Encouraging Results in Psoriasis
Intravenous Infliximab Shows Promise in Psoriasis
Intravenous Alefacept May Induce Significant Remissions in Psoriasis
Narrowband UVB Is as Effective as PUVA
Excimer Laser Clears Psoriasis Lesions
Vascular Lasers Are Getting Better
Laser Hair Removal Is Safe and Effective
New Laser Treatment Stimulates Collagen Without Ablating Epidermis
Alternate Treatments Studied in Molluscum Contagiosum
Wart Therapy Remains Frustrating
Pityriasis Rosea Responds to Erythromycin
Linezolid Available for MRSA
New Treatments Emerging for Kasabach-Merritt Syndrome
Resiquimod Gel May Be Effective in Herpes Simplex
A Vaccine to Prevent HSV Infection?
Tissue-Engineered Skin Becoming More Popular
Estrogen Helps Wounds Heal Faster
Warm-up Therapy May Heal Chronic Wounds
Vacuum-Assisted Closure of Wounds Is Increasingly Popular
Stress Is Not Good for Wound Healing
Introduction
The New and Emerging Therapies Symposium[1] at the 59th Annual Meeting of the American Academy of Dermatology presented new medical and surgical therapies for common dermatologic conditions. (Because these treatments are so new, data are not always published, so references are not always provided.)What percentage of rosacea patients have some degree of ocular rosacea?
As Barbara A. Burrall, MD, states in a report from the 59th Annual Meeting of the American Academy of Dermatology, about 50% of cutaneous rosacea patients will have some degree of ocular rosacea. The dermatologist should always look for and ask about ocular manifestations, which include dry eyes, ocular discharge, frequent sty formation, sensation of foreign body, and conjunctival erythema. Generally, prominent hyperemia of the lid margins and conjunctiva with telangiectases will be noted. The conjunctiva may appear granular. Corneal ulcers and granulomas may be present. Ocular meibomian glands -- modified sebaceous glands that help form the tear film -- are involved and become obstructed and inflamed.
What's New in Medical Dermatology?
Imiquimod May Prevent Recurrence of Keloid Scars After Surgery
Keloid scars are notoriously difficult to treat.[2] Because keloids often occur at sites of trauma and are stimulated by trauma, surgical excision is not always helpful. Surgical excision alone results in recurrence of keloid scars more than 50% of the time. This rate is decreased to 18% when interferon is injected into the wound postoperatively. Interferon seems to reduce collagen synthesis and glycosaminoglycans while upregulating apoptosis (programmed cell death), thus decreasing keloidal fibroblasts.Imiquimod 5% cream (Aldara) is a novel new drug described as an immune-response modifier and approved for the treatment of external genital and perianal warts. Studies are under way using the cream for the treatment of superficial basal cell carcinomas and actinic keratoses. Imiquimod upregulates several cytokines in the skin, including interferon alpha, but without systemic symptoms.
Given the nature of keloids, their response to intralesional interferon, and the pharmacologic action of imiquimod, Brian Berman, MD, PhD, of the University of Miami School of Medicine, Miami, Florida, used imiquimod in an attempt to prevent keloid recurrence. He presented data on 13 keloids from 12 different patients who applied imiquimod 5% cream to the surgical site nightly for 2 months after removal of the keloid. Ten of the initial 12 patients completed the study. After 6 months, none of the keloids had recurred. Half of the patients developed hyperpigmentation at the application site, which was mild and barely noticeable to the patients. Treatment frequency was decreased to every other day for patients who developed irritation at the treatment site, which is common with imiquimod.
It appears that imiquimod 5% cream may significantly decrease recurrence of keloid scars following surgical excision, but further blinded, placebo-controlled trials are needed to confirm these preliminary data.
