Feature: Atopic Dermatitis Update - Larisa Hubbs, Executive Editor, and Stefanie Tuleya, Managing Editor Highlights of news, trends and research. Plus, experts discuss the impact the black box warnings on TCIs have had on some dermatologists’ prescribing habits. Economic Burden of Atopic Manifestations in Atopic Dermatitis Patients Atopic dermatitis often predates development of atopic manifestations, such as asthma, symptoms indicating allergic rhinitis, allergic conjunctivitis, and adverse reactions to foods. Researchers, wanting to estimate the incremental economic burden attributable to atopic manifestations, designed a study to: • examine and compare the characteristics of AD patients (with and without atopic manifestations). • determine the relative risk of developing atopic manifestations in patients with atopic dermatitis. • calculate incremental costs attributable to atopic manifestations in patients with atopic dermatitis. For the study, researchers used MarketScan research databases from Jan. 1, 1999, through Dec. 31, 2004, which included claims data for pharmacy and medical services and prescriptions received by more than 3 million privately insured people enrolled in various managed-care organizations in the United States. The date of the first atopic dermatitis diagnosis during the index period was defined as the index date. Patients were followed from the index date until either the end of their enrollment, or, if earlier, the end of the study period. Patients were included in the study if they had one of the following ICD-9 codes based on primary or secondary diagnoses during the index period: atopic dermatitis or related conditions (691.8x) or contact dermatitis or other eczema with unspecified cause (692.9x). Patients also included were never diagnosed with atopic dermatitis during the 1-year history period, did not have any atopic manifestations of asthma (ICD-9 codes of 493), allergic rhinitis (477), allergic conjunctivitis (372.05 or 372.14), or food allergy (693.1x, 692.5x, 995.60) during the 1-year history period, and had continuous health and prescription coverage during the history and follow-up periods. Results The annual treatment costs per atopic dermatitis patient after developing atopic manifestations were 2.3 times higher than those before atopic manifestations. • Treatment costs prior to developing manifestations were $205 (95% confidence interval (CI)=$193-$216). • Treatment costs after developing atopic manifestations were $681 (95% CI=$639-$709). • Incremental costs were $476 (95% CI=437-$507 p<0.001) per patient per year. • Among atopic dermatitis patients with manifestations, the largest portion of the incremental treatment costs attributable to atopic manifestations was outpatient services ($272), followed by prescription drugs ($169) and hospitalization ($35). Attributable costs to atopic dermatitis and atopic manifestations were calculated based on primary or secondary ICD-9 diagnosis codes in claims data, so it was not possible to verify whether the services were used for atopic dermatitis or atopic manifestations only. Atopic dermatitis patients with atopic manifestations consumed a substantial amount more of medical and prescription services than atopic dermatitis patients without manifestations. Treatment costs increased by 2.3 times for atopic dermatitis patients after the development of atopic manifestations. Poster Authors: Dong-Churl Suh, Insun Choi, Monika Raut, Douglas Gause.   How has the black box warning for topical calcineurin inhibitors (TCIs) affected the way in which you prescribe these drugs? Mark Lebwohl, M.D. Patients are aware of the black box warning but not as much now as when it was first in the news. They tend not to look at package inserts. This warning has not affected the way in which I prescribe these drugs. I explain to patients that the warning was very controversial and probably unwarranted. In fact, using TCIs is frequently a much safer choice than prescribing a strong steroid. TCIs have undergone more safety testing than many systemic drugs. When given orally to animals at much higher amounts than the maximum human exposure, they are associated with an increase in lymphomas. Based on their proven safety in large clinical trials, I, and most of my colleagues, do not believe that a black box warning was warranted. I encourage patients to use these drugs and to ignore the black box warnings. Dr. Lebwohl is Professor and Chairman of the Department of Dermatology at the Mount Sinai School of Medicine in New York City. Amy S. Paller, M.D. The black box warning has largely not affected the way in which I prescribe the topical calcineurin inhibitors (TCIs) pimecrolimus (Elidel) or tacrolimus (Protopic), although it has increased the time I spend with each patient for whom I prescribe these medications. Because of the media scare or the urging of the primary care doctor, many patients on a TCI stopped using their medication when the FDA issued the public health advisory regarding the potential risk for cancer. At that time, we were receiving about 100 calls per day, and everyone in the office was providing information to families. Other patients just stopped the medications, then generally experienced flares, and advised