Arch Dermatol Res (1992) 284 [Suppl]: $27 $29
9 Springer-Verlag 1992
Therapy with topical corticosteroids W. Sterry Department of Dermatology,Universityof Ulm, Oberer Eselsberg 40, W-7900 Ulm, Federal Republic of Germany
Summary. Therapy with topical corticosteroids has improved greatly in recent years due to both advanced understanding of their mode of action and awareness of their side effects, as well as newly developed derivatives with specifically designed pharmacological properties. Paradoxically, the fear of using corticosteroids has increased on the part of the public during the same period. Treatment of inflammatory or neoplastic skin disorders with topical corticosteroids can be both successful and safe only if certain points are clarified before it is begun. These include (a) specific diagnosis, (b) choice of strength of the compound needed for control of the disease, (c) time schedule for length of therapy and planned patient visits, and (d) choice of vehicle adequate to the skin lesion. Topical corticosteroids of different potency are available today; one can classify these into four groups (weak, medium, strong, very strong) and use them in a patient-tailored treatment. When large areas are to be treated, systemic side effects must be taken into consideration, and compounds that are degraded quickly after absorption are recommended. Finally, the corticophobia of many patients must be addressed by careful information to ensure compliance. Using these guidelines, treatment with corticosteroids is highly effective, easy to use by the patient, and allows a maximum of safety. Key words: Corticosteroids - Topical therapy - Skin disorders - Systemic side effects
Skin disorders include a wide variety of noninfectious inflammatory dseases that affect only the skin. The etiology of these entities may be known or be idiopathic. Their existence is generally of great personal impact for the affected persons, who may suffer from negative social feedback, severe itching, sleeping disturbances, psychological distress, and occasionally disabling scar formations and mutilations. Therefore, after appropriate diagnostic procedures and establishment of diagnosis, treatment must be initiated toward rapid cure or relief of symptoms. Since many skin disorders are of a chronic,
relapsing course, the therapeutic modalities that are chosen must be well tolerated on both a short- and a long-term basis; in particular, it should be possible to calculate side effects, and the choice of compounds must take into consideration above all the long-term side effects. Regarding treatment with topical corticosteroids, an interesting paradox has emerged. On the one hand, the synthesis of new compounds as well as sophisticated medical edication allows a virtually safe treatment even for prolonged periods; on the other hand, a phobia toward corticosteroids has arisen in patients, resulting their unwillingness or fear of using topical corticosteroids. Only the combination of correct indication, choice of the appropriate substance, and awareness of possible side effects together with patient compliance in following the dermatologist's instructions can solve this problem. This chapter lists corticosteroid-sensitive dermatoses and discusses their mode of action, their possible side effects, and guidelines for the use of local corticosteroids in the treatment of skin diseases.
Mode of action Corticosteroids, as other steroid hormones, diffuse across the cell membrane and bind to a specific receptor protein. The corticosteroid receptor protein belongs to a large family of cytosolic receptors, which also bind other steroid hormones,'retinoic acid, and thyroxine. After the corticosteroid has bound to its receptor, the receptor molecule translocates into the nucleus and binds to specific DNA sequences. Genes that are influenced in their transcription by corticosteroids contain specific response elements to which the corticosteroid receptor dimer binds. This results in increased or reduced transcription of the respective gene(s), and the gene product exerts the effects of the corticosteroid. Since many genes are influenced, and different cells probably express different steroid receptors, a rather heterogeneous pattern of effects emerges. Among the well-defined proteins playing a role in the anti-inflammatory action of corticosteroids is lipocortin
$28 (macrocortin), which inhibits phospholipase A2, an enzyme that releases free arachidonic acid from membranebound phospholipids. Arachidonic acid is the precursor molecule of many proinflammatory molecules such as prostaglandins, leukotrienes, and thromboxanes. However, corticosteroids affect far more inflammatory pathways and also have a strong suppressive effect on the secretion of various proinflammatory cytokines released by many cells involved in cutaneous inflammation. We are far from a complete understanding of the complex action of corticosteroids in inflammatory and neoplastic disorders.
