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Dermatologic therapy in the new millennium
Dermatologic Therapy in the New Millennium ANDREAS D. KATSAMBAS, MD ALEXANDER J. STRATIGOS, MD Introduction At the turn of the new millennium, dermatology faces new challenges and exciting opportunities. Over the past century, dermatology has been completely transformed from a rather focused and sequestered specialty to a broad, diverse, and multifaceted field that encompasses many active and developing branches, such as dermatopharmacology, dermatooncology, dermatoimmunology, dermatopathology, dermatologic surgery, and pediatric dermatology. Reflecting back to the beginning of the 20th century, dermatology was a morphologic specialty that was primarily focused in the clinical description and classification of skin diseases. There was very little known about the pathology and pathophysiology of cutaneous disorders, and the therapeutic armamentarium of dermatologists were limited to a handful of effective agents. Advances in microbiology, pathology, and, later on, immunology and genetics refined our concepts of normal skin function and helped us understand the etiopathogenesis of many dermatologic diseases. The skin was recognized not just as an inert wrapping of the body that protected it from the environment and maintained its homeostatic balance, but also as a vital organ that contributes to the general body physiology and interacts closely with internal organs. Our knowledge of skin biology has greatly expanded, as we now appreciate the delicate details of keratinocyte differentiation, the role of stratum corneum lipids in the maintenance of the barrier function, the synthetic pathways of extracellular matrix, the process of melanization, the cellular and subcellular effects of various environmental agents (eg, ultraviolet radiation), and the molecular events that characterize the growth and replication of epidermal cells. Using the tools of molecular biology we have been able to clone successfully many skin genes that regulate important functions of the skin and to identify others that are responsible for certain genetic diseases of the skin. From the Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Athens, Greece. Address correspondence to Andreas D. Katsambas, MD, Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, 5 Dragoumi Street, Athens 161 21, Greece. © 2001 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
The elucidation of the underlying pathophysiology of skin diseases has fostered the development of new pharmaceutical agents that have revolutionized the management of skin diseases. The development and use of topical steroids in a variety of dermatoses, the production of new antibiotic, antifungal, and antiviral agents, the use of systemic corticosteroids for the management of life-threatening condition (eg, pemphigus vulgaris, systemic lupus erythematosus), the chemotherapy of psoriasis with antimetabolites and immunosuppressives, and the use of topical and systemic retinoids for acne, keratinization disorders, and skin cancer chemoprevention are only some examples of the major advances accomplished in dermatologic therapy. Mortality and morbidity from cutaneous diseases, hence, has decreased significantly, with malignant melanoma being currently responsible for nearly half of the deaths attributed to dermatologic diagnoses. In addition, the application of modern sophisticated laboratory techniques such as immunofluorescence, electron microscopy, in situ hybridization, and polymerase chain reaction have offered new insights into dermatologic research and diagnosis and have aided significantly to the selection of the appropriate treatment.
Factors That Will Influence Dermatologic Therapy What will be the direction of dermatologic therapy in the next millennium? At the present time, the answer to this question remains elusive. The tremendous advances in immunology, molecular biology, and genetics will probably play a leading role in the diagnosis, prognosis, and treatment of skin diseases. There are, however, certain important factors that, in our opinion, will influence the progress of skin therapy in the following years. First, the diagnosis and classification of skin diseases will be made based on a new set of cellular and molecular criteria rather than the traditional pattern recognition techniques. Inflammatory and proliferative diseases, such as atopic dermatitis, psoriasis, and mycosis fungoides, will be completely reclassified based on new pathophysiological knowledge, and novel prognostic variables or molecular markers will greatly influ0738-081X/01/$–see front matter PII S0738-081X(00)00214-5
66
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KATSAMBAS AND STRATIGOS