me that they had stopped using the medications at their next appointments. There has been a significant decrease in the use of TCIs, but I think this primarily reflects fewer prescriptions from primary care physicians. Doctors with less experience using TCIs tend to be more concerned about the warnings. Although we are all concerned about safety, especially in pediatric patients, and recognize that we need a few more decades for total assurance, I have been told by some doctors that their hesitancy to use TCIs is based on legal concerns. While I continue to prescribe TCIs, I now spend quite a bit of time discussing the FDA warning with patients. I discuss the theoretical risk of cancer, but explain the science behind the use of topical medications versus systemic medications, and the lack of correlation at this time. I stress the importance of sun protection as well as continued monitoring for potential side effects. I also try to document the discussion. I am comfortable using TCIs, but if I sense that a patient is very concerned about potential side effects, I don’t push it. I use the medications off-label, particularly with the facial area of children with vitiligo, and also in infants. However, I most commonly use these medications on a rotational basis with topical corticosteroids to minimize the continued usage of either type of topical medication. Each patient requires an individual treatment plan. Our role as physicians is to be only as aggressive as is needed to safely treat the dermatitis, and to use less aggressive medications or even emollients alone as the condition improves. The studies to date with both tacrolimus ointment and pimecrolimus cream show safety of TCIs for a short time, and for as long as 4 years in a relatively limited number of patients with tacrolimus ointment. Until we have more long-term data, I like to juggle the use of both corticosteroids and TCIs, and teach parents and patients how to make choices based on their responses and needs. Dr. Paller is the Walter J. Hamlin Professor and Chair of Dermatology, Professor of Pediatrics at Northwestern University, Feinberg School of Medicine in Chicago, IL. Lawrence F. Eichenfield, M.D. Most dermatologists have been very frustrated with the incredible delay between when the “black box issues” were first brought up and discussed at the Pediatric Advisory Committee and when the warnings were finally published. Many of us are in agreement that the degree of the warning seems out of step with the perceptions of these drugs’ safety when used in their topical formulations and when used appropriately. It is clear that the drugs are now being written at a lower rate than before, especially among pediatricians, and we are seeing more patients referred by pediatricians who are under-treating patients due to fears about TCIs in addition to traditional fears of topical corticosteroids. My practice peers and I have not changed our prescription patterns because we generally niched the TCIs as second-line therapies that are especially useful in patients with frequently flaring or persistent eczema that otherwise required almost constant use of topical corticosteroids. We continue to use the products liberally for facial and intertriginous dermatitis, as well as “off-label” for non-dermatitis indications, such as facial vitiligo. Dr. Eichenfield is Professor of Pediatrics and Medicine (Dermatology) and Chief, Pediatric and Adolescent Dermatology at the University of California, San Diego School of Medicine and Children’s Hospital in San Diego. Alan B. Fleischer, Jr., M.D. The black box warning has not affected my prescribing behavior at all. Since randomized controlled trials in humans show that the risk of oncogenesis is lower than the oncogenesis risk associated with using corticosteroid agents, I side with the evidence suggesting safety. Corticosteroids are excellent agents, but are not ideal long-term drugs. Over the years, corticosteroid agents have not been studied long-term. Although my prescribing habits haven’t been profoundly affected by the black box warning, the way in which I counsel patients has been. It is important to broach the topic with patients before their pharmacist tells them, “This drug causes cancer.” I now explain the human vs. animal data to patients and differentiate between systemic use, which has been shown to increase the risk of cancer, and topical use. Undoubtedly, some patients may not fill their prescriptions for these drugs, or they may be more reluctant to use them appropriately. I saw one patient this week who has been using a medium-potency corticosteroid daily for months and the TCI only for flares. Needless to say, I explained to her that this is the more hazardous approach to take. Patients with non-atopic conditions also need counseling in the same way. These agents remain among the safest of drugs ever introduced into the marketplace. My practice benefits by having large numbers of treatment options, and intelligent patients and their families can understand the primarily political motivation behind these warnings, which do not rest on human scientific information. Dr. Fleischer is Professor and Chair of Dermatology at Wake Forest University School of Medicine in Winston-Salem, NC. Adelaide