Tacrolimus Ointment Now Available for Atopic Dermatitis
Tacrolimus 0.1% and 0.03% ointment (Protopic) is a new topical immunomodulator and immunosuppressant recently approved by the US Food and Drug Administration (FDA) and now available for the treatment of moderate-to-severe atopic dermatitis. (The 0.1% and 0.03% formulations are indicated for adults, and the 0.03% formulation is indicated for children 2 years of age and older.)Although the mechanism of action is similar to that of oral cyclosporine, tacrolimus is applied topically, thus bypassing the systemic side effects seen with oral immunosuppressants. The drug specifically inhibits T lymphocytes by binding to an immunophilin, which blocks calcineurin phosphatase. Inhibition of this enzyme prevents dephosphorylation of nuclear factor of activated T cells (NF-AT). Without dephosphorylation of NF-AT, T-lymphocyte production of interleukin-2 and other cytokines is significantly reduced. These cytokines are believed to be responsible for the pruritus and eczematous changes seen in atopic dermatitis.
Phase 3 studies have shown that 36.8% of patients had greater than 90% improvement in their skin condition after 12 weeks of treatment.[3] Almost 8000 patients have been enrolled in a phase 4 safety trial, but the data are not yet available. Burning after application occurs in more than half of patients,[4] but this resolves quickly and decreases with time.
The standard topical therapy for atopic dermatitis has been corticosteroids. While steroids work well, they can lead to cutaneous atrophy and striae. The major advantage of topical tacrolimus is that it is as efficacious as topical steroids for atopic dermatitis but does not carry the risk of atrophy or thinning of the skin. Steroids have also been known to cause glaucoma and cataracts when applied periocularly, so they cannot be used around the eyes in high doses for long periods of time. Tacrolimus can be used around the eyes and eyelids without worry of developing or exacerbating glaucoma. This is extremely good news for atopic patients with chronic dermatitis on the face and around the eyes. Studies have shown that this ointment is also safe and effective for children 2 years of age and above.[5]
Ascomycin Cream Promising in Inflammatory Dermatoses
Ascomycin 1% cream is a new macrolactam immunomodulator that will probably soon be approved by the FDA. It selectively inhibits T cells and may be used to treat many inflammatory disorders, including atopic dermatitis. Ken Washenik, MD, PhD, of New York University School of Medicine, New York, NY, discussed data from early trials with ascomycin. Thirty-five percent of patients cleared within 6 weeks of treatment, compared with 17% in the vehicle-control group. Burning after application is the major side effect. While these results are encouraging, Dr. Washenik pointed out that patients enrolled in this study had mild-to-moderate disease, not moderate-to-severe disease as did patients in tacrolimus ointment studies. This difference in disease severity may account for the high rate of improvement seen in the ascomycin trials. While efficacy may be similar to tacrolimus, the advantage of ascomycin is that it is a cream. A cream formulation may be preferred by patients who do not like ointments.Oral Ascomycin Shows Encouraging Results in Psoriasis
The oral form of ascomycin was reportedly effective in 5 cohorts of patients.Dr. Washenik discussed unpublished data from Dr. Klaus Wolff that showed a decrease in the PASI (Psoriasis Area and Severity Index) of 60% when patients with moderate-to-severe psoriasis took 20 mg of ascomycin twice daily and 75% when patients took 30 mg of ascomycin twice daily. Unlike cyclosporine, serious adverse events such as hypertension and elevated BUN and creatinine were not reported. This improved side-effect profile is a major advantage for patients who cannot continue cyclosporine due to renal toxicity. While this agent will not be available for some time, these results are extremely encouraging for psoriasis sufferers.
* Eventhough Topical ocular cyclosporine seems safe & effective & well tested already, I'm Curious about the potential of Topical Ocular Ascomycins for dry eye considering its preliminary superior systemic safety profile.
