Dermatologica 152 (Suppl. 1): 139-146(1976)
Mechanism of Local Skin Atrophy Caused by Intradermally Injected Corticosteroids E. F u l o p Department of Dermatology, Semmelweis Medical University, Budapest
Key Words. Hydrocortisone, intradermally • Skin atrophy Abstract. Different hydrocortisone microcrystal suspensions applied intradermally in rabbits caused skin atrophy. This could be ascribed to secondary tissue degeneration as was ascertained histologically. The degree of degeneration was related to the concentration of the suspension, size of the microcrystals and frequency of the intervals between the injections. The ground substance of the connective tissue changes and is characterized by a basophilic granular mass, homogenized collagen fibers and degeneration of the elastic fibers. The pathomechanism of local skin atrophy not only differs from connective tissue degeneration caused by systemic corticosteroid treatment but also from the degeneration caused by topical treatment.
Introduction
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Medical literature contains evidence of the important role played by the various forms of application of corticosteroid preparations in inducing skin atrophy [12]. The effect of topical or intradermal corticosteroid therapy on connective tissue is known [4,5], Skin atrophy is mainly caused by suspen sions which are applied intralesionally. The difference in the clinical picture is also reflected in the difference in the localization of the inflammatory cellular infiltrations. There is also a difference in the character of tissue injuries at the site of the injections. T a n e n b a u m and B e c k e r [18] observed anetoderma- or poikiloderma-like atrophy. The subcutaneous fatty tissue may also be affected but it only rarely causes persisting atrophy [2]; accord ing to L ee [13] an individual disposition is necessary. The effect of corticosteroids on the cells of the epithelium and connective tissue was examined by C a s t o r and B a k e r [3] in rats. G o l d m a n et al.
140
F ülöp
[10,11] and S c h e t m a n el al. [14] reported on the formation of local con nective tissue reactions following steroid suspensions injected intradermally in human skin. We also performed such investigations. We investigated the damaging effect of steroid suspensions on the tissues, first in animals [7], and on the basis of this data, subsequently in cases of alopecia areata of the human scalp [8,9], Trying to determine the causal factors we investigated in our experiments the mechanism of atrophy of the skin and therefore wished to answer the following questions: (1) the absorption of corticosteroid crystals injected intradermally; (2) the importance of the size of the microcrystals, fine or rough granules constituting the 'quality' of the suspension ; (3) the influence of the concentration on the formation of connective tissue injuries (dose, dilution), and (4) the effect of repeated infiltrations on the development of atrophy.
Materials and Methods Corticosteroids Hydrocortisone (Gideon Richter): 17a-hydrocortisonum aceticum microcristallisatum, 25 mg/ml, consisting of large, rough-grained microcrystals Referred to as preparation HC, (fig. 1). Hydrocortisone (Ciba): 17a-hydrocorticosterone acetate microcrystal suspension, 25 mg/ml. small, fine microcrystals. Referred to as preparation HC2 (fig. 2).
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Fig. 1. Referred to as preparation H C,, larger, rough-grained microcrystals.
141
Atrophy Caused by Intradermal Corticosteroid Injection
.
.-V - i V 'V ' ’ »* . - '
i
' i ■
fig. 2. Referred to as preparation HC2, smaller, finer microcrystals.
Fig. 3. The depilated back skin of the experimental rabbit with HC, and HC2 suspensions marked with trypan blue.
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Materials Into the depilated skin of the backs of rabbits we carried out, intradermally, symmetrical serial infiltrations with HC, and HC2 suspensions (fig. 3). To examine the absorption we excised the infiltrated areas after half an hour, and after 1, 2, 3, 4 and 6 weeks. To examine the effect of the concentration, HC, and HC2 suspensions were injected first undiluted (0.1 ml) then in diluted form with lidocaine 1 :2 in increasing doses (0.1 up to 0.5 ml). We repeated the injections in the same area twice at 4-week intervals, then three and four times. Six weeks following the last injection an excision was performed. The excised tissues were frozen by a cryostat and after formalin fixation embedded in paraffin.
142
F ulop
Histological Examinations For the examination we employed a light and polarization microscope. Hematoxylin and eosin, van Gieson, orcein, H-sudan. Mallory III, cresyl violet, toluidine blue, PAS and Hale stains were used.
