CME #121: Major Treatment Trends for 2004: From Bedbugs to Fillers

Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. This year has been a productive one with many advances in dermatology, including medical dermatology, infectious diseases, cutaneous carcinoma, medications and laser and cosmetic procedures. This article, which is authored by Julie A. Neville, M.D., and Manisha J. Patel, M.D., provides a nice overview of many dermatology advances in 2004. At the end of this article, you’ll find a 10-question exam. Mark your responses in the designated area, and fax page 60 to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: Julie A. Neville, M.D., and Manisha J. Patel, M.D. Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 52 to 59 and successfully answering the questions found on pp. 59 and 60. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 2 hours Date of Original Release: December 2004 Expiration Date: December 2005 This activity has been planned and produced in accordance with ACCME essentials. Accreditation Statement: The North American Center for Continuing Medical Education (NACCME) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: NACCME designates this continuing medical education activity for the maximum of two category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: The authors disclose that the Wake forest University Department of Dermatology, where they are both residents, has the following relationships with industry through either membership to speakers’ bureaus, or the department has received research or grant support: Acuderm, Advanced Tissue Sciences, Allergan, Aventis, Bristol-Myers Squibb, Combe, Curatek, Ferndale, Fujisawa, Hermal, Hoffman-La Roche, Galderma, Genderm, Glaxo Wellcome, Hill, Janssen, Mayrand, NeoStrata, Neutrogena, Novartis, Oclassen, Ortho, Person & Cxovey, Procter & Gamble, RJR Nabisco, Schering-Plough, Shelton, SmithKline, Stiefel, 3M, United Catalyst, Upjohn and Wolff Systems. Learning Objectives: 1. Identify recent advances in medical dermatology including new uses for existing medications 2. Identify new advances in surgical dermatology 3. Identify new advances in cosmetic dermatology 4. Identify and become familiar with recent studies affecting dermatology that were heavily publicized, including the risk of antibiotic use and the development of breast cancer and the possible association between finasteride and the development of more aggressive prostate cancer matomyositis and scleroderma. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None T his year in dermatology has seen numerous advances in the medical, surgical and cosmetic realms of the field. In this article, we will highlight new developments in dermatologic diseases, infectious diseases, cutaneous carcinoma, medications, lasers and light therapy, and cosmetics. This CME will provide a look at some of the year’s therapeutic advances in dermatology. Psoriasis Biologic Agents Once again, this year’s literature has been dominated by the biologics. In the table below, we emphasize the current FDA-approved indications and dosing for the various therapies available. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. A randomized controlled clinical trial comparing methotrexate and cyclo-sporine in terms of effectiveness, side effects and quality of life was published in August 2003. Until this trial, these commonly used systemic drugs have never gone head-to-head in a study. Patients were assigned to receive 15 mg/week of methotrexate versus 3 mg/kg/day of cyclosporine for 16 weeks and were followed for another 36 weeks. The PASI 75 score, defined as a reduction in the baseline score of more than 75%, was attained by 26 (60%) of the patients in the methotrexate group and by 30 (71%) of the patients in the cyclosporine group. After adjustment for baseline values, these results suggested no significant difference in efficacy between the two groups. In addition, the time to and rates of remission and quality of life measures were similar.1 This information now allows physicians to guide treatment decisions based on differences in side effects, ease of administration and cost. Oral Tazarotene and Oral Pimecrolimus Retinoids have been a mainstay in the treatment of psoriasis. While older retinoids indiscriminately activate retinoic acid receptors (RAR) alpha, beta, and gamma, the synthetic retinoid tazarotene selectively binds to the beta and gamma class of nuclear RARs.2 Already proven effective as a topical preparation (Tazorac), Allergan filed a new drug application with the FDA in November of 2003 for oral tazarotene (Tazoral). Two Phase III multicenter, double-blind, randomized, placebo-controlled trials found that more than half of adult patients with plaque type psoriasis covering at least 10% of their body surface area achieved moderate to complete clearance by week 12 of therapy.3 These patients took 4.5 mg daily for up to 52 weeks with no significant side effects. However, two FDA advisory committees voted in July 2004 to recommend against approving oral tazarotene for the treatment of moderate to severe psoriasis. Reports from the joint session meeting revealed concern over reports of bone mineral density loss and teratogenicity with potential off-label use of the drug for acne.4 Although the FDA has not made a final decision, this medication is not expected to be approved as the FDA usually follows the advisory committees’ recommendations 5 Pimecrolimus is another new medication studied for the treatment of psoriasis and atopic dermatitis. Pimecrolimus exerts its action through the blockage of T-cell activation via a calcineurin inhibitor.2 Developed as a topical agent in the treatment of atopic dermatitis, this drug’s effective immunomodulating activity is being studied in oral form for chronic plaque type psoriasis and atopic dermatitis. Results from a Phase II study were reported at the 61st Annual Meeting of the American Academy of Dermatology. The efficacy of oral pimecrolimus in the treatment of psoriasis and atopic dermatitis was evaluated in two multi-national, randomized, double-blind, parallel-group dose-finding studies. The efficacy in reducing psoriasis/eczema area and severity index (PASI/EASI) scores, relative to baseline, were dose-dependent with doses between 20 mg and 30 mg achieving statistically significant improvement in PASI and EASI scores, while the 10-mg dose was not significantly more effective than placebo.6,7 No clinically significant changes were observed in blood pressure or laboratory analyses. Infectious Diseases HSV Herpes simplex virus serologic tests that can distinguish between HSV-1 and HSV-2 infections are now available. These tests detect antibodies to glycoproteins G-1 and G-2 and have greater than 90% sensitivity and specificity for detecting HSV-2. Glycoprotein G based tests are recommended over other serologic tests that have a lower accuracy rate and an inability to detect HSV-2 in seropositive HSV-1 patients.8 A multicenter, randomized, placebo-controlled study published in the New England Journal of Medicine (NEJM) revealed that once-daily suppressive therapy with valacyclovir significantly reduced the risk of transmission of genital herpes among heterosexual, HSV-2 discordant couples.9 It is estimated that 1.6 million