From the academy American Academy of Dermatology 1996 Awards for Young Investigators in Dermatology

FROM THE ACADEMY American Academy of Dermatology 1996 Awards for Young Investigators in Dermatology Sponsored by an educational grant from Janssen Pharmaceutica Research Foundation The role of Langerhans cells in the immunopathogenesis of HIV disease Andrew Blauvelt, MD,* National Cancer Institute, Bethesda, Md. Sponsored by Stephen I. Kat~ MD, PhD, Chief, Dermatology Branch, National Cancer Institute

Skin disease commonly occurs in patients infected with HIV, although the reasons are unknown. Langerhans cells, the major antigen-presenting cells of epidermis, have been previously reported to be infected with H1V (and depleted) in patients, although immune function of these cells isolated from HIV-positive patients had not been studied. In addition, normal Langerhans cells and other dendritic cells pulsed with HIV in vitro have been shown to transmit HIV to co-cultured T cells, thereby suggesting a possible role for mucosal Langerhans cells as "carriers" of virus to blood and lymph node T cells during primary exposure and infection with H1V. However, mechanisms by which Langerhans cells transmit virus were unknown. To determine the role that Langerhans cells play in the immunopathogenesis of HIV disease, we assessed the antigen-presenting cell function of both Langerhans cells isolated from skin of HIV-positive patients and of Langerhans cell-like dendritic cells (propagated from HIV-negative blood) exposed to HIV in vitro. In addition, we determined cellular mechanisms by which Langerhans cell-like dendritic cells interact with HIV in vitro, during both productive infection of these cells and transmission of virus from these cells to co-cultured T cells. Epidermis was obtained from suction blister roofs of 27 HIV-positive patients and 27 HIV-negative control subjects (including nine pairs of HIV-discordant identical twins), and Langerhans ceils were *Dermatology Branch, National Cancer Institute, Bldg. 10, Room 12N238, 10 Center Dr., MSC 1908, Bethesda, MD 20892-1908.

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tested for their ability to induce mitogen-, alloantigen-, and recall antigen-stimulated immune responses. Langerhans cell-like dendritic cells were propagated from cord and adult peripheral HIVnegative blood in the presence of exogenous cytokines (granulocyte-macrophage colony-stimulating factor, interleukin-4, and/or tumor necrosis factoro0, purified, and exposed to HIV (lymphocytotropic and monocytotropic strains) overnight. HIV-pulsed dendritic cells were then assessed for productive infection by HIV, their ability to transmit virus to cocultured target T cells, and their ability to process and present antigens to T cells. Langerhans cells from patients with AIDS were impaired in their ability to stimulate allogeneic T cells, although they were quantitatively normal, expressed normal levels of major histocompatibifity complex class 1I molecules, and stimulated secondary immune responses well (as assessed in the identical twin pairs). Immune function abnormalities were not detected in Langerhans cells isolated from HIV-posifive patients but without AIDS and in HIV-exposed Langerhans cell-like dendritic cells. In vitro-generated Langerhans cell-like dendritic ~ cells were productively infected with both strains of HIV at low levels in a CD4- and proliferationdependent/zidovudine sensitive manner. In contrast, the ability of these cells to capture HI-V (virus encircled by cell surface dendritic processes) did not require dendritic cell infection, that is, HIV was captared in a CD4- and proliferation-independent/zidovudine insensitive manner. Captured virus was transmitted and induced high levels of infection in antigen-stimulated co-cultured T cells. In summary, Langerhans cells isolated from skin of HIV-positive patients did not demonstrate markedly abnormal immune function, which suggests that cutaneous manifestations of H1V disease and, in a more broad view, the inability of HIV-positive patients to respond to common antigens is not due to

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defects in antigen presentation by dendritic cells. In addition, we found that HIV simultaneously interacted with Langerhans cell-like dendritic cells through two independent pathways; (1) cellular mechanisms were involved in productive infection of dendritic ceils by HIV and (2) the ability of these cells to capture vires was mediated through separate pathways. Elucidation of the mechanisms involved in HIV-Langerhans cell interactions may be critical in the design of vaccines or agents (or both) that block dendritic cell-mediated HIV infection of CD4 ÷ T cells, which may prevent depletion of these cells in IMV-positive persons.