ence treatment-guided decisions, along with clinical and histologic parameters. The changing environment is another factor that will influence the course of dermatologic therapy in the future. The environmental pollution and the ecologic damage that have been brought about by the industrialization of the 20th century have ultimately affected human health with serious and unpredictable consequences. The use of chlorofluorocarbons and nitrogen oxides, for example, has led to a significant depletion of the ozone layer of the atmosphere. As a result, the amount of ultraviolet (UV) radiation reaching the surface of the skin (particularly the UVB portion) has increased, enhancing its carcinogenic effects and potentially causing a dramatic increase in the incidence of nonmelanoma skin cancer and perhaps of malignant melanoma. These effects may be potentiated by the excessive sun exposure and other outdoor behavioral habits that are largely dictated by today’s lifestyle. Effective preventive measures, hence, are necessary, particularly in children and high-risk patients. Novel ways of photoprotection are likely to develop in an effort to protect from the short- and long-term detrimental effects of UV radiation including eythema, photoaging, and skin cancer. Equally important will be the early diagnosis and effective management of skin cancer. The elucidation of the oncogenic pathways that characterize the development of skin cancer will improve our ability to detect early or precancerous changes and eliminate them before they progress to skin tumors. The prevalence and types of skin diseases are expected to change as the human life span increases and the proportion of elderly people in the population continues to grow. Aging of the skin, either chronological or sun-induced, will become inevitably the most common skin disease, and necessary adjustments in dermatologic services will have to be implemented to face this new reality. More emphasis will be given in the prevention or restoration of these changes using topical retinoids or other aesthetic skin procedures (chemical peeling, laser resurfacing, soft tissue augmentation).1 Finally, regardless of the therapy or therapeutic approach, skin diseases can cause disfigurement, discomfort, and disability, all of which contribute to human suffering. It is now well known that dermatologic disease, either acute or chronic, accounts for a large proportion of employment compensation cases and constitutes an important source of health expenditure in many countries around the world. Validated research instruments are now available to address the issue of quality of life in patients with skin disease. As they become more sophisticated and more widely used, they will serve as useful clinical tools by which dermatologists can monitor the effect of a chosen therapy on the overall health of their patients.2.
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2001;19:65– 67
New Therapeutic Agents Glucocorticoids have been the mainstay of dermatological therapy since their introduction in the 1950s, but have a potential for serious side effects. Therefore, safer and equally effective therapies have been sought to treat inflammatory skin diseases. Cyclosporin, methotrexate, and azathioprine have been used but are also associated with undesired toxicities. Certain immunomodulatory and antiinflammatory agents have recently emerged, for example, mycophenolate mofetil, tacrolimus FK/506, and ascomycin derivatives. These agents hold promise in overcoming the side effects of corticosteroids and are currently under investigation for their safety and efficacy in the treatment of skin diseases. In the future, new therapeutic agents will be developed with a much more focused and selective cellular action. These agents will target specific cell surface molecules or components of the cytokine network that are involved in the pathogenesis of skin inflammation. A new generation of immunosuppressive agents that inhibit immune activation, such as anticytokines, antiadhesion molecule antibodies, and intravenous immunoglobulins, have already been developed and have been partly put into clinical practice. Retinoids will continue to be a powerful therapeutic tool in a variety of skin diseases. In contrast to the older nonselective retinoids that indiscriminately activated all retinoid receptors and produced both undesirable and beneficial effects, the new generation of retinoid drugs is designed to have sufficient receptor or function selectivity that only biological systems relevant to a specific disease will be affected. Tarazotene is an example of such a retinoid, its structure being engineered in such a way as to make it selective for retinoic acid receptor beta and gamma. So far, most retinoids in use are retinoid receptor agonists, but it is almost certain that as retinoid research progresses, retinoid antagonists and inverse retinoid agonists will be employed in clinical practice, offering new opportunities for the treatment of various skin diseases.3 New antibiotic and antiviral agents will be developed based on the potential emergence of new or resistant pathogens. With the current HIV epidemic, new antiviral drugs have been developed, for example, the protease inhibitors that have already been shown to reduce morbidity and prolong life in HIV disease.4 Systemic antifungals with better pharmacokinetics and improved safety profiles are currently being investigated. Appendageal diseases, such as acne, hair loss, and abnormal sweating, will be treatable with specific pharmacologic agents.