new cases of HSV-2 infection are acquired annually.10 Nucleoside analogues targeted against HSV-2 have been previously shown to suppress shedding of the virus on mucosal skin.11 Given that both symptomatic and asymptomatic reactivations of HSV infection result in sexual transmission,12 this study documented the suppressive action of antivirals not only on mucosal shedding but also viral transmission. Leishmaniasis and the U.S. Military The war in Iraq has greatly heightened the need for U.S. physicians to expand their differential diagnosis to include infectious diseases non-endemic to our country, much as anthrax and smallpox did in 2002 with the increased threat of bioterrorism. Now, we find new diagnostic challenges as U.S. military troops return from deployment in the Middle East. As originally seen in Operations Desert Storm and Shield in the early 1990s, cases of cutaneous Leishmaniasis are on the rise. A small study published in the Journal of the American Academy of Dermatology looked at the value of diagnostic techniques for cutaneous leishmaniasis.13 The PCR technique was compared to traditional tests, including smear, culture and histopathology. PCR was shown to have the highest sensitivity when used as a single diagnostic procedure. However, when compared to the combined results from the three traditional tests, PCR provided no diagnostic advantage. Presently, the Walter Reed Army Medical Center and the Centers for Disease Control and Prevention provide diagnostic services and procurement of sodium stibogluconate for treatment of leishmaniasis as it is not licensed for use in the United States.14 Smallpox Vaccine The currently licensed smallpox vaccine is composed of a live orthopoxvirus (vaccinia virus). This highly effective vaccine brought forth the eradication of the disease in nature by 1980. Two decades later, the threat of bioterrorism has spurred interest in re-instituting vaccination programs. Adverse events associated with the smallpox vaccine have presented concerning obstacles to vaccination campaigns. Two new advances in the field of virology this year appear to offer a safer vaccine that could benefit the millions of people, including those with atopic dermatitis, who are unable to receive the live vaccinia virus secondary to their susceptibility to side effects. A derivative of the current vaccine, called modified vaccinia Ankara (MVA), has shown promise as an effective and safer smallpox vaccine.15 Produced by passaging vaccinia virus greater than 500 times in chick embryo fibroblasts, MVA causes no adverse effects even when high doses are injected into immune-deficient non-human primates.16 During each passage, the virus acquires multiple deletions and mutations, thereby losing its capacity to replicate efficiently in human cells. Moss and colleagues have shown that this highly attenuated vaccine is effective in protecting mice and monkeys against lethal doses of vaccinia virus and monkeypox, respectively.17 Also in the pipeline is the development of a DNA vaccine that could provide an even safer option for vaccine campaigns. A team of U.S. Army researchers, spearheaded by P. B. Jahrling, reported this year on a new DNA vaccine that can protect rhesus monkeys from severe disease after an otherwise lethal challenge with monkeypox virus.18 This vaccine, known as 4pox, consists of the genes for four vaccinia proteins that are thought to be important in the host’s immune response.19 Although limited by a small sample size, this study may provide evidence for use of DNA rather than a live virus in a smallpox vaccine. Monkeypox Infected pet prairie dogs, all obtained from a common source, brought the first cases of monkeypox to the Western Hemisphere. In Wisconsin during May and June of 2003, 11 cases of monkeypox were reported with patients developing a febrile illness and accompanying vesiculopustular eruption. This disease, while present in Africa, had not previously been reported in the United States.20 Don’t Let the Bedbugs Bite The residents of the Allston-Brighton section of Boston have recently been waking up to “breakfast, lunch and dinner.” Although no longer thought to be pathognomic for bedbug bites, the residents of this Boston community have been battling an infestation.21 As data on infestations are not systematically collected, it is not possible to relate the increase in cases reported to an overall trend, but it does raise the possibility of a real increase which may be associated with international trade and travel.22 A lesson quickly learned by this small Boston community is that Cimex lenticularis is no longer limited to low-end motels, and a lesson learned by dermatologists is that patients presenting with nocturnally acquired bites or itchy rashes without obvious cause should raise the possibility of bedbugs.23 Malignancy The CXR and Melanoma The chest radiograph continues to be routinely used in the initial staging and surveillance of patients with cutaneous melanoma. Although a paucity of data exists supporting this practice, a survey of 30 dermatologists, surgical oncologists, and medical oncologists revealed that more than 70% of physicians treating patients with melanoma ordered annual chest films.24 To answer the question of survival advantage in the early detection of asymptomatic pulmonary metastases, a group from Massachusetts General Hospital in Boston performed a retrospective case review. In that study, there was no evidence to support the notion that earlier detection of asymptomatic pulmonary metastasis conferred a survival advantage in an unselected melanoma population.25 A second study conducted at the University of Michigan examined the yield of a chest radiograph (CXR) and serum lactate dehydrogenase (LDH) in the work-up for newly diagnosed localized melanoma. This prospective study of 224 patients found a true positive CXR rate with confirmed melanoma metastases in none of the patients and a false positive CXR rate with melanoma metastases in 7% of patients. From a sample size of 96 patients, elevations in LDH were found in 15% and did not lead to detection of occult disease in any patients. They concluded that the low yield, high rate of false-positive tests and lack of significant impact of early detection of metastases on survival argue that CXR and serum LDH should probably not be routine practice in patients with clinically localized melanoma. 