Dermatology laboratory tests: A database containing difficult-to-locate information on rare dermatologic diseases Jean A. Byarlay, MD,* East Tennessee State University, Johnson City, Tenn. Sponsored by Lowell A. Goldsmith, MD, Professor and Chair, Internal Medicine, University of Rochester, Rochester, N.Y. The need to access and manage information is a frequent theme expounded when describing one of the challenges of modem medicine. Information in toto is abstract, but one of the real conundrums encountered in direct patient care is to obtain the relevant information efficiently and precisely so that it may be applied to the care of an individual patient. Reasoning that an on-line database kept up to date, available 24 hours a day, with no days off would be a practical solution to this problem, we developed a dermatologic-directed database on the Intemet to rink the physician with this information. Forms were mailed to more than 150 investigators studying genetic and immunologic disorders involving the skin. A similar form was created targeting patient advocate groups. Data from the completed forms was entered into a gopher in the medical library of the University of Rochester School of Medicine and Dentistry. The database was designed so that one may choose to search by a key word, browse a particular disease or researcher's name, or obtain information on a patient advocate group or disease registry. Information concerning each dis*Department of Internal Medicine, Division of Dermatology, East Tennessee State University, Box 21160A, Johnson City, TN 376140002.

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ease including the contact person, addresses, telephone numbers, type of test performed and specimen needed, shipping instructions, cost, and recent reference was placed in the database. Sample pages are enclosed in the appendix. The database may be directly accessed by the Intemet address (minergopher.lib.rochester.edu) or a World Wide Web site such as the home page of the Department of Dermatology at the University of Rochester School of Medicine and Dentistry (http://www.cc.rochester.edu/med/derm/). Twenty-nine researchers, representing 88 different diseases and 48 types of diagnostic tests, responded to our initial inquiry. Twenty patient advocate groups and five registries have also been added to the database to broaden the utility of the service. Since the database went on-line in January 1995, 11,199 accesses to the gopher have been documented, 1508 of these during October 1995. The Intemet is an electronic network that encompasses many services such as e-mail, MEDLINE searches, World Wide Web sites, and gophers. As a tool, the Intemet can be a valuable asset in the physician's daily practice. Many databases are being created daily; therefore much information is currently available on topics ranging from AIDS, the Centers for Disease Control and Prevention, dermatology, and research topics (even gardening). Because redundancy is not a problem with computers, relevant information may be stored and accessed from a variety of addresses instead of one file cabinet. In April 1991, the University of Minnesota developed an experimental program on the Intemet and called it Gopher. It caught on as an easily accessed and used database with many different topics found in multiple locations around the world. Once on the Gopher network, one can travel to any other Gopher database, much as a true gopher's tunnels are complex and interrelated. The Intemet is still in its infancy for medical access and has not reached its full potential in being an aid to physicians. As it exists today, the Intemet is ideal for a physician's medical practice because it can provide useful information and searching capabilities in a relatively short amount of time. This may change the way a difficult diagnostic dilemma is diagnosed and managed and will save time for the physician as well as the patient. With continual expansion of the network and users, the computer can

272 AAD become an integral part of every physician's practice.

Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2): A phase I clinical study and histopathologic assessment Scott L. Gottlieb,MD,* University of Pennsylvania,Philadelphia, Pa., and Rockefeller.University,New York, N.Y. Sponsoredby John Stanley, MD, Professorand Chairman, Department of Dermatology, Universityof Pennsylvania Psoriasis is a papulosquamous disease of the skin characterized by epidermal hyperplasia and immune activation. However, it is not known whether the epidermal hyperplasia is the result of the action of cytokines produced by activated T lymphocytes or whether the lymphocytes are nonspecifically activated by cytokines produced by the abnormal keratinocytes. The relative contributions of epidermal activation and immtmologic activation to the maintenance of active psoriatic lesions might be determined by examining the effects of therapies that specifically target either the activated epidermal cells or the activated T cells. To address the role of T cells in psoriasis, we used a fusion protein between human interleukin-2 (IL-2) and the membrane-translocating, cytotoxic domains o f diphtheria toxin (DAB389IL-2). Studies in experimental and clinical T-cell lymphomas indicate that this toxin is a unique tool for the selective destruction of cells bearing high-affinity IL-2 receptors. Because activated T lymphocytes but not keratinocytes in psoriatic tissue express IL-2 receptors, a clinical study with DAB389IL-2 could dissect the pathogenic relevance of activated T cells in psoriasis. Before conducting this clinical study, we verified that DAB389IL-2 specifically inhibits the proliferation of activated T cells but not epidermal keratinocytes in vitro. This was indeed the case, where lymphocyte proliferation was effectively inhibited by 10-11 DAB389IL-2. No consistent effects were noted on keratinocytes even at significantly higher concentrations. Reciprocal to these effects of DAB3891L-2, a diphtheria toxin--epidermal growth factor fusion protein (DAB389EGF) selectively in-