Results
Fig. 4. Site o f HC, crystal grains among the fibers of the connective tissue half an hour after injection. Frozen native preparation, x 80. Fig. 5. Larger HC, crystals among the fibers of the connective tissue 4 weeks after injection. Frozen native preparation. x400.
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We followed by means of a polarization microscope the absorption of the microcrystals of the H Q and HC2 suspensions which were of different sizes. The crystals could be demonstrated after half an hour as a band in the connective tissue of the cutis (fig. 4). Their size diminished by about half after the 2nd week, since the absorption was gradual and slow. The larger H Q crystals were still demonstrable among the fibers of the connec tive tissue after 4 weeks (fig. 5), but not the finer H Q crystals. After 6 weeks the crystals were entirely absorbed.
Atrophy Caused by Intradermal Corticosteroid Injection
143
The injection of undiluted HC, and HC2 suspensions performed twice did not yet cause any connective tissue alterations. After the third applica tion, however, a close condensation of the fibers of the connective tissue or parallel coordination with a mild basophilic staining was induced. Following the fourth repeated injection ivory-colored papules could be observed macroscopically and later atrophic areas developed on the skin in this region. In the circumscribed areas of the connective tissue the HC! suspension caused degenerative histological changes (fig. 6): the fibers were broken and homogenized. Between the fibers an amassment of baso philic ground substance had developed. The collagen fibers maintained their structure for a long time. The elastic fibers degenerated first and their volume diminished. The HC2 suspension caused the same pathological
Fig. 7. Connective tissue alteration with a mild basophilic staining after four injections of diluted HC, suspensions. HE. x 80.
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Fig. 6. Degenerative changes of the connective tissue: breaking of the fibers with a mass-like basophilic ground substance after four injections of concentrated HC, suspension. HE. x 80.
144
F ulop
changes in the connective tissue but to a minor degree. No double refraction could be demonstrated in these areas of the connective tissue by means of the polarization microscope. Injections of diluted H Q microcrystal suspensions repeated four times caused a moderate condensation of the connective tissue fibers in the dermis with a mild basophilic staining (fig. 7). At the same time repeated injections of diluted HC2 suspensions containing finer microcrystals, did not cause any apparent damage to the connective tissue. This was likewise not the case, even if the doses were increased from 0.3 up to 0.5 ml.
In cases of endogenous or exogenous cortisone surplus various mecha nisms of skin atrophy are supposed. Due to the effect of corticosteroids the inflammatory tissue reactions diminish, at the same time the ground substance of the connective tissue and likewise the synthesis of the collagen fibers are impeded, due to the transformation of the pluripotent mesenchyma cells, i.e., the mastocytes, fibroblasts, histocytes [1,15,16], The infiltration of amino acids is reduced as well [4]. The atrophy of the epithe lium is secondary, mostly in close relation with the pathophysiological process of the dermis. T o u r a in e et a!. [19] reported diffuse and circumscribed skin atrophy of different types during high doses and long-term cortico steroid therapy. We observed this irreversible atrophy in connection with a systemic corticosteroid treatment long ago. We also examined the pathomechanism of this phenomenon [5,6], The question arose whether in cases of systemic and topical or intradermal corticosteroid treatment the connective tissue injury occurs because of an identical mechanism? The therapeutic and tissue damaging effect of the suspensions is limited only to the area where it is directly infiltrated. In administering microcrystal suspensions a corticosteroid depot is established intralesionally in order to achieve an immunosuppres sive or anti-inflammatory effect. Thus, we assured locally such a high corticosteroid concentration which if administered orally or parenterally would damage the whole organism. The hydrocortisone microcrystal suspensions H Q and HC2 remained in the connective tissue when applied intradermally and they were slowly absorbed. The process of decomposition of the larger crystals lasted longer; there was no cellular reaction in the connective tissue. It was possible to
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
Discussion
Atrophy Caused by Intradermal Corticosteroid Injection
145
induce injuries to the fibers of the connective tissue experimentally. The degree of injury was related to the quality of the crystals, the dose and the concentration of the corticosteroid preparation and the frequency of the injections. Following repeated injections of undiluted hydrocortisone microcrystal suspensions (25 mg/0.1 ml) into the skin of rabbits, the fibrous structure of the connective tissue was decomposed and homogenized. C a s t o r and B a k e r [3] observed similar changes in rats. By means of histological examinations we have found similar alterations in the connective tissue of the human skin. Repeated intradermal injections of steroid suspensions were followed by a progressive homogenization of the collagen fibers and a decrease in the elastic ones [8,9]. S t r e it m a n [17] also observed an injury of the connective tissue resembling pseudoxanthoma elasticum. Based on our experiments we may suppose that there are physico chemical alterations in the connective tissue which are induced by cortico steroids locally. These alterations result in a basophilic granular substance which can be demonstrated between the fibers of the connective tissue, and which is probably only a ‘reactive’ and reversible modified ground sub stance. In this process the quality of the corticosteroids, i.e. their concentra tion and size of the microcrystals, play an important role. In the case of frequent injections, first the elastic then secondly the collagen of the con nective tissue are damaged in a chain reaction. This degenerative process causes a reversible local atrophic alteration in the skin.