A. Hebert, M.D. I continue to use the topical calcineurin inhibitors in much the same way that I did prior to the black box labeling. The FDA’s statement that “there is no known proven causal” effect between malignancies in humans and the use of TCIs is very important. To date, not a single case of malignancy has been directly attributed to these topical medications. This is the first time that the FDA has supported a black box warning without a “known adverse event” in the patients treated with a given medication. All previous black box warnings applied to medications for which a known adverse event in humans occurred. In addition, many physicians and patients are not aware that the FDA has given black box warnings in the past only to withdraw them after attaining additional clinical data. Both of the TCIs represent the most studied medications for atopic dermatitis that have ever been in the armamentarium of dermatologists and other physicians. Both short- and long-term studies support the safety of this drug class in topical formulation. Many of the topical steroid preparations currently approved by the FDA for use in inflammatory dermatoses have far less clinical trial data and shorter drug application study times. The TCIs offer certain advantages over first-line treatments in some patients. The basic way that I manage patients with atopic dermatitis has not changed, although visits do take longer when parents or patients have concerns about the black box warnings. I do provide education regarding the warning when I use these medications to treat atopic dermatitis. Some insurance companies place additional obstacles on the use of TCIs in pediatric patients below the age of 2 years, and some refuse to pay for these medications. Although the use of TCIs in this age group is considered “off-label”, many drugs for children fall into this category. With regard to patient awareness of the black box warning, concerns seem to have abated probably because the actual wording of the black box warning came 11 months after the FDA’s statement was issued that such a warning would be forthcoming. While some patients and physicians are more cautious about the use of TCIs, many realize that the FDA has not been apprised of any cases of cancer to date that have been directly attributed to TCIs. Dr. Hebert is Professor of Dermatology at The University of Texas Medical School in Houston.   Patients Flare Upon Discontinuing Treatment with TCIs Pimecrolimus cream 1% (Elidel), with as-needed pulses of a moderately potent topical corticosteroid, has been proven effective in treating atopic dermatitis. However, anxieties resulting from the black box warnings on topical calcineurin inhibitors (TCIs) have caused patients and caregivers to discontinue use of pimecrolimus and seek alternative, often very potent, interventions with varying degrees of success. Researchers presented four case studies in a poster at this year’s American Academy of Dermatology Annual Meeting in San Francisco. The patients in the case reports were between the ages of 3 and 8 and were all well controlled with pimecrolimus cream (in combination with a low- or mid-potency topical corticosteroid, as required) prior to discontinuing treatment. Two of the patients had moderate and two had moderate to severe atopic dermatitis. Within 2 weeks of discontinuing pimecrolimus treatment, all four patients experienced significant atopic dermatitis flare, including generalized, near-erythrodermic disease. The flares necessitated prescribing potent therapies, including oral cyclosporine in two of the four cases. Success of the interventions was variable. CASE 1 A 6-year-old Hispanic male patient had significant worsening of his atopic dermatitis once discontinuing pimecrolimus treatment. His facial erosions and severe pruritus made him extremely uncomfortable and unable to concentrate in school. To try to control the flare, he was treated with a brief course of topical cyclosporine and improved after a 2-week period. He was then tapered to a mid-potency topical steroid. This patient had not experience any flares during the 12 months he was using intermittent b.i.d. application of pimecrolimus 1% cream and emollients. Case 2 An 8-year-old Hispanic female patient had an abrupt flare of atopic dermatitis after her parents discontinued her used of pimecrolimus in February 2005 after the FDA warning. Her skin grew red, raw and tender with occasional pustules developing on her abdomen. Control of this flare required oral cyclosporine and twice-weekly dilute bleach baths. It took more than 3 weeks to bring the flare under control. She now requires wet wrap dressings with triamcinolone 0.1% cream and UVA/UVB phototherapy three times per week. Case 3 A 4-year-old Caucasian male patient had discontinued pimecrolimus treatment after the 2005 FDA warning. Within 10 days, his eczema worsened with increasing pruritus and erythema. He had been well controlled with pimecrolimus and rare use of a low-potency topical steroid and emollients for 18 months. His parents brought him to the dermatology clinic after he lost sleep due to itching and developed superficial erosions from scratching. Control of the eczema flare was possible after using potent topical