*Department of Dermatology, University of Pennsylvania, The Hospital of the University of Pennsylvania, 2 Rhodes Pavilion, 3400 Spruce St., Philadelphia, PA 19104.

Jotliilal of the American Academy of Dermatology February 1997

hibited keratinocyte growth but not lymphocyte growth. We proceeded to administer the D A B 3 8 9 I L - 2 to 10 patients with chronic, extensive plaque-type psoriasis. Each patient received five daily intravenous doses followed by a 23-day assessment period. Then an additional round of five daily doses was given, followed by another 23-day assessment period. The doses of DAB3s9IL-2 used in this study (100 kU/kg or 200 kU/kg, five patients at each dose level) are relatively low compared with ongoing trials in human T-cell lymphomas. Of the 10 patients treated with DAB389IL-2, four showed striking clinical improvement (as defined by the clearing or near-clearing of an index psoriatic plaque), four had moderate improvement, and two did not respond. Clinical severity, quantified with the Psoriasis Area Severity Index showed a mean 42% improvement, with up to 90% improvement in some patients. To monitor the action of DAB389IL-2 at the cellular level, we studied biopsy specimens of lesionai skin before and after treatment. In each of the 10 patients, the clinical outcomes after the study period correlated with reductions in quantitative measures of epidermal hyperproliferafion and T-cell infiltration. The four patients with marked clinical improvement showed marked reductions in total (CD3 +) lesion-infiltrating T cells (mean reduction, 80%) and intraepidermal CD3 + T cells (mean reduction, 95%), as well as marked reductions in epidermal thickness, in keratinocyte proliferation (assessed with a monoclonal antibody to the Ki-67 cell cycle antigen), and in the frequency of cells expressing keratin 16, a keratin synthesized only by activated keratinocytes. Overall, 8 of 10 patients showed reduced epidermal thickness after DAB3s9IL-2 treatment. The mean reduction of CD3 +, CD8 +, and CD25 + (IL-2 receptor positive) lymphocytes among the 10 patients treated was 46%, 55%, and 59%, respectively. The ability of DAB389IL-2, a selective immune modulator, to reverse the characteristic clinical and histopathologic features of psoriasis suggests that this disease represents a conditional state of tissue activation linked to activated T lymphocytes infiltrating defined regions of skin. A better understanding of the "autoimmune" nature of psoriasis will require the identification of antigens triggering T-cell activation and elucidation of potential immunoregulatory roles of non-major histocompatibility complex genes linked to psoriasis. In addition, fur-

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ther clinical trials are needed to better clarify the role of this novel agent in the treatment of psoriasis.

GIyCAM-1, a physiologic ligand of L-selectin, activates B1 and B2 integrins on peripheral blood lymphocytes: Implications for mediating the migration of lymphocytes to peripheral tissue Sam Tzen-yue Hwang, MD, PhD,* University of CaliforniaSan Francisco Sponsored by Richard B. Odom, MD, Professor and Interim Chair, Clinical Dermatology, University of California-San Francisco The trafficking of lymphocytes from blood to tissue reqnires the participation of a cascade of adhesion molecules. A family of adhesion molecules called "selectins" are currently thought to mediate early interactions between leukocytes and endothelium leading to the"rolling" of leukocytes along the vascular endothelium. L-selectin, a member of the selectin family that is found on all classes of leukocytes, mediates the initial attachment of leukocytes to high endothelial venules during the constitutive process of lymphocyte recirculafion at peripheral lymph nodes and at sites of inflammation. Next, it has been postulated that other factors trigger activation of leukocyte integrins, which mediate firm attachment of the leukocyte to the endothelium through high-affinity binding to integrin-specific ligands, such as intercellular adhesion molecule type 1 (ICAM-1) or fibronectin. The factors that trigger integrin activation in neutrophils are well known and include formyl peptides and interleukin-8 0L-8). However, the factors that trigger lymphocyte integrins have not been elucidated. This lack of understanding of a critical step in lymphocyte trafficking has prompted our search for additional factors that may contribute to selective lymphocyte homing. In our laboratory, we have purified chemical amounts of a high endothelial venule~lefived, mucinlike ligand of L-selectin called glycosylation-dependent cell adhesion molecule- 1 (GlyCAM- 1) from serum. This ligand differs from other ligands of Lseleclin in that it is secreted and not bound to the en*Department of Dermatology, Box 0316, University of California-San Francisco, 400 Parnassus Ave., A 328, San Francisco, CA 941430316.