Indications for treatment with topical cortieosteroids Three decades ago those skin disorders that respond to treatment with topical corticosteroids were identified. Since topical corticosteroids have both anti-inflammatory and antiproliferative effects, depending on their strength, they are useful in disorders as different as dermatitis, psoriasis, lichen planus, and lupus erythematosus. Therefore the first question to be answered regarding a given patient is: does the dermatosis respond completely or partially to topical corticosteroid treatment? A list of skin disorders responding to topical corticosteroid treatment can be found in every major dermatological textbook and is also presented during the course of dermatological education. Once this question has been answered, one should think of possible therapeutic alternatives, weighting their advantages and disadvantages in the given clinical situation. On the basis of this, one should choose a single or combination therapy which may or may not include topical corticosteroids. The second question to be answered is: how long does one plan to treat the skin lesions with topical corticosteroids? One should never initiate treatment with topical corticosteroids without having a idea of the time period within which a clearing or healing can be expected. According to this and in conjunction with the area of affected skin, the quantity of the prescribed ointment or lotion can be estimated. This avoids the patient continuing treatment without dermatological control and thus helps to prevent the development of unwanted side effects. The patient should also be informed of the length of the treatment period and should be instructed to return during or after this period.
Choice of compound and vehicle For practical use, topical corticosteroids are classified according to the potency required for treatment. Examples of corticosteroid-sensitive dermatoses, in terms of the required potency, include the following: Mild to moderate potency Contact dermatitis, allergic Contact dermatitis, irritant Atopic dermatitis
Moderate to strong potency Lichen planus Psoriasis vulgaris Hand dermatitis Strong to very strong potency Lupus erythematosus Keloids Urticaria pigmentosa It is the aim to control the skin disease with a corticosteroid of as low a potency as possible. This requires knowledge of the pathogenesis of a given skin disease. A major point is that only potent and very potent corticosteroids are able to suppress hyperproliferation; weak corticosteroids fail in the treatment of diseases in which hyperproliferation is a major pathogenetic event. Furthermore, the choice of vehicle, as in every dermatological treatment, should take into account the general appearance of the patient's skin, presence of hyperkeratosis and desquamation, or localization such as scalp involvement. The rules for choosing the vehicle in treatment with topical corticosteroids are the same as those for treatment with other local agents.
Side effects in topical corticosteroid treatment The unwanted effects of topical corticosteroid treatment are directly related to the potency of the compound used. Despite numerous attempts, no compound has yet been developed for clinical use which successfully dissociates between wanted and unwanted effects. However, intelligent strategies have been developed to achieve this dissociation, and the use of such modern compounds in clinical dermatology will prove or disprove their superiority. The side effects of topical corticosteroids are well known to the dermatologist and are discussed only briefly below; they can be distinguished according to their localization.
Epidermal side effects The most prominent unwanted effects in the epidermis include thinning of the epidermis together with decreased proliferative activity within the basal layer of the epidermis and flattening of the fete ridges. Furthermore, the melanin synthesis of melanoeytes can be reduced, resulting in hypopigmented areas.
Dermal effects Dermal effects include the reduction of collagen synthesis with thinning of the dermis. Furthermore, the mechanical strength of the dermis is reduced, resulting in increased vulnerability with stellate scar formation as well as rupture of wide dermal areas in localizations such as inner aspects of the arms, female breasts, and buttocks, a condition known striae distensae. Also, the walls of the vessels are not protected due to reduced collagen, and hemorrhage after minor traumas are common.
$29 Topical corticosteroids also have an effect on dermal bloom vessel tension and induce a short-term vascoconstriction; on the long term they induce vasodilation, resulting in teleangiectases. A problem seldomly considered is systemic absorption of topically applied corticosteroids, resulting in inhibition of the pituitary-adrenal axis. This side effect may be most relevant in children, in whom growth inhibition also has been observed. In adults, absorption of relevant quantities of corticosteroids after topical applications must be anticipated if large areas of the body are treated with potent or very potent compounds, or if occlusive dressings are used to increase their efficacy. Systemic absorption and the resulting problems could be solved by synthesis of compounds that are rapidly cleaved or metabolized, thus absolishing their biological activity.
Clinical disorders associated with the use topical corticosteroids Conditions known to occur during topical corticosteroid treatment include perioral dermatitis, steroid-suppressed tinea, granuloma gluteale infantum, and pustular psoriasis. These diseases do not occur under appropriate use of topical corticosteroids, and ceasing their application results in improvement and disappearance of such diseases, but often other supportive treatment modalities are necessary for rapid clearing.