corticosteroids on the trunk and extremities for 3 weeks. CASE 4 A 3-year-old fair-skinned female patient was described as having increased redness in her skin after her parents discontinued pimecrolimus cream abruptly after the FDA warning. Her atopic dermatitis had been well controlled with b.i.d. application of pimecrolimus cream and emollients since she was 2 years old. Upon presentation of her condition after stopping pimecrolimus, improvement only started to be seen after 3 to 5 weeks of treatment with a potent topical corticosteroid. Warning About Discontinuing Pimecrolimus Treatment Researchers concluded that physicians, caregivers and patients should be aware that discontinuing treatment with pimecrolimus cream can have disease-management consequences for patients, including significant exacerbation of disease and the need to resort to more potent alternative treatments. Poster Authors: Adelaide A. Herbert, M.D., and Jason H. Miller, M.D.   Examining the Efficacy and Safety of Atopiclair To examine the efficacy and safety of MAS063DP (Atopiclair) in adult patients with mild to moderate atopic dermatitis, a multi-center, randomized, vehicle controlled study was conducted. For this study, the 218 patients, 18 years of age or older, were randomized to apply Atopiclair (145 patients) or vehicle (73 patients) to their affected areas three times per day for 50 days. Measurements on eczema area and severity index (EASI) pruritus, (visual analog scale [VAS] 0 to 100 mm), percentage of affected body surface area (BSA) and investigator global assessment (IGA) of clinical response, need for rescue medication, patient acceptance and adverse events were taken at baseline, day 8, 22, 36 and 50. Results EASI. At day 22, the vehicle group showed no change (-0.15) compared to baseline, while there was appreciable improvement (-3.82) in the Atopiclair group, a statistically significant difference (p<0.0001). The changes in EASI scores versus baseline showed statistically significant differences between treatments at all visits (p<0.0001). Need for Rescue Medication. In the event of flare, patients were allowed a rescue medication (topical cortico-steroid) at any time during the 50-day period. A total of 37 patients (17%) opted to use one — 8 patients (5.5%) in the Atopiclair group versus 29 (39.7%) in the vehicle group. The difference was statistically significant (p<0.0001). VAS. The mean VAS values of itch on one target lesion (selected at baseline) decreased sharply from baseline (70 mm) to day 50 (12 mm) in the Atopiclair group versus a slight decrease observed in the vehicle group (from 70 mm to 50 mm). This difference was also statistically significant (p<0.0001). Patient Acceptance. In the Atopiclair group, 92% said they would definitely (77%) or likely (15%) continue using Atopiclair. Also, 95% said that their skin did not look greasy after applying the treatment, and most found the odor to be pleasant or neutral. n Poster Authors: William Abromovits, M.D., Steven E. Kempers, M.D., et al.   Ineffective Skin Barrier and Immune Reactions A recent study by researchers at the National Human Genome Research Institute, the National Eye Institute and the National Institute of Child Health and Human Development, all part of the National Institutes of Health, found that excessive production of specific protein disrupts the protective properties of the skin barrier. The findings, which were published in the May issue of The Journal of Clinical Investigation, found that once the skin barrier is compromised, immune-system-stimulating chemicals, or allergens, can enter the body and cause an inflammatory reaction that stimulates skin cells to grow rapidly, further diminishing the protective function of the skin. This causes the compromised barrier to become porous to allergens that stimulate more inflammation — a cycle that eventually produces conditions such as psoriasis and eczema. Researchers found that creating a temporary, artificial barrier on the skin to block the incoming allergens could possibly break this cycle. To test whether a defective skin barrier can produce these diseases, a team of NIH researchers focused on the gene connexin 26, which makes a protein that forms connections between skin cells that create the normal barrier. Connexin 26 is turned on when skin is damaged, and turned off once the skin is repaired. To determine the gene’s role in psoriasis, researchers created a line of transgenic mice that over-produce connexin 26. The resulting mice developed psoriatic-type skin sores, just like humans with psoriasis. This discovery broadens the basic understanding of the cause of psoriasis and eczema, and may contribute to the understanding of asthma and hay fever, which result when allergens penetrate the tissue barriers of the lungs and nose, respectively. Researchers suggest that the genetic studies show that research should now focus on both turning down the immune response, as well as restoring a normal skin barrier.   