References
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1 A sboe-H ansen , G .: Corticosteroids in dermatology; in J adassohn and Schirren 13th Congr. Int. Dermatologiae, vol. 1, pp. 133-135 (Springer, Berlin 1968). 2 Beardwell , A.: Subcutaneous atrophy after local corticosteroid injection. Br. med. J. iii: 600(1967). 3 C astor , C. W. and Baker , B. L .: The local action of adrenocortical steroids on epidermis and connective tissue of the skin. Endocrinology 47: 234-241 (1950). 4 F öldvari, F .; V értes, B. és F ülöp, É .: A steroidok által okozott bbratrophiák pathomechanizmusárói és jelentó'ségükról. Bbrgyógy, vener. Szle. 37: 241-245 (1961). 5 F öldvari. F .; Vértes, B. und F ülöp , É .: Über den Pathomechanismus und die Bedeutung der durch Steroide bewirkten Hautatrophien. Dermatológica 125:93-100 (1962). 6 F rieden , E.; C ohen , E., and H arper , A.: The effects of steroid hormones upon amino acid incorporation into mouse kidney homogenates. Endocrinology 68: 862 866 (1961). 7 F ülöp , É. és V ajda , T . : Kötöszöveti elváltozások helyi steroid hatásra. Borgyógy. vener. Szle. 44: 109-113 (1968). 8 F ülöp , É. és Vajda , T .: Szöveti károsodás vizsgálata steroid suspensiók hatására alopecia areatában. Bbrgyógy. vener. Szle. 45: 154- 159 (1969).
146
F ülöp
9 F ülöp , É, und Vajda , T .: Experimentelle Untersuchungen über die therapeutische und schädigende Wirkung der intrafokalen Steroidhandlung. Derm. Wschr. 157: 269-277 (1971). 10 G oldman , L.: Reactions following intralesional and sublesional injections of cortico steroids. J. Am. med. Ass. 182: 613-615 (1962). 11 G oldman , L .; O ’H ara , H., and Baskett, J . : A study of the local tissue reactions in man to Cortisone and compound F. 1V. Histopathological studies of the local effect of compound F in normal and pathologic skin of man. J. invest. Derm. 2 0 :271-279 (1953). 12 K aiser, H.: Cortisonderivate in Klinik und Praxis; 6. Aufl., pp. 26-79 (Thieme, Stuttgart 1973). 13 Lee, F . : Erfahrungen mit intracutanen Triamcinolon-Injectionen bei Hautkrankheiten. Dermatológica 127: 74-82 (1963). 14 SCHETMAN. D.; H ambrich , G. W., jr., and W ilson , C. E.: Cutaneous changes following local injection of triamcinolone. Archs Derm. 88: 820-828 (1963). 15 Schnitzer , A.: Experimentelle histologische Untersuchungen zur Abwehrreaktion der Haut. Dermatológica 114: 257-265 (1957). 16 Sel ye, H.: The effect of topically administered hydrocortisone upon dystrophic skin, as revealed by the 'pneumoderma’ technic. J. invest. Derm. 2 1 :91-98 (1953). 17 Streitman , B .: Eigenartige Elasticaveränderung nach lokaler Cortison-Infiltration. Z. Haut-Geschl.Krankh. 123: 16-19(1968). 18 T anenbaum , M. H. and Becker , S. W .: Scarring from corticosteroid therapy. Archs Derm. 89: 560 (1964). 19 T ouraine , M. R .; F ournet , M. et B elaich , S.: Les atrophies cutanées au cours de la corticothérapie genérale; in J adassohn and Schirren 13th Congr. Int. Dermatologiae, vol. 1, pp. 153-156 (Springer, Berlin 1968).