AAD 273 dothefial surface, although it bears the same terminal carbohydrate residues that confer specific binding to the carbohydrate-binding domain of L-selecfin. The goals of this project are (1) to determine the biologic functions of GlyCAM-1 and (2) to isolate, characterize, and clone a ligand or figands of L-selecfirl in dermal microvasculamre. In the past year, we have been able to show that GlyCAM-1 stimulates the adhesion of human peripheral blood lymphocytes to ICAM-1 and fibronectin via [32 and [31 integrin-dependent mechanisms, respectively, in static adhesion assays of isolated lymphocytes to either a ICAM-l-transfected cell line or to purified fibronectin coated onto plastic wells. This stimulation in adhesion was mediated by L-selecfin because antibodies against L-selectin blocked this effect. To see whether GlyCAM-1 could "activate" integfins by inducing the high-affinity states of these integrins, we used activation-sensitive monoclonal antibodies, which verified that the addition of GlyCAM-1 to isolated lymphocytes increased the amount of activated integrin by more than fivefold for [32 integrins and at least twofold for [31 integrins. This result showed that, in addition to its function in mediating rolling interactions, L-selecfirl can function as a signaling receptor (and GlyCAM-1, the signal) for the activation of lymphocyte integrins--a critical step in the process of lymphocyte migration. The activation of lymphocyte integrins by L-selectin is mediated in part by the clustering of L-selectin because we have subsequently shown that cross-linking antibodies to cell surface L-selectin can duplicate the effect caused by the addition of GlyCAM-1. The mulfivalency of the carbohydrate residues by the highly glycosylated GlyCAM-1 affords a physiologic means by which clustering of Lselectin can occur in vivo. Finally, although all classes of leukocytes express L-selectin, only lymphocytes are capable of homing to peripheral lymph nodes, whereas neutrophils and other leukocytes appear to be excluded. We compared the expression of high-affinity [32 integrin epitopes in response to GlyCAM-1 in neutrophils and lymphocytes and found that only lymphocytes responded by upregulating their numbers of highaffinity [32 epitopes. Thus the secretion of GlyCAM- 1 by high endothelial venules in lymph nodes and at sites of chronic inflammation may be a selec-

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tive means to preferentially recruit lymphocytes over granulocytes at those locations. In terms of the second goal, we and others have shown that an antibody (MECA 79), which is relatively specific for L-selectin ligands, stains dermal vessels in conditions such as cutaneous T-cell lymphoma and psoriasis by immunohistochemical staining. The next phase of the project will involve characterizing the conditions necessary to stimulate expression of dermal L-selectin ligands. These conditions will then be applied to human dermal microvascular endothelial cells to determine whether wecan actively produce detectable L-selecfin ligands that can be isolated by affinity chromatography and then peptide sequenced to clone the human equivalent of GlyCAM-1. We have shown that a physiologic ligand of L-selectin on lymphocytes can activate at least two classes of integrins that mediate r u m adhesion and that this effect strongly favors lymphocytes over neutrophils. The mechanism for this activation appears to be the clustering of L-selectin on the cell surface via the multivalent carbohydrate epitopes found on GlyCAM-1. Ongoing studies include experiments that will elucidate the intracellular signaling pathway by which GlyCAM-1 stimulates lymphocyte integrins and whether L-selectin itself may be associated with integrins in the activation process. Furthermore, the second phase of the project will attempt to clone the human microvasculature equivalent of GlyCAM-1 in skin and to understand its biologic role in cutaneous inflammation. The clinical significance of understanding Lselectin/ligand interactions is already apparent in several animal models, which show that blocking this early interaction reduces inflammation. There is intense interest in synthesizing carbohydrate analogues of the L-selecfin-specific carbohydrates found on GlyCAM-1, and some of these analogues are already in clinical trials. Because we already have evidence that L-selectin ligands are synthesized in the skin in chronic inflammation, the cloning of L-selectin ligand genes is critical in understanding the molecular basis for regulation and synthesis of these important biologic glycoproteins that regulate leukocyte migration and may be the basis for the development of novel classes of drugs that interfere with L-selectin function or inhibit the synthesis of Lselectin figands.