26 Imiquimod The uses for imiquimod 5% cream in dermatology continue to expand with this medication now approved for the treatment of actinic keratosis (AK). Two randomized, double-blind, vehicle-controlled studies were conducted at 24 study sites with 436 subjects comparing imiquimod cream to a vehicle in treating AKs on the face and scalp. The cream was applied once daily, twice a week for 16 weeks. Complete clearance was obtained in 45% of the imiquimod group compared with only 3% of the vehicle group. Fifty-nine percent of the treatment group achieved partial clearance (75%) compared with 11% of the vehicle group. Overall, the treatment group had an 83% reduction in lesion count.27 In addition to AKs, imiquimod was recently approved for the treatment of superficial basal cell carcinomas (sBCC) on the body.28 Two identical multicenter, randomized, double-blind, vehicle-controlled, dose-response studies with 724 subjects having biopsy-proven non-facial sBCC were published in early 2004. The pooled results showed a clinical/histologic clearance rate of 75% in the five times a week for 6 weeks treatment group and 73% in the seven times weekly group. Histologic clearance rates were 82% for the five times weekly group and 79% for the seven times weekly group. Local site reactions were the most common adverse event, occurring more often in more frequently treated patients.29 Another study evaluated imiquimod 5% in the treatment of lentigo maligna in 28 subjects with histologically confirmed disease who were treated daily for 3 months. Of these patients, 26 (93%) completely responded to treatment. More than 80% of the 28 initial patients have been followed for over 1 year after treatment with no recurrence.30 Acitretin and Organ Transplant Patients Acitretin is the best studied systemic retinoid shown to be effective in decreasing the number of new AKs and non-melanoma skin cancers in organ transplant patients. The dosage and duration of treatment with acitretin is often mitigated by its side effects, and one randomized study looked at the use of low-dose acitretin in preventing malignancies.31 Researchers followed 26 renal transplant patients for 1 year with half on an acitretin dose of 0.4 mg/kg/day and half on 0.2 mg/kg/day. Both groups had a 50% decrease in AKs but no effect was noted on the development of new non-melanoma skin cancers.32 Recent recommendations on systemic retinoids in transplant patients suggest that initial therapy should be a low dose, between 10 to 30 mg/day, with the intention of increasing the dose to 30 mg/day if insufficient benefits are obtained and side effects are tolerated.31 Medications Antibiotics and Breast Cancer A retrospective, case-control study from the University of Washington found an association between the development of breast cancer and antibiotic use. Investigators looked at 2,266 female patients with primary breast cancer who were enrolled in a group health cooperative and matched them with 7,953 controls. They found an association between increased days of antibiotic usage and increased incidence of breast cancer. When examining the subset of patients who used antibiotics for acne or rosacea, the patients had the same increased risk for cancer as those using the medication for respiratory tract infections. Patients who took antibiotics longer than 500 days or took more than 25 prescriptions had more than twice the risk of developing breast cancer during the 17-year period studied.33 This article prompted a response from the AAD that discussed that the conditions that caused these patients to be on antibiotics may elevate the patient’s risk of developing cancer independent of antibiotic use.34 In addition, others have noted that the study had numerous missing values in the statistical analysis for patients with known or suspected risk factors for breast cancer such as body mass index, family history of breast cancer, and age of menarche. This possible incomplete analysis along with not evaluating other medications that might have had influence may compromise the results.35, 36 While future studies are warranted, the study authors agreed that their findings should not discourage women who need antibiotics to take them.37 Intravenous Immunoglobulin Intravenous immunoglobulin (IVIg) has continued to develop new uses in dermatology, proving effective in the treatment of dermatomyositis, autoimmune bullous disease, toxic epidermal necrolysis, graft-versus-host disease, Behçet’s disease, pyoderma gangrenosum and Kawasaki’s disease.38,39 Recommended guidelines for treatment with IVIg for mucocutaneous diseases include failure of or adverse effects from conventional therapy, contraindications to the use of high-dose long-term systemic therapy, and progressive disease despite conventional therapy.40 Although severe adverse reactions, including thrombophlebitis, anaphylactic reactions in patients with IgA deficiency, and acute renal failure can occur, the main inhibitor of more widespread use of IVIg therapy in dermatology is the high treatment cost.41 Initial concerns, such as the need for infusion centers for administration, have been obviated by the development of home infusion services. Isotretinoin The FDA voted in favor of enacting mandatory registration for both male and female patients taking isotretinoin along with registration of all healthcare providers who prescribe the medication. These regulations were prompted by noncompliance with previous voluntary regulations and would provide for a central registry of patients, physicians and pharmacists, similar to the thalidomide registration program.42 Since its initiation in 2001, the System to Manage Accutane-Related Terato-genicity (S.M.A.R.T.) program for monitoring of Accutane has resulted in only a small decrease in the number of pregnancies while patients are on the medication.43 When enacted, most of what has been voluntary for providers would become mandatory, and patients would need to undergo two pregnancy tests before receiving a prescription. Monthly pregnancy tests will also be required before refills are authorized. The tentative date for implementation of this program is July 2005.44 Finasteride Finasteride is the only oral FDA-approved product available for use in men with androgenetic alopecia. It is a specific inhibitor of type II 5-alpha reductase, which catalyzes the conversion of testosterone to dihydrotestosterone (DHT). DHT is the primary androgen in the prostate and is known to influence the development of prostate cancer.45, 46,47 Findings from the Prostate Cancer Prevention Trial were published this year in the New England Journal of Medicine. This study enrolled men 55 years of age or older with normal digital rectal examinations and a PSA level of 3.0 ng/ml or lower to the treatment arm (finasteride 5 mg/day) vs. placebo for 7 years. They concluded that finasteride prevents or delays the appearance of prostate cancer; however, a small percentage of patients in the treatment arm were noted to have an increased incidence of high-grade tumors.48 As expected, sexual side effects were more common in the finasteride-treated men, whereas urinary symptoms were more common in the placebo arm. Given the differences in patient population and medication dosage, which is higher than the 1-mg dose used in most dermatology practices, these results should be cautiously interpreted when discussing the long-term effects of finasteride with patients. Stevens-Johnson Syndrome and Carbamazepine The new world of pharmacogenomic analysis took a step forward with a study from Taiwan comparing 44 subjects who developed Stevens-Johnson syndrome (SJS) after taking carbamazepine with 101 subjects taking the medication without complications and 93 healthy controls. Researchers found 100% of the patients developing SJS had human leukocyte antigen (HLA) B*1502 compared with 3% of the carbamazepine-tolerant patients and 8.6% of healthy controls. Although this is a preliminary study with all subjects being from the Han Chinese population, these findings suggest a very strong association between an HLA marker and a disease (stronger than the association between HLA-B27 and ankylosing spondylitis). If confirmed