Strategies for development of safer topical corticosteroid compounds The ideal topical corticosteroid is rapidly absorbed, exhibits a strong but short activity, and is rapidly inactivated after reaching the circulation. Modern pharmacology seeks to develop compounds that fulfill these conditions as far as possible. It is important to follow
such new compounds during their clinical application, and to monitor both efficacy and side effects to obtain a clinical impression of advantages and disadvantages. Although the ideal corticosteroid has not yet been brought onto the market, modern pharmacology and intelligent molecular design will undoubtedly allow a safer and probably more effective treatment of many skin diseases with topical corticosteroids.
References 1. Bos JD, Havu VK (1989) Topical corticosteroids today. Acta Derm Venereol (Stockh) 69 [Suppl]: t51 2. Flower R (1989) Lipocortin. Biochem Soc Trans 17:276-278 3. Frosch PJ, Behrenbeck EM, Frosch K (1981) The Duhring chamber assay for corticosteroid atrophy. Br J Dermatol 104: 57-65 4. Gibson JR, Kirsch J, Darley CR (1983) An attempt to evaluate the relative clinical potencies of various diluted and undiluted proprietary corticosteroid preparations. Clin Exp Dermatol 8: 489-493 5. Gibson JR, Kirsch J, Darley CR (1989) An assessment of the relationship between vasoconstrictor assay findings, clinical efficiency and thinning effects of a variety of undiluted and diluted corticosteroid preparations. Br J Dermatol 111 [Suppl 27]: 204 212 6. Greaves MW, Camp RDR (1988) Prostaglandis, leukotrienes, phospholipase, platelet activating factor, and cytokines: an integrated approach to inflammation of human skin. Arch Dermatol Res 280:533-541 7. Harding SM, Sohail S, Busse MJ (1985) Percutaneous absorption of clobetasol propionate from novel ointment and cream foundations. Clin Exp Dermatol 10:13-21 8. Polano MK, Ponec M (1976) Dependence of corticosteroid penetration on the vehicle. Arch Dermatol 112:675-680 9. Ryatt KS, Feather JW, Mehta A e t al. (1982) The stability and blanching efficacy of betametasone-17-valerate m emulsifying ointment. Br J Dermatol 107:71-76 10. Solito E, Parente L (1989) Modulation of phospholipase A2 activity in human fibroblasts. Br J Pharmacol 96:656-660
9 Springer-Verlag 1992
Therapy with topical corticosteroids W. Sterry Department of Dermatology,Universityof Ulm, Oberer Eselsberg 40, W-7900 Ulm, Federal Republic of Germany
Summary. Therapy with topical corticosteroids has improved greatly in recent years due to both advanced understanding of their mode of action and awareness of their side effects, as well as newly developed derivatives with specifically designed pharmacological properties. Paradoxically, the fear of using corticosteroids has increased on the part of the public during the same period. Treatment of inflammatory or neoplastic skin disorders with topical corticosteroids can be both successful and safe only if certain points are clarified before it is begun. These include (a) specific diagnosis, (b) choice of strength of the compound needed for control of the disease, (c) time schedule for length of therapy and planned patient visits, and (d) choice of vehicle adequate to the skin lesion. Topical corticosteroids of different potency are available today; one can classify these into four groups (weak, medium, strong, very strong) and use them in a patient-tailored treatment. When large areas are to be treated, systemic side effects must be taken into consideration, and compounds that are degraded quickly after absorption are recommended. Finally, the corticophobia of many patients must be addressed by careful information to ensure compliance. Using these guidelines, treatment with corticosteroids is highly effective, easy to use by the patient, and allows a maximum of safety. Key words: Corticosteroids - Topical therapy - Skin disorders - Systemic side effects
Skin disorders include a wide variety of noninfectious inflammatory dseases that affect only the skin. The etiology of these entities may be known or be idiopathic. Their existence is generally of great personal impact for the affected persons, who may suffer from negative social feedback, severe itching, sleeping disturbances, psychological distress, and occasionally disabling scar formations and mutilations. Therefore, after appropriate diagnostic procedures and establishment of diagnosis, treatment must be initiated toward rapid cure or relief of symptoms. Since many skin disorders are of a chronic,
relapsing course, the therapeutic modalities that are chosen must be well tolerated on both a short- and a long-term basis; in particular, it should be possible to calculate side effects, and the choice of compounds must take into consideration above all the long-term side effects. Regarding treatment with topical corticosteroids, an interesting paradox has emerged. On the one hand, the synthesis of new compounds as well as sophisticated medical edication allows a virtually safe treatment even for prolonged periods; on the other hand, a phobia toward corticosteroids has arisen in patients, resulting their unwillingness or fear of using topical corticosteroids. Only the combination of correct indication, choice of the appropriate substance, and awareness of possible side effects together with patient compliance in following the dermatologist's instructions can solve this problem. This chapter lists corticosteroid-sensitive dermatoses and discusses their mode of action, their possible side effects, and guidelines for the use of local corticosteroids in the treatment of skin diseases.