Journal of the American Academy of Dermatology February 1997

Development of a transgenic mouse model for biologic assay of topical glucocorticosteroid potency Stacy D. Katchman, MD,* Thomas Jefferson University, Philadelphia, Pa. Sponsored by Jouni Uitto, MD, PhD, Professor and Chair, Dermatology and Cutaneous Biology, Thomas Jefferson University

This research project was based on the cloning of the entire human elastin gene, including approximately 5.2 kb of the 5'-flanking sequences, by Dr. Uitto and his associates at the Department of Dermatology and Cutaneous Biology, Thomas Jefferson University. These investigators then embarked on the development of a transgenic mouse line to examine the tissue-specific expression of the elastin gene, linked to the chloramphenicol acetyl transferase (CAT) reporter gene. They were able to demonstrate that the human elastin promoter was expressed in a tissue-specific and developmentally regulated manner tested in these transgenic mice. During sequencing of the human elastin promoter, it was noted that it contains three putative glucocorticosteroid response elements (GRE). To test the functionality of these putative cis-elements, transgenic mice were injected with triamcinolone acetonide or dexamethasone, two glucocorticosteroids in clinical use. Both subcutaneous and intraperitoneal injection of these steroids resulted in significant increases in the elastin promoter activity in various organs, including the skin. Furthermore, incubation of skin fibroblasts and aortic smooth muscle cell cultures established from these transgenic animals with triamcinolone acetonide resulted in marked increases in the elastin promoter activity. These studies therefore demonstrated that glucocorticosteroids act as powerful upregulators of the human elastin promoter activity in these transgenic mice and suggested that the three GREs are indeed functional. On the basis of these observations, it was suggested that topical application of glucocorticosteroids might also lead to enhanced activity of the elastin promoter. If true, this transgenic mouse line would provide a novel model for biologic assay of topical glucocorticosteroid potency. The importance of a novel assay was emphasized by the fact that many different models have been *Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S. 10th St., BLSB 450, Philadelphia, PA 19107.

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developed for the assay of topical glucocorticosteroid potency. Each model is able to highlight only one particular effect from the broad spectrum of glucocorticoid action. For example, the test that is most commonly used today to assay the potency of topical steroid preparations is the vasoconstrictor assay of McKenzie and Stoughton. This assay assesses the ability of alcoholic solutions of a glucocorticosteroid applied to erythematous skin to produce vasoconstriction, as subjectively observed by blanching of the skin. Other tests of corticoid potency rely on their ability to inhibit blister and pustule formation, the ability to prevent cell-mediated immune response to challenge with Rhus antigen, the ability to heal psoriasis plaques, and the ability to produce skin atrophy in psoriasis patients. To test the hypothesis that our assay system could correctly predict topical steroid potency, different commercially available topical glucocorticosteroid preparations were tested by topical application to the mouse skin at day 4 or 5, before the mouse grew hair. The goals of the study were threefold. First, experiments were performed to validate the assay and to establish its reproducibility. Second, the potencies of selected, commercially available topical steroid preparations in this assay system were compared with the established potencies, based on their vasoconstrictive ability. Third, the potential importance of the glucocorticosteroid vehicle in contributing to the potency of a particular