by future studies, this may identify patients who are at risk of developing SJS from carbamazepine.49 Lasers and Light Therapy Laser Treatment for Acne The use of lasers and light-based treatment for acne vulgaris has continued to grow over the past year. Current FDA-approved devices for acne treatment include blue light (407 nm to 420 nm) and ClearTouch, a broad-spectrum (430 nm to 1200 nm) flashlamp light source. Both devices work by destroying the bacterium Propionibacterium acnes through targeting of porphyrins in the bacteria. The 1450 nm diode laser has been successfully used for acne and works by reducing the size of the sebaceous glands.50 The pulsed dye laser (595 nm) may decrease the erythema associated with acne, and although one study showed a significant clinical improvement, a second randomized controlled trial did not show similar improvement.51, 52 Although the small sample size and lack of controls in many of these studies call for further research in this area, this technology has become increasingly popular as a safe, fast, effective therapy for acne. Photodynamic Therapy Photodynamic therapy (PDT) has proven effective in the treatment of superficial BCC, Bowen’s disease and actinic keratosis (AK). This treatment results in better cosmesis than other conventional therapies, but patients often require multiple treatments and the treatment is typically painful.53 A randomized, placebo-controlled study with 243 patients receiving either a topical vehicle or 20% 5-aminolevulinic acid (Levulan) followed 14 to 18 hours later with blue light PDT (417 nm) showed improvement, defined as at least 75% clearance in 77% of the treatment group at 8 weeks and 89% at 12 weeks. Of the patients, 33% needed retreatment at 8 weeks, and this is reflected in the higher improvement rate at 12 weeks. Pain was a common side effect with erythema and edema also frequently occurring at the site of medication application.54 A second study looked at ALA/PDT using a long-pulsed pulsed-dye laser (595 nm) as the light source with an incubation time of either 3 or 14 to18 hours. The study found similar improvement in AKs with greater clearance noted on the head compared to body lesions. No difference in efficacy or safety was noted between the two incubation times.55 PDT has also been used to treat BCC with clearance rates between 79% and 100% for superficial BCC and 10% to 75% for nodular BCC using ALA/PDT.56-58 A prospective, randomized study looked at 101 patients with nodular BCC comparing methyl 5-aminolevulinate (Metvix) PDT with red light (570 nm to 670 nm) to surgical excision. This derivative of 5-aminolevulinic acid that is now approved by the FDA, is thought to have improved specificity for neoplastic cells and improved efficacy over 5-ALA. PDT was performed twice, 7 days apart, and response was measured by clinical, but not histologic, clearance. Of the patients treated, 24% of the PDT group needed to receive an additional two PDT treatments, and 83% of the PDT group obtained clinical clearance compared to 96% of the surgical excision group. The incidence of recurrence was higher in the PDT treated group than the surgically treated group and pain was common.59 Based on these findings, PDT may be an option for large or multiple lesions and for those patients with BCC who would not tolerate other treatments, or who wish to decrease the chance of scarring.53 Cosmetics Fillers Two hyaluronic acid-based dermal fillers, Restylane and Hylaform, and even more recently, Hylaform Plus, received FDA approval and neither require skin testing prior to administration. They are marketed for use in the correction of moderate to severe facial rhytides and folds by injection into the mid to deep dermis. The most common adverse effects experienced were local site reactions. These fillers join the existing products Cosmoderm/Cosmoplast, both human-collagen-based fillers that also do not require pre-treatment skin testing, and Zyderm/Zyplast, bovine collagen fillers that do require skin testing.60 The FDA recently approved Sculptra (poly-L-lactic acid) for treatment of HIV associated facial lipoatrophy.61 This filler works initially through a volume effect and subsequently through increased collagen synthesis. Sculptra is intended for injection into the deep dermis or subcutaneous layers and does not require skin testing before injection.62 Botox Already approved for treatment of glabellar rhytides, Botox cosmetic gained FDA approval for treatment of primary axillary hyperhydrosis if topical therapy is unsuccessful.63 Two multicenter, randomized, placebo-controlled, double-blind studies led to this approval. The first study compared a placebo to either 50 units or 75 units of Botox in the axilla with 81% of those receiving 50 units having a greater than 50% reduction in sweat production compared to 41% of the placebo group. There was no significant difference between the 50 unit and 75 unit groups and the mean duration of response was 201 days. The second study compared the use of 50 units of Botox to placebo and showed similar results with 91% attaining a greater than 50% reduction in sweat production at 4 weeks.64 Sclerotherapy Although not yet approved by the FDA, polidocanol sclerosant microfoam has been highlighted in several studies for its efficacy for varicosities and in the treatment of venous ulcerations. The advantages of foam over liquid sclerosants include the ability to reduce the amount of medication necessary by decreasing the drug dilution by blood and increasing the active surface area of the drug. An initial study found improved results using a foam over the liquid polidocanol sclerosant, both in the immediate post-treatment period and 1 year after treatment.65 The use of this sclerosant foam for treatment of venous leg ulcers was evaluated, and 83% of patients treated had healed ulcers at the 6-month follow-up. Although this study did not use a control group or comparison group to other conventional therapies such as compressive therapy or superficial venous surgery, the results appear promising if validated by future studies.66 Non-Surgical Facelift In the quest to develop a procedure that will improve skin laxity without the recovery time incurred from surgical lifting techniques, dermatologists have begun using non-ablative radiofrequency devices. They are thought to work initially through collagen contraction with subsequent increased collagen synthesis. Several studies have shown an improved appearance of the skin with decreased skin laxity. The nasolabial and mesolabial folds were more responsive to treatment than the neck, and younger patients responded more favorably than older patients. Side effects were minimal and included moderate pain with treatment, post-treatment erythema and soreness. The longevity of the effects is yet unknown and patients should be aware that improvement is subtle.67-71 A Productive Year This past year has brought many treatment advances as well as new medications and products into our realm. We’ve highlighted many of the advances in dermatology, including medical dermatology, infectious diseases, cutaneous carcinoma, medications, laser and cosmetic procedures that have developed over the preceding year, and we look forward to the changes in the coming year.

Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. This year has been a productive one with many advances in dermatology, including medical dermatology, infectious diseases, cutaneous carcinoma, medications and laser and cosmetic procedures. This article, which is authored by Julie A. Neville, M.D., and Manisha J. Patel, M.D., provides a nice overview of many dermatology advances in 2004. At the end of this article, you’ll find a 10-question exam. Mark your responses in the designated area, and fax page 60 to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills. Amy McMichael, M.D. CME Editor Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: Julie A. Neville, M.D., and Manisha J. Patel, M.D. Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 52 to 59 and successfully answering the questions found on pp. 59 and 60. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 2 hours Date of Original Release: December 2004 Expiration Date: December 2005 This activity has been planned and produced in accordance with ACCME essentials. Accreditation Statement: The North American Center for Continuing Medical Education (NACCME) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: NACCME designates this continuing medical education activity for the maximum of two category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: The authors disclose that the Wake forest University Department of Dermatology, where they are both residents, has the following relationships with industry through either membership to speakers’ bureaus, or the department has received research or grant support: Acuderm, Advanced Tissue Sciences, Allergan, Aventis, Bristol-Myers Squibb, Combe, Curatek, Ferndale, Fujisawa, Hermal, Hoffman-La Roche, Galderma, Genderm, Glaxo Wellcome, Hill, Janssen, Mayrand, NeoStrata, Neutrogena, Novartis, Oclassen, Ortho, Person & Cxovey, Procter & Gamble, RJR Nabisco, Schering-Plough, Shelton, SmithKline, Stiefel, 3M, United Catalyst, Upjohn and Wolff Systems. Learning Objectives: 1. Identify recent advances in medical dermatology including new uses for existing medications 2. Identify new advances in surgical dermatology 3. Identify new advances in cosmetic dermatology 4. Identify and become familiar with recent studies affecting dermatology that were heavily publicized, including the risk of antibiotic use and the development of breast cancer and the possible association between finasteride and the development of more aggressive prostate cancer matomyositis and scleroderma. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None T his year in dermatology has seen numerous advances in the medical, surgical and cosmetic realms of the field. In this article, we will highlight new developments in dermatologic diseases, infectious diseases, cutaneous carcinoma, medications, lasers and light therapy, and cosmetics. This CME will provide a look at some of the year’s therapeutic advances in dermatology. Psoriasis Biologic Agents Once again, this year’s literature has been dominated by the biologics. In the table below, we emphasize the current FDA-approved indications and dosing for the various therapies available. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. A randomized controlled clinical trial comparing methotrexate and cyclo-sporine in terms of effectiveness, side effects and quality of life was published in August 2003. Until this trial, these commonly used systemic drugs have never gone head-to-head in a study. Patients were assigned to receive 15 mg/week of methotrexate versus 3 mg/kg/day of cyclosporine for 16 weeks and were followed for another 36 weeks. The PASI 75 score, defined as a reduction in the baseline score of more than 75%, was attained by 26 (60%) of the patients in the methotrexate group and by 30 (71%) of the patients in the cyclosporine group. After adjustment for baseline values, these results suggested no significant difference in efficacy between the two groups. In addition, the time to and rates of remission and quality of life measures were similar.1 This information now allows physicians to guide treatment decisions based on differences in side effects, ease of administration and cost. Oral Tazarotene and Oral Pimecrolimus Retinoids have been a mainstay in the treatment of psoriasis. While older retinoids indiscriminately activate retinoic acid receptors (RAR) alpha, beta, and gamma, the synthetic retinoid tazarotene selectively binds to the beta and gamma class of nuclear RARs.2 Already proven effective as a topical preparation (Tazorac), Allergan filed a new drug application with the FDA in November of 2003 for oral tazarotene (Tazoral). Two Phase III multicenter, double-blind, randomized, placebo-controlled trials found that more than half of adult patients with plaque type psoriasis covering at least 10% of their body surface area achieved moderate to complete clearance by week 12 of therapy.3 These patients took 4.5 mg daily for up to 52 weeks with no significant side effects. However, two FDA advisory committees voted in July 2004 to recommend against approving oral tazarotene for the treatment of moderate to severe psoriasis. Reports from the joint session meeting revealed concern over reports of bone mineral density loss and teratogenicity with potential off-label use of the drug for acne.4 Although the FDA has not made a final decision, this medication is not expected to be approved as the FDA usually follows the advisory committees’ recommendations 5 Pimecrolimus is another new medication studied for the treatment of psoriasis and atopic dermatitis. Pimecrolimus exerts its action through the blockage of T-cell activation via a calcineurin inhibitor.2 Developed as a topical agent in the treatment of atopic dermatitis, this drug’s effective immunomodulating activity is being studied in oral form for chronic plaque type psoriasis and atopic dermatitis. Results from a Phase II study were reported at the 61st Annual Meeting of the American Academy of Dermatology. The efficacy of oral pimecrolimus in the treatment of psoriasis and atopic dermatitis was evaluated in two multi-national, randomized, double-blind, parallel-group dose-finding studies. The efficacy in reducing psoriasis/eczema area and severity index (PASI/EASI) scores, relative to baseline, were dose-dependent with doses between 20 mg and 30 mg achieving statistically significant improvement in PASI and EASI scores, while the 10-mg dose was not significantly more effective than placebo.6,7 No clinically significant changes were observed in blood pressure or laboratory analyses. Infectious Diseases HSV Herpes simplex virus serologic tests that can distinguish between HSV-1 and HSV-2 infections are now available. These tests detect antibodies to glycoproteins G-1 and G-2 and have greater than 90% sensitivity and specificity for detecting HSV-2. Glycoprotein G based tests are recommended over other serologic tests that have a lower accuracy rate and an inability to detect HSV-2 in seropositive HSV-1 patients.8 A multicenter, randomized, placebo-controlled study published in the New England Journal of Medicine (NEJM) revealed that once-daily suppressive therapy with valacyclovir significantly reduced the risk of transmission of genital herpes among heterosexual, HSV-2 discordant couples.9 It is estimated that 