Future Trends The most important evolution that will take place in the next century will undoubtedly be related to the ongoing
Clinics in Dermatology
Y
2001;19:65– 67
gene revolution. The complete characterization of the human genome by the Human Genome Project will make it possible to identify specific genes that are responsible for cutaneous diseases. Due to this unique achievement, it is likely that all susceptibility loci and genes responsible for congenital skin diseases will be detected and cloned during the early 21st century. Genetic counseling, which is currently used in certain conditions, will become available for most inherited diseases of the skin. Recent advances in the molecular characterization of dermatologic disease coupled with progress in gene delivery technologies have paved the way for introducing cutaneous gene therapy. Gene therapy represents a new form of molecular therapeutics, which is defined as the introduction and expression of new genetic information in somatic cells for therapeutic purposes, for example, to replace an inactive or abnormal gene. Somatic gene therapy has been successfully employed for certain conditions like severe combined immunodeficiency, familial hypercholesterolemia, and cystic fibrosis. Accessibility of gene delivery, clinical evaluation, and topical modulation of gene expression render the skin an attractive organ for gene therapy. In addition, many hereditary cutaneous disorders have well-characterized genetic defects, making them ideal candidates for cutaneous gene therapy. The applications of gene therapy are not limited to the correction of genetic diseases but also include genetic vaccination, introduction of suicide genes for cancer therapy, immunomodulation, and genetic pharmacology. Currently there are clinical trials using gene therapy for melanoma immunotherapy and for certain genodermatoses, such as junctional epidermolysis bullosa and lamellar ichthyosis. New area of interest will also involve the role of neurotransmitters in the skin. There is a substantial evidence of a neurogenic component in certain skin diseases, such as urticaria, psoriasis, atopic dermatitis, and hypersensitivity reactions as well as in the physio-
THE BRAVE NEW WORLD
67
logic process of wound healing.5 Studies have shown a close anatomic association of mast cells and Langerhans cells with cutaneous nerve cells, thus providing physical evidence of a close interaction between the two systems. There is also a well-established effect of neurotransmitters, such as substance P, on the immune system, particularly on mast cells and on the elicitation of contact and delayed-type hypersensitivity reactions of the skin. Interestingly, released neuropeptides may modulate a number of important aspects of normal wound healing, such as cell proliferation, production of growth factors and cytokines, and neovascularization. Based on these exciting findings, it is possible that the future therapies of inflammatory skin diseases will exert their action by modifying these neurocutaneous interactions.
Conclusions The innovations and changes in the understanding of skin biology are more likely to affect profoundly dermatology in the next century and enhance our ability to improve the health and welfare of humanity. The future of our specialty looks more radiant and promising than it ever has before. As we enter this new era we should continue to work with devotion and enthusiasm, never forgetting Hippocrates’ teaching of respects and compassion to our patients.
References 1. Katsambas AD, Katoulis AC. Dermatology in the next millennium: New hopes. Int J Dermatol 1999;38:509 –10. 2. Finlay AY. Quality of life measurement in dermatology: A practical guide. Br J Dermatol 1997;136:305–14. 3. Chandraratna RA. Current research and future developments in retinoids: Systemic and topical agents. Cutis 1998; 61:40 –5. 4. Flexner C. HIV-protease inhibitors. N Engl J Med 1998;338: 1281–92. 5. Lotti T, Hautmann G, Panconesi E. Neuropeptides in the skin. J Am Acad Dermatol 1995;33:482.
The elucidation of the underlying pathophysiology of skin diseases has fostered the development of new pharmaceutical agents that have revolutionized the management of skin diseases. The development and use of topical steroids in a variety of dermatoses, the production of new antibiotic, antifungal, and antiviral agents, the use of systemic corticosteroids for the management of life-threatening condition (eg, pemphigus vulgaris, systemic lupus erythematosus), the chemotherapy of psoriasis with antimetabolites and immunosuppressives, and the use of topical and systemic retinoids for acne, keratinization disorders, and skin cancer chemoprevention are only some examples of the major advances accomplished in dermatologic therapy. Mortality and morbidity from cutaneous diseases, hence, has decreased significantly, with malignant melanoma being currently responsible for nearly half of the deaths attributed to dermatologic diagnoses. In addition, the application of modern sophisticated laboratory techniques such as immunofluorescence, electron microscopy, in situ hybridization, and polymerase chain reaction have offered new insights into dermatologic research and diagnosis and have aided significantly to the selection of the appropriate treatment.