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preparation was assessed. Preliminary studies summarized in an article in Archives of Dermatology (1995;131:1274-8.) reported the findings, suggesting the usefulness of the transgenic mice as a model system for assaying the potency of topical glucocorticosteroid preparations. This article pointed out some limitations of this assay model, including significant histologic and pharmacokinetic differences between mouse and human skin. Thus the findings of this study were considered preliminary with respect to establishing this approach as a valid assay for relative potency in human skin. At the same time, the advantages of this test system over previously used methods include its ability to make quantitative, rather than qualitative, comparisons. Furthermore, this assay system tests for the biologic action of the glucocorticosteroid on a GRE, an element specifically responsive to steroids in a dose-dependent manner. The transgenic mouse system is also quick and can yield quantitative data within 72 hours. This feature makes this assay system particularly suitable for the rapid screening and development of new topical glucocorticosteroid preparations. Finally, it was noted that this mouse model represents a novel biologic assay system for glucocorticosteroids, and similar approaches can be taken to develop mice with transgenes that contain response elements to other classes of compounds, such as retinoids and vitamin D derivatives.

The 1997 Awards for Young Investigators in Dermatology will be presented to the winhers at the Janssen Reception to be held Saturday, March 22, 1997, during the annual meeting of the AAD in San Francisco.

EDITORIAL Inpatient dermatology: Should we let it die or should we work towards regional centers? Dermatology is predominantly an outpatient specialty. Although many dermatologists have hospital privileges, this is usually to maintain relations with other local physicians and to be available for consults. Office practitioners rarely if ever admit patients to hospitals; when they do, the patient is usually admitted by a primary care physician with the dermatologist acting as a consultant. In contrast, training centers with departments or divisions of dermatology historically have admitted patients to their inpatient services. In this setting, patients with diseases such as psoriasis, atopic dermatitis, drug reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, immunobullous diseases, as well as cutaneous ulcerations and infections have been managed directly by dermatologists. However, in this era of managed care and diagnostic related groups (DRGs), even academic centers have begun to decrease the number of hospitalized patients or have discontinued hospitalizing dermatology patients. Some of these patients are instead managed by nondermatologists and many with non-life-threatening but widespread and debilitating conditions "linger" with suboptimal treatment and a poor quality of life. The reasons for this shift are numerous. In addition to DRGs and managed care, the development of outpatient regimens for diseases such as psoriasis has facilitated the general transition toward outpatient services. Undoubtedly, outpatient treatment has improved the quality of life for many patients suffering from diseases such as psoriasis. However, a subset of patients From the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine (Drs. Kirsner and Kerdel), and the Department of Dermatology, New York University School of Medicine (Dr. Freedberg). Supported by the Dermatology Foundation Leaders Society Clinical Career Development Award for Health Care Policy (to R. S. K.) Reprint requests: Robert S. Kirsner, MD, Cedars Medical Center, University of Miami, 1400 NW 12th Ave., 6 South Dermatology, Miami, FL 33136. J Am Acad Dermatol 1997;36:276-8. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0

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still exists that requires inpatient care. Given this trend we have described, inpatient management of skin diseases treated by dermatologists could become of historical significance only. If so, should we allow this to occur or should we try to revitalize inpatient care of skin disease by dermatologists? We think the latter is the right decision, but to accomplish goal this cooperation and support among all members of our specialty are essential. Therefore we believe our entire specialty should be informed of this issue. THE I M P O R T A N C E OF INPATIENT DERMATOLOGY

We believe that inpatient treatment of dermatologic diseases under the direction of dermatologists should not be abandoned for several important reasons. Most importantly, it produces the best results for our patients. The Goeckerman and the Ingram regimens for psoriasis were developed for hospitalized patients and are a major part of the care of many patients. Even with newer and powerful drags and physical modalities, they are still important weapons. Hospitalization of patients with refractory leg ulcers as well as isolation of patients with suspected contact allergens are also important tools in the dermatologic arsenal. Specialized skilled nursing care around the clock is vital for patients with severe skin disease and only on a bona fide dermatology unit can patients get the care they deserve. Why should our patients receive less than optimal care? As dermatologists we are ultimately responsible for skin care in this cotmtry, even though the majority of patients with skin disease may currently be seen by nondermatologists and other specialties hospitalize patients with severe skin disease. Traditionally dermatologists have provided inpatient skin care and we believe dermatologists should continue to do so. Hospitalized patients with skin disease typically have more severe skin disease than nonhospitalized patients. Loss of this subset of patients would likely shift the severity of disease within our specialty to