1.6 million new cases of HSV-2 infection are acquired annually.10 Nucleoside analogues targeted against HSV-2 have been previously shown to suppress shedding of the virus on mucosal skin.11 Given that both symptomatic and asymptomatic reactivations of HSV infection result in sexual transmission,12 this study documented the suppressive action of antivirals not only on mucosal shedding but also viral transmission. Leishmaniasis and the U.S. Military The war in Iraq has greatly heightened the need for U.S. physicians to expand their differential diagnosis to include infectious diseases non-endemic to our country, much as anthrax and smallpox did in 2002 with the increased threat of bioterrorism. Now, we find new diagnostic challenges as U.S. military troops return from deployment in the Middle East. As originally seen in Operations Desert Storm and Shield in the early 1990s, cases of cutaneous Leishmaniasis are on the rise. A small study published in the Journal of the American Academy of Dermatology looked at the value of diagnostic techniques for cutaneous leishmaniasis.13 The PCR technique was compared to traditional tests, including smear, culture and histopathology. PCR was shown to have the highest sensitivity when used as a single diagnostic procedure. However, when compared to the combined results from the three traditional tests, PCR provided no diagnostic advantage. Presently, the Walter Reed Army Medical Center and the Centers for Disease Control and Prevention provide diagnostic services and procurement of sodium stibogluconate for treatment of leishmaniasis as it is not licensed for use in the United States.14 Smallpox Vaccine The currently licensed smallpox vaccine is composed of a live orthopoxvirus (vaccinia virus). This highly effective vaccine brought forth the eradication of the disease in nature by 1980. Two decades later, the threat of bioterrorism has spurred interest in re-instituting vaccination programs. Adverse events associated with the smallpox vaccine have presented concerning obstacles to vaccination campaigns. Two new advances in the field of virology this year appear to offer a safer vaccine that could benefit the millions of people, including those with atopic dermatitis, who are unable to receive the live vaccinia virus secondary to their susceptibility to side effects. A derivative of the current vaccine, called modified vaccinia Ankara (MVA), has shown promise as an effective and safer smallpox vaccine.15 Produced by passaging vaccinia virus greater than 500 times in chick embryo fibroblasts, MVA causes no adverse effects even when high doses are injected into immune-deficient non-human primates.16 During each passage, the virus acquires multiple deletions and mutations, thereby losing its capacity to replicate efficiently in human cells. Moss and colleagues have shown that this highly attenuated vaccine is effective in protecting mice and monkeys against lethal doses of vaccinia virus and monkeypox, respectively.17 Also in the pipeline is the development of a DNA vaccine that could provide an even safer option for vaccine campaigns. A team of U.S. Army researchers, spearheaded by P. B. Jahrling, reported this year on a new DNA vaccine that can protect rhesus monkeys from severe disease after an otherwise lethal challenge with monkeypox virus.18 This vaccine, known as 4pox, consists of the genes for four vaccinia proteins that are thought to be important in the host’s immune response.19 Although limited by a small sample size, this study may provide evidence for use of DNA rather than a live virus in a smallpox vaccine. Monkeypox Infected pet prairie dogs, all obtained from a common source, brought the first cases of monkeypox to the Western Hemisphere. In Wisconsin during May and June of 2003, 11 cases of monkeypox were reported with patients developing a febrile illness and accompanying vesiculopustular eruption. This disease, while present in Africa, had not previously been reported in the United States.20 Don’t Let the Bedbugs Bite The residents of the Allston-Brighton section of Boston have recently been waking up to “breakfast, lunch and dinner.” Although no longer thought to be pathognomic for bedbug bites, the residents of this Boston community have been battling an infestation.21 As data on infestations are not systematically collected, it is not possible to relate the increase in cases reported to an overall trend, but it does raise the possibility of a real increase which may be associated with international trade and travel.22 A lesson quickly learned by this small Boston community is that Cimex lenticularis is no longer limited to low-end motels, and a lesson learned by dermatologists is that patients presenting with nocturnally acquired bites or itchy rashes without obvious cause should raise the possibility of bedbugs.23 Malignancy The CXR and Melanoma The chest radiograph continues to be routinely used in the initial staging and surveillance of patients with cutaneous melanoma. Although a paucity of data exists supporting this practice, a survey of 30 dermatologists, surgical oncologists, and medical oncologists revealed that more than 70% of physicians treating patients with melanoma ordered annual chest films.24 To answer the question of survival advantage in the early detection of asymptomatic pulmonary metastases, a group from Massachusetts General Hospital in Boston performed a retrospective case review. In that study, there was no evidence to support the notion that earlier detection of asymptomatic pulmonary metastasis conferred a survival advantage in an unselected melanoma population.25 A second study conducted at the University of Michigan examined the yield of a chest radiograph (CXR) and serum lactate dehydrogenase (LDH) in the work-up for newly diagnosed localized melanoma. This prospective study of 224 patients found a true positive CXR rate with confirmed melanoma metastases in none of the patients and a false positive CXR rate with melanoma metastases in 7% of patients. From a sample size of 96 patients, elevations in LDH were found in 15% and did not lead to detection of occult disease in any patients. They concluded that the low yield, high rate of false-positive tests and lack of significant impact of early detection of metastases on survival argue that CXR and serum LDH should probably not be routine practice in patients with clinically localized melanoma. 