Intravenous Infliximab Shows Promise in Psoriasis
There has been an explosion in the introduction of specific antibodies that bind to antigens on the surface of the T lymphocyte, which is believed to be the most important cell in the pathogenesis of psoriasis. Two new monoclonal antibodies were discussed by Dr. Washenik.Infliximab (Remicade) is an intravenously infused chimeric monoclonal antibody currently approved for rheumatoid arthritis and Crohn's disease. This antibody binds to TNF-alpha, a well-known psoriatic inflammatory cytokine, and inhibits its action. Dr. Washenik reviewed a report in which 3 infusions (at doses of 5 mg/kg and 10 mg/kg) over 6 weeks achieved greater than 75% improvement in PASI score in 70% of patients at both dose levels. The drug was well tolerated overall. Headache was the most common side effect, but none of the patients dropped out of the study due to this adverse reaction.
Intravenous Alefacept May Induce Significant Remissions in Psoriasis
Alefacept (LFA-3tip) is an entirely human monoclonal antibody that is also administered intravenously. The drug binds to CD-2, a T-cell surface marker that interferes with antigen-presenting cell binding to the T cell. This may lead to apoptosis of the T cells. The phase 2 trial data discussed by Dr. Washenik showed a decrease in PASI score in 75% of patients.What is most encouraging about this study is that patients continued to improve several months after the infusions were stopped. Median relapse was at 8 months. The drug can also be administered intramuscularly. Further studies with this antibody are needed, but these preliminary data suggest that alefacept may not only treat but also induce significant remissions in psoriasis.
What's New in Cosmetic and Medical Laser Treatment?
Narrowband UVB Is as Effective as PUVA
While broadband UVB has been around for decades, it is now becoming increasingly evident that most of the spectrum is not needed for immunosuppression of inflammatory dermatoses. Narrowband UVB -- or UV light in the 310- to 315-nm range -- produces a peak therapeutic effect. Narrowband UVB at 311 nm is more efficacious than broadband UVB, and is equally efficacious as PUVA therapy. The benefits are that narrowband UVB therapy does not require eye protection, can be used in pregnant women, and may cause less skin cancer than PUVA. Narrowband UVB can be used to treat psoriasis, eczema, mycosis fungoides, and many photodermatoses.Excimer Laser Clears Psoriasis Lesions
The excimer laser (XTRAC, PhotoMedex) emits UVB at 308 nm and is an emerging therapeutic alternative for local psoriatic disease. Jeffrey Dover, MD, of Beth Israel Hospital, Boston, Massachusetts, and Dartmouth Medical School, Lebanon, New Hampshire, discussed his experience with this new technology. After only 6 treatments (2 times weekly), 72% of patients cleared over 75% of their psoriasis. Effectiveness increased slightly with further treatment. Patients tend to stay clear or in remission for 6 months, sometimes longer. Because the energy emitted by laser light is focal, normal skin is not exposed, thus decreasing the carcinogenic potential that is difficult to avoid with UVA therapy. A "laser comb" using the same technology is under development, which may be a much needed addition to scalp psoriasis therapy.The excimer laser has also been purported to be effective for vitiligo, cutaneous T-cell lymphoma, lichen planus, and other inflammatory dermatoses. These diseases were not discussed in detail, but we will look for more information in the future.
Vascular Lasers Are Getting Better
Newer lasers are now available that have a longer pulse duration. This technology is different from other lasers in that there is no rupture of the blood vessels, thus no purpura. Longer wavelengths also allow deeper vessels to be reached, producing a better therapeutic effect. Dr. Dover likened these longer pulsed, longer wavelength lasers to "slow cooking." Better treatment effects and fewer adverse effects are good news for all patients with unwanted vascular lesions, from port-wine stains to mild rosacea.Laser Hair Removal Is Safe and Effective
Dr. Dover addressed the issue of nomenclature and definitions used in laser hair removal. In order to avoid confusion, he suggested that we should tell our patients that laser light can produce "permanent hair reduction." This means that there will be fewer, finer, lighter hair and about 20% permanent hair removal with each treatment. In other words, the majority of the terminal hairs treated will be reduced to vellus hairs, or "peach fuzz." Dark hair responds best (fair hair does not do well). Most patients need an average of 6 treatments. This laser procedure is very safe.New Laser Treatment Stimulates Collagen Without Ablating Epidermis
The definition of skin rejuvenation may be difficult, but procedures such as chemical peels and particulate resurfacing, which improve texture and tone while removing dyspigmentation, are considered rejuvenation procedures. Dr. Dover discussed an emerging laser technology that can stimulate collagen without ablating the epidermis.There are many lasers available for this procedure, which is known as nonablative laser resurfacing. Most patients average 6 treatments lasting 40 minutes each. Eighty percent of patients who have the procedure would have it again and would recommend it to a friend. Laser photorejuvenation is becoming one of the most common cosmetic procedures today.[6]
What's New in Pediatric Dermatology?