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milder and perhaps, as viewed by others, less medically important problems. We need to retain the ability to treat patients with severe skin disease for several reasons. The first and by fax the most important is to ensure that such patients get the best care. The more severe their disease, the more patients need a dermatologist. Second, dermatologists should treat the entire spectrum of skin disease. It would be unfommate if dermatologists did not or could not care for patients with the most severe skin disease. Third, it is a way to remind patients, other physicians, and legislators of the importance of dermatologists. It is also possible that future allocation of federal funds may be based on a formula that includes inpatient care. In this scenario, dermatology would be a big loser. Finally, the inpatient setting is an ideal place to study new therapies. As an example, pulse systemic (intravenous) corticosteroids might never been utilized for the treatment of pyoderma gangrenosum and pemphigus vulgaris if dermatologists had not treated hospitalized patients. The present course we are on will likely lead to either the end of inpatient dermatology or leave us with minimal activity. The consequence of this occurrence would be loss of an important part of our specialty and it would jeopardize future training in this important area. Future dermatologists will not have the oppommity to learn about skin behavior under the most severe conditions and become confident in their ability to deal with all situations. POSSIBLE SOLUTIONS

When caring for severely ill patients, most dermatologists are either unable to afford the time away from their office or are not inclined to do so. It is difficult to schedule time on an episodic basis or to take time away from a busy practice to see a single hospitalized inpatient on a daily basis. The office practitioner also lacks a team of skilled nurses trained to care for patients with skin disease. Therefore one solution is for community dermatologists to refer patients needing hospitalization to an inpatient dermatology service. This would not only allow a sufficient volume of patients to keep a unit active but would also ensure a critical number of these patients to enable continued care and investigation by dermatologists with a special interest in these patients. These physicians are also likely to be most knowl-

Kirsner, Freedberg, and Kerdel 277 edgeable about and have at their disposal the latest scientific tools that can be brought to bear on these serious but uncommon skin diseases. It would also allow sustained communication between community and academic dermatologists. Dermatology residents also would benefit from training in the care of hospitalized patients. However, many dermatology programs have already discontinued or severely reduced their inpatient service. They have found that reduced volume has often made inpatient dermatology financially impractical. Another solution is the development or designation of specific sites as inpatient centers. In other fields and contexts similar centers have been called Centers of Excellence. Even in our own specialty we have a few Research Centers of Excellence but what we are proposing are "service" Centers of Excellence. These new Dermatologic Centers of Excellence could be either within selected cities or in regions of the United States. This designation would allow dermatologists as well as other referring physicians to be aware that dermatologic care for patients with skin disease is still under the auspices of dermatologists. By limiting the number of centers, the larger volume of patients referred to these centers would ensure proficiency, cost effectiveness, and fmancial feasibility. In time, managed care companies and other insurance carriers would be aware of centers that provide cost-effective quality care for their patients. Patients would then be encouraged to travel to these centers to receive faster, better, and less expensive treatment. The cost savings could be used to compensate the patients for the cost of travel and other family dislocation. Dermatology residents at programs other than those designated as inpatient centers should be provided the opportunity to rotate through the inpatient services at one of these centers. This oppommity would provide continued education for future dermatologists in inpatient dermatology. Many programs have already serf-selected themselves to be designated centers by continuing to treat inpatients with dermatologic diseases. There is, however, the need for rapid development of inpatient services in regions that are currently underserved. Dermatologists from these regions should be encouraged to begin the planning for such centers. In conclusion, dermatology has begun to lose an

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important part of our specialty. With current trends, the vast majority of inpatients with skin disease will be treated by physicians other than dermatologists. This will lead to an important and probably unwanted shift of our specialty toward caring only for patients with less severe skin disease as well as failing to provide our patients with the best care possible. Our goal must be to ensure care of the highest quality for patients with skin disease by rejuvenating hospitalized care of these diseases by dermatologists. A realistic way to accomplish this goal is to create regional inpatient dermatology units (Centers of

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Excellence) to treat hospitalized patients with skin disease. Practitioners and faculty from other academic centers should be encouraged to refer patients needing hospitalization to these centers. In ram, residents throughout the country's training institutions should rotate through these units as part of their education. Robert S. Kirsner, M D a Irwin M. Freedberg, M D b Francisco A. Kerdel, BSc, M B B S a Miami, Florida ~ N e w York, N e w York b