26 Imiquimod The uses for imiquimod 5% cream in dermatology continue to expand with this medication now approved for the treatment of actinic keratosis (AK). Two randomized, double-blind, vehicle-controlled studies were conducted at 24 study sites with 436 subjects comparing imiquimod cream to a vehicle in treating AKs on the face and scalp. The cream was applied once daily, twice a week for 16 weeks. Complete clearance was obtained in 45% of the imiquimod group compared with only 3% of the vehicle group. Fifty-nine percent of the treatment group achieved partial clearance (75%) compared with 11% of the vehicle group. Overall, the treatment group had an 83% reduction in lesion count.27 In addition to AKs, imiquimod was recently approved for the treatment of superficial basal cell carcinomas (sBCC) on the body.28 Two identical multicenter, randomized, double-blind, vehicle-controlled, dose-response studies with 724 subjects having biopsy-proven non-facial sBCC were published in early 2004. The pooled results showed a clinical/histologic clearance rate of 75% in the five times a week for 6 weeks treatment group and 73% in the seven times weekly group. Histologic clearance rates were 82% for the five times weekly group and 79% for the seven times weekly group. Local site reactions were the most common adverse event, occurring more often in more frequently treated patients.29 Another study evaluated imiquimod 5% in the treatment of lentigo maligna in 28 subjects with histologically confirmed disease who were treated daily for 3 months. Of these patients, 26 (93%) completely responded to treatment. More than 80% of the 28 initial patients have been followed for over 1 year after treatment with no recurrence.30 Acitretin and Organ Transplant Patients Acitretin is the best studied systemic retinoid shown to be effective in decreasing the number of new AKs and non-melanoma skin cancers in organ transplant patients. The dosage and duration of treatment with acitretin is often mitigated by its side effects, and one randomized study looked at the use of low-dose acitretin in preventing malignancies.31 Researchers followed 26 renal transplant patients for 1 year with half on an acitretin dose of 0.4 mg/kg/day and half on 0.2 mg/kg/day. Both groups had a 50% decrease in AKs but no effect was noted on the development of new non-melanoma skin cancers.32 Recent recommendations on systemic retinoids in transplant patients suggest that initial therapy should be a low dose, between 10 to 30 mg/day, with the intention of increasing the dose to 30 mg/day if insufficient benefits are obtained and side effects are tolerated.31 Medications Antibiotics and Breast Cancer A retrospective, case-control study from the University of Washington found an association between the development of breast cancer and antibiotic use. Investigators looked at 2,266 female patients with primary breast cancer who were enrolled in a group health cooperative and matched them with 7,953 controls. They found an association between increased days of antibiotic usage and increased incidence of breast cancer. When examining the subset of patients who used antibiotics for acne or rosacea, the patients had the same increased risk for cancer as those using the medication for respiratory tract infections. Patients who took antibiotics longer than 500 days or took more than 25 prescriptions had more than twice the risk of developing breast cancer during the 17-year period studied.33 This article prompted a response from the AAD that discussed that the conditions that caused these patients to be on antibiotics may elevate the patient’s risk of developing cancer independent of antibiotic use.34 In addition, others have noted that the study had numerous missing values in the statistical analysis for patients with known or suspected risk factors for breast cancer such as body mass index, family history of breast cancer, and age of menarche. This possible incomplete analysis along with not evaluating other medications that might have had influence may compromise the results.35, 36 While future studies are warranted, the study authors agreed that their findings should not discourage women who need antibiotics to take them.37 Intravenous Immunoglobulin Intravenous immunoglobulin (IVIg) has continued to develop new uses in dermatology, proving effective in the treatment of dermatomyositis, autoimmune bullous disease, toxic epidermal necrolysis, graft-versus-host disease, Behçet’s disease, pyoderma gangrenosum and Kawasaki’s disease.38,39 Recommended guidelines for treatment with IVIg for mucocutaneous diseases include failure of or adverse effects from conventional therapy, contraindications to the use of high-dose long-term systemic therapy, and progressive disease despite conventional therapy.40 Although severe adverse reactions, including thrombophlebitis, anaphylactic reactions in patients with IgA deficiency, and acute renal failure can occur, the main inhibitor of more widespread use of IVIg therapy in dermatology is the high treatment cost.41 Initial concerns, such as the need for infusion centers for administration, have been obviated by the development of home infusion services. Isotretinoin The FDA voted in favor of enacting mandatory registration for both male and female patients taking isotretinoin along with registration of all healthcare providers who prescribe the medication. These regulations were prompted by noncompliance with previous voluntary regulations and would provide for a central registry of patients, physicians and pharmacists, similar to the thalidomide registration program.42 Since its initiation in 2001, the System to Manage Accutane-Related Terato-genicity (S.M.A.R.T.) program for monitoring of Accutane has resulted in only a small decrease in the number of pregnancies while patients are on the medication.43 When enacted, most of what has been voluntary for providers would become mandatory, and patients would need to undergo two pregnancy tests before receiving a prescription. Monthly pregnancy tests will also be required before refills are authorized. The tentative date for implementation of this program is July 2005.44 Finasteride Finasteride is the only oral FDA-approved product available for use in men with androgenetic alopecia. It is a specific inhibitor of type II 5-alpha reductase, which catalyzes the conversion of testosterone to dihydrotestosterone (DHT). DHT is the primary androgen in the prostate and is known to influence the development of prostate cancer.45, 46,47 Findings from the Prostate Cancer Prevention Trial were published this year in the New England Journal of Medicine. This study enrolled men 55 years of age or older with normal digital rectal examinations and a PSA level of 3.0 ng/ml or lower to the treatment arm (finasteride 5 mg/day) vs. placebo for 7 years. They concluded that finasteride prevents or delays the appearance of prostate cancer; however, a small percentage of patients in the treatment arm were noted to have an increased incidence of high-grade tumors.48 As expected, sexual side effects were more common in the finasteride-treated men, whereas urinary symptoms were more common in the placebo arm. Given the differences in patient population and medication dosage, which is higher than the 1-mg dose used in most dermatology practices, these results should be cautiously interpreted when discussing the long-term effects of finasteride with patients. Stevens-Johnson Syndrome and Carbamazepine The new world of pharmacogenomic analysis took a step forward with a study from Taiwan comparing 44 subjects who developed Stevens-Johnson syndrome (SJS) after taking carbamazepine with 101 subjects taking the medication without complications and 93 healthy controls. Researchers found 100% of the patients developing SJS had human leukocyte antigen (HLA) B*1502 compared with 3% of the carbamazepine-tolerant patients and 8.6% of healthy controls. Although this is a preliminary study with all subjects being from the Han Chinese population, these findings suggest a very strong association between an HLA marker and a disease (stronger than the association between HLA-B27 and ankylosing spondylitis). If