Evaluating the Impact of Steroid Pre-Treatment on Tacrolimus Therapy A double-blind, randomized, multi-center study of adult and pediatric patients with moderate to severe atopic dermatitis was conducted to evaluate the impact of topical corticosteroids on the safety and efficacy of tacrolimus ointment (Protopic) in the short-term treatment. Patients participating had to have a washout of up to 4 weeks prior to randomization for previous systemic atopic dermatitis treatments and a 4-day washout for prior topical immunomodulator or corticosteroid use. Patients were randomized to the tacrolimus therapy alone group (190) or to the steroid pre-treatment for 4 days group (193). Patients were evenly distributed with respect to age, gender and race. Results Patients were evaluated at day 4, week 2, week 6, week 12, and at the end of the study at week 16. Improvement in Eczema Area and Severity Index scores, percent of body surface area affected and physicians static global assessment (PSGA) were comparable in all groups at 2 weeks and beyond, with about 70% of the patients who completed the study reaching clear or almost clear in the PSGA by week 16. Overall, reported adverse events were similar in the tacrolimus and steroid pre-treatment patients, though fewer patients pre-treated with a topical steroid experienced application site burning within the first few days.   Extending Remission Times A study of 74 patients with atopic dermatitis, who underwent treatment with a topical barrier repair cream (MimyX Cream) in conjunction with a non-medicated emollient cream (vehicle) vs. vehicle alone, showed that the side treated with the addition of MimyX Cream experienced a remission period that was 48% longer. Patients also experienced 25% more flares to the areas that were not treated with MimyX Cream. (At left are side-by-side comparisons of patients treated in this study. The patients’ right arms were not treated with MimyX Cream in the study; patients’ left arms were.) MimyX Cream, a steroid-free, topical prescription barrier repair cream, can be used alone for maintenance or with short-term anti-inflammatory agents when patients experience flares. During the multi-center, investigator-blinded, randomized 12-week long study, patients applied MimyX Cream and vehicle twice daily to all affected areas on one-half of their body; on the other half, they applied vehicle alone twice a day. Patients were evaluated at the beginning of the study and again at weeks, 2, 4, 6, 8, 10 and 12. The option of using triamcinolone cream 0.1% as a “rescue” medication was allowed, and 55% of patients on the MimyX side opted to use it, while 68% used it on the vehicle-only treated side. Side effects reported in the study were minimal, and only 4% of patients experienced them.   Anacor Announced Phase II Results Anacor Pharmaceuticals announced promising results from a Phase IIa study of AN0128, a novel topical anti-inflammatory drug candidate for atopic dermatitis. The multi-center, randomized, placebo-controlled study of AN0128, enrolled 103 patients with mild to moderate atopic dermatitis at eight centers. Patients in the study received twice-daily treatment for 4 weeks with either AN0128 Cream 1% or vehicle cream. Efficacy was measured by a 6-point (clear, almost clear, mild, moderate, severe, very severe) investigator static global assessment (ISGA) scale. At the end of the 4-week study, 47% of the patients enrolled with moderate atopic dermatitis in the AN0128 group showed at least a two-grade improvement in the ISGA scale and were judged by investigators as “clear” or “almost clear” of disease, while 29% in the vehicle group reached the same endpoint. AN0128 was well tolerated at the application site. No serious adverse effects were reported.n Ceragenix Received IRB Approval for Eczema Study Ceragenix Pharmaceuticals, Inc. announced that it has received Institutional Review Board (IRB) approval to commend a multi-center study involving 90 children aged 6 months to 18 years with moderate to severe atopic dermatitis. The study, which was expected to begin in July in dermatology offices in Santa Rosa, CA, and Trenton, NJ, will compare EpiCeram, a non-steroidal skin barrier cream that received FDA marketing clearance in April, to Cutivate, a commonly used mid-strength topical steroid that is approved for use in infants and children. The objective of the study is to determine if EpiCeram can be as effective as a mid-strength steroid in alleviating the signs and symptoms of eczema in pediatric patients. The outcome measurements of the study will include eczema area and severity index (EASI) scores as well as evaluations based on Scorad and Ossad scores. Both products will be applied twice a day in the study, and patients’ trans-epidermal water loss will also be measured throughout the study. FDA Approves New Size Available for Locoid Ferndale Laboratories recently announced that it received FDA approval to launch a 60-g tube of its hydrocortisone butyrate 0.1% (Locoid Lipocream Cream). According to Ferndale, the new size, which will be available in August, will offer added convenience as a treatment for larger body areas and the possibility of reduced insurance co-pays. The company says it is launching the new size in response to continued demand from its core dermatology customers. Locoid Lipocream is indicated for first-line relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.   Skin & Aging - ISSN: 1096-0120 - Volume 14 - Issue 7_2006 - July 2006 - Pages: 64 - 70