Mode of action Corticosteroids, as other steroid hormones, diffuse across the cell membrane and bind to a specific receptor protein. The corticosteroid receptor protein belongs to a large family of cytosolic receptors, which also bind other steroid hormones,'retinoic acid, and thyroxine. After the corticosteroid has bound to its receptor, the receptor molecule translocates into the nucleus and binds to specific DNA sequences. Genes that are influenced in their transcription by corticosteroids contain specific response elements to which the corticosteroid receptor dimer binds. This results in increased or reduced transcription of the respective gene(s), and the gene product exerts the effects of the corticosteroid. Since many genes are influenced, and different cells probably express different steroid receptors, a rather heterogeneous pattern of effects emerges. Among the well-defined proteins playing a role in the anti-inflammatory action of corticosteroids is lipocortin
$28 (macrocortin), which inhibits phospholipase A2, an enzyme that releases free arachidonic acid from membranebound phospholipids. Arachidonic acid is the precursor molecule of many proinflammatory molecules such as prostaglandins, leukotrienes, and thromboxanes. However, corticosteroids affect far more inflammatory pathways and also have a strong suppressive effect on the secretion of various proinflammatory cytokines released by many cells involved in cutaneous inflammation. We are far from a complete understanding of the complex action of corticosteroids in inflammatory and neoplastic disorders.
Indications for treatment with topical cortieosteroids Three decades ago those skin disorders that respond to treatment with topical corticosteroids were identified. Since topical corticosteroids have both anti-inflammatory and antiproliferative effects, depending on their strength, they are useful in disorders as different as dermatitis, psoriasis, lichen planus, and lupus erythematosus. Therefore the first question to be answered regarding a given patient is: does the dermatosis respond completely or partially to topical corticosteroid treatment? A list of skin disorders responding to topical corticosteroid treatment can be found in every major dermatological textbook and is also presented during the course of dermatological education. Once this question has been answered, one should think of possible therapeutic alternatives, weighting their advantages and disadvantages in the given clinical situation. On the basis of this, one should choose a single or combination therapy which may or may not include topical corticosteroids. The second question to be answered is: how long does one plan to treat the skin lesions with topical corticosteroids? One should never initiate treatment with topical corticosteroids without having a idea of the time period within which a clearing or healing can be expected. According to this and in conjunction with the area of affected skin, the quantity of the prescribed ointment or lotion can be estimated. This avoids the patient continuing treatment without dermatological control and thus helps to prevent the development of unwanted side effects. The patient should also be informed of the length of the treatment period and should be instructed to return during or after this period.
Choice of compound and vehicle For practical use, topical corticosteroids are classified according to the potency required for treatment. Examples of corticosteroid-sensitive dermatoses, in terms of the required potency, include the following: Mild to moderate potency Contact dermatitis, allergic Contact dermatitis, irritant Atopic dermatitis
Moderate to strong potency Lichen planus Psoriasis vulgaris Hand dermatitis Strong to very strong potency Lupus erythematosus Keloids Urticaria pigmentosa It is the aim to control the skin disease with a corticosteroid of as low a potency as possible. This requires knowledge of the pathogenesis of a given skin disease. A major point is that only potent and very potent corticosteroids are able to suppress hyperproliferation; weak corticosteroids fail in the treatment of diseases in which hyperproliferation is a major pathogenetic event. Furthermore, the choice of vehicle, as in every dermatological treatment, should take into account the general appearance of the patient's skin, presence of hyperkeratosis and desquamation, or localization such as scalp involvement. The rules for choosing the vehicle in treatment with topical corticosteroids are the same as those for treatment with other local agents.
Side effects in topical corticosteroid treatment The unwanted effects of topical corticosteroid treatment are directly related to the potency of the compound used. Despite numerous attempts, no compound has yet been developed for clinical use which successfully dissociates between wanted and unwanted effects. However, intelligent strategies have been developed to achieve this dissociation, and the use of such modern compounds in clinical dermatology will prove or disprove their superiority. The side effects of topical corticosteroids are well known to the dermatologist and are discussed only briefly below; they can be distinguished according to their localization.