confirmed by future studies, this may identify patients who are at risk of developing SJS from carbamazepine.49 Lasers and Light Therapy Laser Treatment for Acne The use of lasers and light-based treatment for acne vulgaris has continued to grow over the past year. Current FDA-approved devices for acne treatment include blue light (407 nm to 420 nm) and ClearTouch, a broad-spectrum (430 nm to 1200 nm) flashlamp light source. Both devices work by destroying the bacterium Propionibacterium acnes through targeting of porphyrins in the bacteria. The 1450 nm diode laser has been successfully used for acne and works by reducing the size of the sebaceous glands.50 The pulsed dye laser (595 nm) may decrease the erythema associated with acne, and although one study showed a significant clinical improvement, a second randomized controlled trial did not show similar improvement.51, 52 Although the small sample size and lack of controls in many of these studies call for further research in this area, this technology has become increasingly popular as a safe, fast, effective therapy for acne. Photodynamic Therapy Photodynamic therapy (PDT) has proven effective in the treatment of superficial BCC, Bowen’s disease and actinic keratosis (AK). This treatment results in better cosmesis than other conventional therapies, but patients often require multiple treatments and the treatment is typically painful.53 A randomized, placebo-controlled study with 243 patients receiving either a topical vehicle or 20% 5-aminolevulinic acid (Levulan) followed 14 to 18 hours later with blue light PDT (417 nm) showed improvement, defined as at least 75% clearance in 77% of the treatment group at 8 weeks and 89% at 12 weeks. Of the patients, 33% needed retreatment at 8 weeks, and this is reflected in the higher improvement rate at 12 weeks. Pain was a common side effect with erythema and edema also frequently occurring at the site of medication application.54 A second study looked at ALA/PDT using a long-pulsed pulsed-dye laser (595 nm) as the light source with an incubation time of either 3 or 14 to18 hours. The study found similar improvement in AKs with greater clearance noted on the head compared to body lesions. No difference in efficacy or safety was noted between the two incubation times.55 PDT has also been used to treat BCC with clearance rates between 79% and 100% for superficial BCC and 10% to 75% for nodular BCC using ALA/PDT.56-58 A prospective, randomized study looked at 101 patients with nodular BCC comparing methyl 5-aminolevulinate (Metvix) PDT with red light (570 nm to 670 nm) to surgical excision. This derivative of 5-aminolevulinic acid that is now approved by the FDA, is thought to have improved specificity for neoplastic cells and improved efficacy over 5-ALA. PDT was performed twice, 7 days apart, and response was measured by clinical, but not histologic, clearance. Of the patients treated, 24% of the PDT group needed to receive an additional two PDT treatments, and 83% of the PDT group obtained clinical clearance compared to 96% of the surgical excision group. The incidence of recurrence was higher in the PDT treated group than the surgically treated group and pain was common.59 Based on these findings, PDT may be an option for large or multiple lesions and for those patients with BCC who would not tolerate other treatments, or who wish to decrease the chance of scarring.53 Cosmetics Fillers Two hyaluronic acid-based dermal fillers, Restylane and Hylaform, and even more recently, Hylaform Plus, received FDA approval and neither require skin testing prior to administration. They are marketed for use in the correction of moderate to severe facial rhytides and folds by injection into the mid to deep dermis. The most common adverse effects experienced were local site reactions. These fillers join the existing products Cosmoderm/Cosmoplast, both human-collagen-based fillers that also do not require pre-treatment skin testing, and Zyderm/Zyplast, bovine collagen fillers that do require skin testing.60 The FDA recently approved Sculptra (poly-L-lactic acid) for treatment of HIV associated facial lipoatrophy.61 This filler works initially through a volume effect and subsequently through increased collagen synthesis. Sculptra is intended for injection into the deep dermis or subcutaneous layers and does not require skin testing before injection.62 Botox Already approved for treatment of glabellar rhytides, Botox cosmetic gained FDA approval for treatment of primary axillary hyperhydrosis if topical therapy is unsuccessful.63 Two multicenter, randomized, placebo-controlled, double-blind studies led to this approval. The first study compared a placebo to either 50 units or 75 units of Botox in the axilla with 81% of those receiving 50 units having a greater than 50% reduction in sweat production compared to 41% of the placebo group. There was no significant difference between the 50 unit and 75 unit groups and the mean duration of response was 201 days. The second study compared the use of 50 units of Botox to placebo and showed similar results with 91% attaining a greater than 50% reduction in sweat production at 4 weeks.64 Sclerotherapy Although not yet approved by the FDA, polidocanol sclerosant microfoam has been highlighted in several studies for its efficacy for varicosities and in the treatment of venous ulcerations. The advantages of foam over liquid sclerosants include the ability to reduce the amount of medication necessary by decreasing the drug dilution by blood and increasing the active surface area of the drug. An initial study found improved results using a foam over the liquid polidocanol sclerosant, both in the immediate post-treatment period and 1 year after treatment.65 The use of this sclerosant foam for treatment of venous leg ulcers was evaluated, and 83% of patients treated had healed ulcers at the 6-month follow-up. Although this study did not use a control group or comparison group to other conventional therapies such as compressive therapy or superficial venous surgery, the results appear promising if validated by future studies.66 Non-Surgical Facelift In the quest to develop a procedure that will improve skin laxity without the recovery time incurred from surgical lifting techniques, dermatologists have begun using non-ablative radiofrequency devices. They are thought to work initially through collagen contraction with subsequent increased collagen synthesis. Several studies have shown an improved appearance of the skin with decreased skin laxity. The nasolabial and mesolabial folds were more responsive to treatment than the neck, and younger patients responded more favorably than older patients. Side effects were minimal and included moderate pain with treatment, post-treatment erythema and soreness. The longevity of the effects is yet unknown and patients should be aware that improvement is subtle.67-71 A Productive Year This past year has brought many treatment advances as well as new medications and products into our realm. We’ve highlighted many of the advances in dermatology, including medical dermatology, infectious diseases, cutaneous carcinoma, medications, laser and cosmetic procedures that have developed over the preceding year, and we look forward to the changes in the coming year.