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Mrs. Dr. E. F ulop , Department of Dermatology, Semmelweis Medical University, Maria u. 41,1085 Budapest (Hungary)
Mechanism of Local Skin Atrophy Caused by Intradermally Injected Corticosteroids E. F u l o p Department of Dermatology, Semmelweis Medical University, Budapest
Key Words. Hydrocortisone, intradermally • Skin atrophy Abstract. Different hydrocortisone microcrystal suspensions applied intradermally in rabbits caused skin atrophy. This could be ascribed to secondary tissue degeneration as was ascertained histologically. The degree of degeneration was related to the concentration of the suspension, size of the microcrystals and frequency of the intervals between the injections. The ground substance of the connective tissue changes and is characterized by a basophilic granular mass, homogenized collagen fibers and degeneration of the elastic fibers. The pathomechanism of local skin atrophy not only differs from connective tissue degeneration caused by systemic corticosteroid treatment but also from the degeneration caused by topical treatment.
Introduction
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Medical literature contains evidence of the important role played by the various forms of application of corticosteroid preparations in inducing skin atrophy [12]. The effect of topical or intradermal corticosteroid therapy on connective tissue is known [4,5], Skin atrophy is mainly caused by suspen sions which are applied intralesionally. The difference in the clinical picture is also reflected in the difference in the localization of the inflammatory cellular infiltrations. There is also a difference in the character of tissue injuries at the site of the injections. T a n e n b a u m and B e c k e r [18] observed anetoderma- or poikiloderma-like atrophy. The subcutaneous fatty tissue may also be affected but it only rarely causes persisting atrophy [2]; accord ing to L ee [13] an individual disposition is necessary. The effect of corticosteroids on the cells of the epithelium and connective tissue was examined by C a s t o r and B a k e r [3] in rats. G o l d m a n et al.
140
F ülöp
[10,11] and S c h e t m a n el al. [14] reported on the formation of local con nective tissue reactions following steroid suspensions injected intradermally in human skin. We also performed such investigations. We investigated the damaging effect of steroid suspensions on the tissues, first in animals [7], and on the basis of this data, subsequently in cases of alopecia areata of the human scalp [8,9], Trying to determine the causal factors we investigated in our experiments the mechanism of atrophy of the skin and therefore wished to answer the following questions: (1) the absorption of corticosteroid crystals injected intradermally; (2) the importance of the size of the microcrystals, fine or rough granules constituting the 'quality' of the suspension ; (3) the influence of the concentration on the formation of connective tissue injuries (dose, dilution), and (4) the effect of repeated infiltrations on the development of atrophy.
Materials and Methods Corticosteroids Hydrocortisone (Gideon Richter): 17a-hydrocortisonum aceticum microcristallisatum, 25 mg/ml, consisting of large, rough-grained microcrystals Referred to as preparation HC, (fig. 1). Hydrocortisone (Ciba): 17a-hydrocorticosterone acetate microcrystal suspension, 25 mg/ml. small, fine microcrystals. Referred to as preparation HC2 (fig. 2).
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
Fig. 1. Referred to as preparation H C,, larger, rough-grained microcrystals.
141
Atrophy Caused by Intradermal Corticosteroid Injection
.
.-V - i V 'V ' ’ »* . - '
i
' i ■
fig. 2. Referred to as preparation HC2, smaller, finer microcrystals.
Fig. 3. The depilated back skin of the experimental rabbit with HC, and HC2 suspensions marked with trypan blue.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
Materials Into the depilated skin of the backs of rabbits we carried out, intradermally, symmetrical serial infiltrations with HC, and HC2 suspensions (fig. 3). To examine the absorption we excised the infiltrated areas after half an hour, and after 1, 2, 3, 4 and 6 weeks. To examine the effect of the concentration, HC, and HC2 suspensions were injected first undiluted (0.1 ml) then in diluted form with lidocaine 1 :2 in increasing doses (0.1 up to 0.5 ml). We repeated the injections in the same area twice at 4-week intervals, then three and four times. Six weeks following the last injection an excision was performed. The excised tissues were frozen by a cryostat and after formalin fixation embedded in paraffin.