Factors That Will Influence Dermatologic Therapy What will be the direction of dermatologic therapy in the next millennium? At the present time, the answer to this question remains elusive. The tremendous advances in immunology, molecular biology, and genetics will probably play a leading role in the diagnosis, prognosis, and treatment of skin diseases. There are, however, certain important factors that, in our opinion, will influence the progress of skin therapy in the following years. First, the diagnosis and classification of skin diseases will be made based on a new set of cellular and molecular criteria rather than the traditional pattern recognition techniques. Inflammatory and proliferative diseases, such as atopic dermatitis, psoriasis, and mycosis fungoides, will be completely reclassified based on new pathophysiological knowledge, and novel prognostic variables or molecular markers will greatly influ0738-081X/01/$–see front matter PII S0738-081X(00)00214-5
66
Clinics in Dermatology
KATSAMBAS AND STRATIGOS
ence treatment-guided decisions, along with clinical and histologic parameters. The changing environment is another factor that will influence the course of dermatologic therapy in the future. The environmental pollution and the ecologic damage that have been brought about by the industrialization of the 20th century have ultimately affected human health with serious and unpredictable consequences. The use of chlorofluorocarbons and nitrogen oxides, for example, has led to a significant depletion of the ozone layer of the atmosphere. As a result, the amount of ultraviolet (UV) radiation reaching the surface of the skin (particularly the UVB portion) has increased, enhancing its carcinogenic effects and potentially causing a dramatic increase in the incidence of nonmelanoma skin cancer and perhaps of malignant melanoma. These effects may be potentiated by the excessive sun exposure and other outdoor behavioral habits that are largely dictated by today’s lifestyle. Effective preventive measures, hence, are necessary, particularly in children and high-risk patients. Novel ways of photoprotection are likely to develop in an effort to protect from the short- and long-term detrimental effects of UV radiation including eythema, photoaging, and skin cancer. Equally important will be the early diagnosis and effective management of skin cancer. The elucidation of the oncogenic pathways that characterize the development of skin cancer will improve our ability to detect early or precancerous changes and eliminate them before they progress to skin tumors. The prevalence and types of skin diseases are expected to change as the human life span increases and the proportion of elderly people in the population continues to grow. Aging of the skin, either chronological or sun-induced, will become inevitably the most common skin disease, and necessary adjustments in dermatologic services will have to be implemented to face this new reality. More emphasis will be given in the prevention or restoration of these changes using topical retinoids or other aesthetic skin procedures (chemical peeling, laser resurfacing, soft tissue augmentation).1 Finally, regardless of the therapy or therapeutic approach, skin diseases can cause disfigurement, discomfort, and disability, all of which contribute to human suffering. It is now well known that dermatologic disease, either acute or chronic, accounts for a large proportion of employment compensation cases and constitutes an important source of health expenditure in many countries around the world. Validated research instruments are now available to address the issue of quality of life in patients with skin disease. As they become more sophisticated and more widely used, they will serve as useful clinical tools by which dermatologists can monitor the effect of a chosen therapy on the overall health of their patients.2.
Y
2001;19:65– 67
New Therapeutic Agents Glucocorticoids have been the mainstay of dermatological therapy since their introduction in the 1950s, but have a potential for serious side effects. Therefore, safer and equally effective therapies have been sought to treat inflammatory skin diseases. Cyclosporin, methotrexate, and azathioprine have been used but are also associated with undesired toxicities. Certain immunomodulatory and antiinflammatory agents have recently emerged, for example, mycophenolate mofetil, tacrolimus FK/506, and ascomycin derivatives. These agents hold promise in overcoming the side effects of corticosteroids and are currently under investigation for their safety and efficacy in the treatment of skin diseases. In the future, new therapeutic agents will be developed with a much more focused and selective cellular action. These agents will target specific cell surface molecules or components of the cytokine network that are involved in the pathogenesis of skin inflammation. A new generation of immunosuppressive agents that inhibit immune activation, such as anticytokines, antiadhesion molecule antibodies, and intravenous immunoglobulins, have already been developed and have been partly put into clinical practice. Retinoids will continue to be a powerful therapeutic tool in a variety of skin diseases. In contrast to the older nonselective retinoids that indiscriminately activated all retinoid receptors and produced both undesirable and beneficial effects, the new generation of retinoid drugs is designed to have sufficient receptor or function selectivity that only biological systems relevant to a specific disease will be affected. Tarazotene is an example of such a retinoid, its structure being engineered in such a way as to make it selective for retinoic acid receptor beta and gamma. So far, most retinoids in use are retinoid receptor agonists, but it is almost certain that as retinoid research progresses, retinoid antagonists and inverse retinoid agonists will be employed in clinical practice, offering new opportunities for the treatment of various skin diseases.3 New antibiotic and antiviral agents will be developed based on the potential emergence of new or resistant pathogens. With the current HIV epidemic, new antiviral drugs have been developed, for example, the protease inhibitors that have already been shown to reduce morbidity and prolong life in HIV disease.4 Systemic antifungals with better pharmacokinetics and improved safety profiles are currently being investigated. Appendageal diseases, such as acne, hair loss, and abnormal sweating, will be treatable with specific pharmacologic agents.