Alternate Treatments Studied in Molluscum Contagiosum
There remains no ideal therapy for molluscum contagiosum. Curettage is appropriate for older children and adults, but topical anesthesia, such as EMLA cream, should be used for younger children. Amy Paller, MD, of Northwestern University Medical School, Chicago, Illinois, summarized a report[7] showing that cantharidin is 98% effective in childhood molluscum contagiosum. Even though a high percentage of patients developed blisters and discomfort, 95% of parents said they would go ahead with the treatment a second time if needed.An analog of imiquimod 1% cream has also been shown to be effective in about 80% of patients when used 3 times daily.[8] Because this is a much more frequent application regimen than is used for warts, there may be increased irritation. Imiquimod is commercially available as a 5% cream and approved for external anogenital warts in adults. However, numerous small studies like the one above have shown that it is safe and effective for common warts and molluscum in children.[9,10]
Cidofovir 1%-3% ointment can be compounded and applied twice daily for molluscum. While it is effective, especially for immunocompromised patients, the cost is exorbitant ($50 for 3 grams).
Wart Therapy Remains Frustrating
Several reports on wart therapy were discussed by Drs. Paller, Micali, and colleagues[11] showed an 84% complete remission of warts in children using squaric acid dibutyl ester (0.03%-3%) twice weekly with 70% salicylic acid without a single recurrence at 24 weeks posttreatment. Another report by Lee and colleagues[12] showed 69% clearance with squaric acid (0.5%-5%). Yet another report by Silverberg and colleagues[13] showed 58% clearance with no recurrences at 4 months. This study allowed parents to treat their children's warts at home 3 times weekly. Wart therapy remains difficult and frustrating for both patients and physicians. While these results are encouraging, treatment with squaric acid in the office or at home can cause a significant inflammatory response and may not be optimal for all patients.Pityriasis Rosea Responds to Erythromycin
The cause of pityriasis rosea remains unknown. Some have suggested that it is an inflammatory process, while others purport an infectious etiology. Luckily, the eruption is usually not symptomatic. Some patients do report pruritus and some may be bothered by the appearance. Erythromycin was recently reported[14] to cause a complete response in 73% of patients when given a 2-week course. Dr. Paller suggested that erythromycin is worth a try in patients who are bothered by the skin changes of pityriasis rosea.Linezolid Available for MRSA
A new oral antibiotic for methicillin-resistant Staphylococcus aureus (MRSA) infection, linezolid, has been reported effective in children. The drug belongs to the oxazolidinone family of antibiotics and is approved in adults but not in children. Early studies suggest that it is well tolerated in infants and children, but further study is needed for approval. This drug is a welcome addition to our antibiotic armamentarium.New Treatments Emerging for Kasabach-Merritt Syndrome
It is now well accepted that tufted angiomas are the principle type of "hemangioma" that causes Kasabach-Merritt syndrome. This leads to a consumption of platelets, thus thrombocytopenia. Many treatments are currently used for this potentially fatal problem, including systemic steroids, interferon-alpha, antifibrinolytics, and surgical intervention. Recently, vincristine given intravenously at weekly intervals resulted in increased platelet count and decrease in the size of the tufted hemangioma after 3-4 weeks of infusion.Looking towards the future, a human recombinant antiangiogenic agent may be the mainstay of therapy. Subcutaneous angiostatin and interleukin-12 are also being studied. Imiquimod has also shown antiangiogenic and anticancer potential, warranting further study of the drug's effect on vascular tumors
What's New in Antivirals and Viral Vaccines?