142
F ulop
Histological Examinations For the examination we employed a light and polarization microscope. Hematoxylin and eosin, van Gieson, orcein, H-sudan. Mallory III, cresyl violet, toluidine blue, PAS and Hale stains were used.
Results
Fig. 4. Site o f HC, crystal grains among the fibers of the connective tissue half an hour after injection. Frozen native preparation, x 80. Fig. 5. Larger HC, crystals among the fibers of the connective tissue 4 weeks after injection. Frozen native preparation. x400.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
We followed by means of a polarization microscope the absorption of the microcrystals of the H Q and HC2 suspensions which were of different sizes. The crystals could be demonstrated after half an hour as a band in the connective tissue of the cutis (fig. 4). Their size diminished by about half after the 2nd week, since the absorption was gradual and slow. The larger H Q crystals were still demonstrable among the fibers of the connec tive tissue after 4 weeks (fig. 5), but not the finer H Q crystals. After 6 weeks the crystals were entirely absorbed.
Atrophy Caused by Intradermal Corticosteroid Injection
143
The injection of undiluted HC, and HC2 suspensions performed twice did not yet cause any connective tissue alterations. After the third applica tion, however, a close condensation of the fibers of the connective tissue or parallel coordination with a mild basophilic staining was induced. Following the fourth repeated injection ivory-colored papules could be observed macroscopically and later atrophic areas developed on the skin in this region. In the circumscribed areas of the connective tissue the HC! suspension caused degenerative histological changes (fig. 6): the fibers were broken and homogenized. Between the fibers an amassment of baso philic ground substance had developed. The collagen fibers maintained their structure for a long time. The elastic fibers degenerated first and their volume diminished. The HC2 suspension caused the same pathological
Fig. 7. Connective tissue alteration with a mild basophilic staining after four injections of diluted HC, suspensions. HE. x 80.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
Fig. 6. Degenerative changes of the connective tissue: breaking of the fibers with a mass-like basophilic ground substance after four injections of concentrated HC, suspension. HE. x 80.
144
F ulop
changes in the connective tissue but to a minor degree. No double refraction could be demonstrated in these areas of the connective tissue by means of the polarization microscope. Injections of diluted H Q microcrystal suspensions repeated four times caused a moderate condensation of the connective tissue fibers in the dermis with a mild basophilic staining (fig. 7). At the same time repeated injections of diluted HC2 suspensions containing finer microcrystals, did not cause any apparent damage to the connective tissue. This was likewise not the case, even if the doses were increased from 0.3 up to 0.5 ml.
In cases of endogenous or exogenous cortisone surplus various mecha nisms of skin atrophy are supposed. Due to the effect of corticosteroids the inflammatory tissue reactions diminish, at the same time the ground substance of the connective tissue and likewise the synthesis of the collagen fibers are impeded, due to the transformation of the pluripotent mesenchyma cells, i.e., the mastocytes, fibroblasts, histocytes [1,15,16], The infiltration of amino acids is reduced as well [4]. The atrophy of the epithe lium is secondary, mostly in close relation with the pathophysiological process of the dermis. T o u r a in e et a!. [19] reported diffuse and circumscribed skin atrophy of different types during high doses and long-term cortico steroid therapy. We observed this irreversible atrophy in connection with a systemic corticosteroid treatment long ago. We also examined the pathomechanism of this phenomenon [5,6], The question arose whether in cases of systemic and topical or intradermal corticosteroid treatment the connective tissue injury occurs because of an identical mechanism? The therapeutic and tissue damaging effect of the suspensions is limited only to the area where it is directly infiltrated. In administering microcrystal suspensions a corticosteroid depot is established intralesionally in order to achieve an immunosuppres sive or anti-inflammatory effect. Thus, we assured locally such a high corticosteroid concentration which if administered orally or parenterally would damage the whole organism. The hydrocortisone microcrystal suspensions H Q and HC2 remained in the connective tissue when applied intradermally and they were slowly absorbed. The process of decomposition of the larger crystals lasted longer; there was no cellular reaction in the connective tissue. It was possible to
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
Discussion
Atrophy Caused by Intradermal Corticosteroid Injection
145
induce injuries to the fibers of the connective tissue experimentally. The degree of injury was related to the quality of the crystals, the dose and the concentration of the corticosteroid preparation and the frequency of the injections. Following repeated injections of undiluted hydrocortisone microcrystal suspensions (25 mg/0.1 ml) into the skin of rabbits, the fibrous structure of the connective tissue was decomposed and homogenized. C a s t o r and B a k e r [3] observed similar changes in rats. By means of histological examinations we have found similar alterations in the connective tissue of the human skin. Repeated intradermal injections of steroid suspensions were followed by a progressive homogenization of the collagen fibers and a decrease in the elastic ones [8,9]. S t r e it m a n [17] also observed an injury of the connective tissue resembling pseudoxanthoma elasticum. Based on our experiments we may suppose that there are physico chemical alterations in the connective tissue which are induced by cortico steroids locally. These alterations result in a basophilic granular substance which can be demonstrated between the fibers of the connective tissue, and which is probably only a ‘reactive’ and reversible modified ground sub stance. In this process the quality of the corticosteroids, i.e. their concentra tion and size of the microcrystals, play an important role. In the case of frequent injections, first the elastic then secondly the collagen of the con nective tissue are damaged in a chain reaction. This degenerative process causes a reversible local atrophic alteration in the skin.