Future Trends The most important evolution that will take place in the next century will undoubtedly be related to the ongoing
Clinics in Dermatology
Y
2001;19:65– 67
gene revolution. The complete characterization of the human genome by the Human Genome Project will make it possible to identify specific genes that are responsible for cutaneous diseases. Due to this unique achievement, it is likely that all susceptibility loci and genes responsible for congenital skin diseases will be detected and cloned during the early 21st century. Genetic counseling, which is currently used in certain conditions, will become available for most inherited diseases of the skin. Recent advances in the molecular characterization of dermatologic disease coupled with progress in gene delivery technologies have paved the way for introducing cutaneous gene therapy. Gene therapy represents a new form of molecular therapeutics, which is defined as the introduction and expression of new genetic information in somatic cells for therapeutic purposes, for example, to replace an inactive or abnormal gene. Somatic gene therapy has been successfully employed for certain conditions like severe combined immunodeficiency, familial hypercholesterolemia, and cystic fibrosis. Accessibility of gene delivery, clinical evaluation, and topical modulation of gene expression render the skin an attractive organ for gene therapy. In addition, many hereditary cutaneous disorders have well-characterized genetic defects, making them ideal candidates for cutaneous gene therapy. The applications of gene therapy are not limited to the correction of genetic diseases but also include genetic vaccination, introduction of suicide genes for cancer therapy, immunomodulation, and genetic pharmacology. Currently there are clinical trials using gene therapy for melanoma immunotherapy and for certain genodermatoses, such as junctional epidermolysis bullosa and lamellar ichthyosis. New area of interest will also involve the role of neurotransmitters in the skin. There is a substantial evidence of a neurogenic component in certain skin diseases, such as urticaria, psoriasis, atopic dermatitis, and hypersensitivity reactions as well as in the physio-
THE BRAVE NEW WORLD
67
logic process of wound healing.5 Studies have shown a close anatomic association of mast cells and Langerhans cells with cutaneous nerve cells, thus providing physical evidence of a close interaction between the two systems. There is also a well-established effect of neurotransmitters, such as substance P, on the immune system, particularly on mast cells and on the elicitation of contact and delayed-type hypersensitivity reactions of the skin. Interestingly, released neuropeptides may modulate a number of important aspects of normal wound healing, such as cell proliferation, production of growth factors and cytokines, and neovascularization. Based on these exciting findings, it is possible that the future therapies of inflammatory skin diseases will exert their action by modifying these neurocutaneous interactions.
Conclusions The innovations and changes in the understanding of skin biology are more likely to affect profoundly dermatology in the next century and enhance our ability to improve the health and welfare of humanity. The future of our specialty looks more radiant and promising than it ever has before. As we enter this new era we should continue to work with devotion and enthusiasm, never forgetting Hippocrates’ teaching of respects and compassion to our patients.
References 1. Katsambas AD, Katoulis AC. Dermatology in the next millennium: New hopes. Int J Dermatol 1999;38:509 –10. 2. Finlay AY. Quality of life measurement in dermatology: A practical guide. Br J Dermatol 1997;136:305–14. 3. Chandraratna RA. Current research and future developments in retinoids: Systemic and topical agents. Cutis 1998; 61:40 –5. 4. Flexner C. HIV-protease inhibitors. N Engl J Med 1998;338: 1281–92. 5. Lotti T, Hautmann G, Panconesi E. Neuropeptides in the skin. J Am Acad Dermatol 1995;33:482.