Resiquimod Gel May Be Effective in Herpes Simplex
As mentioned earlier, imiquimod 5% cream is currently approved for the treatment of external anogenital warts, but the drug has been reported effective in many off-label uses. An analog of imiquimod, resiquimod, is believed to be 100 times more potent than imiquimod. Resiquimod activates Langerhans cells, which in turn increase the appropriate cytokine production and response to herpes simplex virus (HSV).In a pilot study conducted by Stephen Tyring, MD, PhD, of University of Texas Medical School, Galveston, Texas, and colleagues, resiquimod gel (0.05% and 0.01%) was applied to immunocompetent patients who had 6 or more HSV outbreaks yearly. Patients began treatment after an HSV outbreak occurred. While twice-daily application of 0.05% gel was not well tolerated, weekly application of 0.05% and 0.01% gel was tolerated, and, more important, was efficacious. Fifty percent of patients with active HSV lesions healed within 8 days, and the time to first recurrence was 169 days compared with 57 days in the placebo group. Thirty-two percent had no recurrence. It appears that resiquimod 0.01% gel applied 2 or 3 times weekly had the best safety and efficacy profile. Future studies will be needed to reaffirm these results, but these initial data are very promising.
A Vaccine to Prevent HSV Infection?
A new herpes simplex vaccine, gD2-SBASA, was evaluated in a double-blind, randomized trial that enrolled patients who had no history of herpes simplex virus infection but who had partners with a history of herpes simplex. The interesting but unexpected results showed that the vaccine worked well for women but not as well for men. Over 70% of the female patients were protected, compared with only 11% of the men. Dr. Tyring suggested that mucosal immunity in women is superior or more protective compared with men. The vaccine was safe and well tolerated. This is the first demonstration of the ability of a vaccine to prevent herpes simplex virus infection. These data will be published soon. Help is on the way for herpes simplex sufferers.What's New in Wound Healing?
Tissue-Engineered Skin Becoming More Popular
Apligraf (Graftskin, Novartis) has been approved for both venous leg ulcers and diabetic foot ulcers. Robert Kirsner, MD, University of Miami School of Medicine, Miami, Florida, presented unpublished data showing that Apligraf not only led to healing of leg ulcers within 3 months but that patients also had a lower incidence of osteomyelitis and amputations. Apligraf continues to be applied for pressure ulcers, epidermolysis bullosa, arterial ulcers, and ulcers associated with pyoderma gangrenosum, as well as many other off-label uses. Apligraf seems to work better when applied to wounds earlier rather than later in the course of therapy.Estrogen Helps Wounds Heal Faster
Although it is not known why, wounds in younger women heal better than wounds in older women. However, older women on estrogen replacement therapy (ERT) heal as well as young women who are not on ERT. Armed with this knowledge, Dr. Kirsner discussed a possible role for estrogen in dermatology and skin surgery. It is also known that older women have less clinical scarring than younger women and women on ERT. There is some basic scientific evidence that estrogen may stimulate TGF-beta, which is known to stimulate collagen production.Taking this one step further, preliminary studies have been done in which elderly women and men were randomized to have skin surgery through an estrogen patch or a placebo patch. The patch was removed 24 hours after surgery. Both men and women who had surgery through the estrogen patch healed faster and had "stronger wounds." Side effects were not discussed. Whether the estrogen would be applied topically or administered via transdermal patch must be worked out in future studies.