Epidermal side effects The most prominent unwanted effects in the epidermis include thinning of the epidermis together with decreased proliferative activity within the basal layer of the epidermis and flattening of the fete ridges. Furthermore, the melanin synthesis of melanoeytes can be reduced, resulting in hypopigmented areas.
Dermal effects Dermal effects include the reduction of collagen synthesis with thinning of the dermis. Furthermore, the mechanical strength of the dermis is reduced, resulting in increased vulnerability with stellate scar formation as well as rupture of wide dermal areas in localizations such as inner aspects of the arms, female breasts, and buttocks, a condition known striae distensae. Also, the walls of the vessels are not protected due to reduced collagen, and hemorrhage after minor traumas are common.
$29 Topical corticosteroids also have an effect on dermal bloom vessel tension and induce a short-term vascoconstriction; on the long term they induce vasodilation, resulting in teleangiectases. A problem seldomly considered is systemic absorption of topically applied corticosteroids, resulting in inhibition of the pituitary-adrenal axis. This side effect may be most relevant in children, in whom growth inhibition also has been observed. In adults, absorption of relevant quantities of corticosteroids after topical applications must be anticipated if large areas of the body are treated with potent or very potent compounds, or if occlusive dressings are used to increase their efficacy. Systemic absorption and the resulting problems could be solved by synthesis of compounds that are rapidly cleaved or metabolized, thus absolishing their biological activity.
Clinical disorders associated with the use topical corticosteroids Conditions known to occur during topical corticosteroid treatment include perioral dermatitis, steroid-suppressed tinea, granuloma gluteale infantum, and pustular psoriasis. These diseases do not occur under appropriate use of topical corticosteroids, and ceasing their application results in improvement and disappearance of such diseases, but often other supportive treatment modalities are necessary for rapid clearing.
Strategies for development of safer topical corticosteroid compounds The ideal topical corticosteroid is rapidly absorbed, exhibits a strong but short activity, and is rapidly inactivated after reaching the circulation. Modern pharmacology seeks to develop compounds that fulfill these conditions as far as possible. It is important to follow
such new compounds during their clinical application, and to monitor both efficacy and side effects to obtain a clinical impression of advantages and disadvantages. Although the ideal corticosteroid has not yet been brought onto the market, modern pharmacology and intelligent molecular design will undoubtedly allow a safer and probably more effective treatment of many skin diseases with topical corticosteroids.
References 1. Bos JD, Havu VK (1989) Topical corticosteroids today. Acta Derm Venereol (Stockh) 69 [Suppl]: t51 2. Flower R (1989) Lipocortin. Biochem Soc Trans 17:276-278 3. Frosch PJ, Behrenbeck EM, Frosch K (1981) The Duhring chamber assay for corticosteroid atrophy. Br J Dermatol 104: 57-65 4. Gibson JR, Kirsch J, Darley CR (1983) An attempt to evaluate the relative clinical potencies of various diluted and undiluted proprietary corticosteroid preparations. Clin Exp Dermatol 8: 489-493 5. Gibson JR, Kirsch J, Darley CR (1989) An assessment of the relationship between vasoconstrictor assay findings, clinical efficiency and thinning effects of a variety of undiluted and diluted corticosteroid preparations. Br J Dermatol 111 [Suppl 27]: 204 212 6. Greaves MW, Camp RDR (1988) Prostaglandis, leukotrienes, phospholipase, platelet activating factor, and cytokines: an integrated approach to inflammation of human skin. Arch Dermatol Res 280:533-541 7. Harding SM, Sohail S, Busse MJ (1985) Percutaneous absorption of clobetasol propionate from novel ointment and cream foundations. Clin Exp Dermatol 10:13-21 8. Polano MK, Ponec M (1976) Dependence of corticosteroid penetration on the vehicle. Arch Dermatol 112:675-680 9. Ryatt KS, Feather JW, Mehta A e t al. (1982) The stability and blanching efficacy of betametasone-17-valerate m emulsifying ointment. Br J Dermatol 107:71-76 10. Solito E, Parente L (1989) Modulation of phospholipase A2 activity in human fibroblasts. Br J Pharmacol 96:656-660