Warm-up Therapy May Heal Chronic Wounds
Heat therapy, or warm-up therapy, can create a "mini-greenhouse effect" and may be good for healing. It is known that chronic wound fluid can be detrimental to wound healing. Warm-up therapy may change the cytokine and growth factor profile in chronic wound fluid, shifting the balance towards healing. This therapy may become more common in the future, especially in chronic, nonhealing wounds.Vacuum-Assisted Closure of Wounds Is Increasingly Popular
Localized negative-pressure closure, or vacuum-assisted closure of wounds, is increasing in popularity. This technique draws wound edges centrally, thus decreasing wound size. It may have a specific niche for pressure ulcers, spinal wounds, sternotomy wounds, and pediatric wound closure. Only small studies have been done to date and statistics are not available.Stress Is Not Good for Wound Healing
While we all know that stress and anxiety are not good for our general health and longevity, there is increasing evidence that stress may also inhibit wound healing. Dr. Kirsner discussed a report by Glaser and colleagues[15] that found patients in stressful situations had a decrease in cytokine production in wound fluid and thus their wounds healed more slowly. This information may have implications for both dermatologists and generalists in their approach to inpatient as well as outpatient wound care. Dr. Kirsner suggested that providing a comfortable environment for our surgical patients may have multiple benefits.References
- Berman B, Dover JS, Kirsner RS, et al. New and emerging therapies. Program of the 59th Annual Meeting of the American Academy of Dermatology; March 2-7, Washington, DC. Page 161.
- English RS, Shenefelt PD. Keloids and hypertrophic scars. Dermatol Surg. 1999;25:631-638.
- Hanifin JM, Ling MR, Langley R, Breneman D, Rafai E. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol. 2001;44:S28-S38.
- Soter NA, Fleischer AB Jr, Webster GF, Monroe E, Lawrence I, and the Tacrolimus Ointment Study Group. Tacrolimus ointment for the treatment of atopic dermatitis in patients: part II, safety. J Am Acad Dermatol. 2001;44:S39-S46.
- Paller A, Eichenfield LF, Leung DYM, Stewart D, Appell M, and the Tacrolimus Ointment Study Group. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol. 2001;44:S47-S57.
- Zelickson BD, Kilmer SL, Bernstein E, et al. Pulsed dye laser therapy for sun damaged skin. Lasers Surg Med. 1999;25:229-236.
- Silverberg NB, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000;43:503-507.
- Syed TA, Goswami J, Ahmadpour OA, Ahmad SA. Treatment of molluscum contagiosum in males with an analog of imiquimod 1% in cream: a placebo-controlled, double-blind study. J Dermatol. 1998;25:309-313.
- Liota E, Smith KJ, Buckley R, Menon P, Skelton H. Imiquimod therapy for molluscum contagiosum. J Cutan Med Surg. 2000;4:76-82.
- Hengge UR, Esser S, Schultewolter T, et al. Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol. 2000;143:1026-1031.
- Micali G, Nasca MR, Tedeschi A, Dall'Oglio F, Pulvirenti N. Use of squaric acid dibutylester (SADBE) for cutaneous warts in children. Ped Dermatol. 2000;17:315-317.
- Lee A, Mallory SB. Contact immunotherapy with squaric acid dibutylester for the treatment of recalcitrant warts. J Am Acad Derm. 1999;41:595.
- Silverberg N, Lim JK, Paller AS, Mancini AJ. Squaric acid immunotherapy for warts in children. J Am Acad Dermatol. 2000;42:803-808.
- Sharma PK, Yadav TP, Gautam RK, Taneja N, Satyanarayana L. Erythromycin in pityriasis rosea: A double blind placebo controlled clinical trial. J Am Acad Dermatol. 2000;42:241-244.
- Glaser R, Kiecolt-Glaser JK, Marucha PT, MacCallum RC, Laskowski BF, Malarkey WB. Stress-related changes in proinflammatory cytokine production in wounds. Arch Gen Psychiatry. 1999;56:450-456.
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