References
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1 A sboe-H ansen , G .: Corticosteroids in dermatology; in J adassohn and Schirren 13th Congr. Int. Dermatologiae, vol. 1, pp. 133-135 (Springer, Berlin 1968). 2 Beardwell , A.: Subcutaneous atrophy after local corticosteroid injection. Br. med. J. iii: 600(1967). 3 C astor , C. W. and Baker , B. L .: The local action of adrenocortical steroids on epidermis and connective tissue of the skin. Endocrinology 47: 234-241 (1950). 4 F öldvari, F .; V értes, B. és F ülöp, É .: A steroidok által okozott bbratrophiák pathomechanizmusárói és jelentó'ségükról. Bbrgyógy, vener. Szle. 37: 241-245 (1961). 5 F öldvari. F .; Vértes, B. und F ülöp , É .: Über den Pathomechanismus und die Bedeutung der durch Steroide bewirkten Hautatrophien. Dermatológica 125:93-100 (1962). 6 F rieden , E.; C ohen , E., and H arper , A.: The effects of steroid hormones upon amino acid incorporation into mouse kidney homogenates. Endocrinology 68: 862 866 (1961). 7 F ülöp , É. és V ajda , T . : Kötöszöveti elváltozások helyi steroid hatásra. Borgyógy. vener. Szle. 44: 109-113 (1968). 8 F ülöp , É. és Vajda , T .: Szöveti károsodás vizsgálata steroid suspensiók hatására alopecia areatában. Bbrgyógy. vener. Szle. 45: 154- 159 (1969).
146
F ülöp
9 F ülöp , É, und Vajda , T .: Experimentelle Untersuchungen über die therapeutische und schädigende Wirkung der intrafokalen Steroidhandlung. Derm. Wschr. 157: 269-277 (1971). 10 G oldman , L.: Reactions following intralesional and sublesional injections of cortico steroids. J. Am. med. Ass. 182: 613-615 (1962). 11 G oldman , L .; O ’H ara , H., and Baskett, J . : A study of the local tissue reactions in man to Cortisone and compound F. 1V. Histopathological studies of the local effect of compound F in normal and pathologic skin of man. J. invest. Derm. 2 0 :271-279 (1953). 12 K aiser, H.: Cortisonderivate in Klinik und Praxis; 6. Aufl., pp. 26-79 (Thieme, Stuttgart 1973). 13 Lee, F . : Erfahrungen mit intracutanen Triamcinolon-Injectionen bei Hautkrankheiten. Dermatológica 127: 74-82 (1963). 14 SCHETMAN. D.; H ambrich , G. W., jr., and W ilson , C. E.: Cutaneous changes following local injection of triamcinolone. Archs Derm. 88: 820-828 (1963). 15 Schnitzer , A.: Experimentelle histologische Untersuchungen zur Abwehrreaktion der Haut. Dermatológica 114: 257-265 (1957). 16 Sel ye, H.: The effect of topically administered hydrocortisone upon dystrophic skin, as revealed by the 'pneumoderma’ technic. J. invest. Derm. 2 1 :91-98 (1953). 17 Streitman , B .: Eigenartige Elasticaveränderung nach lokaler Cortison-Infiltration. Z. Haut-Geschl.Krankh. 123: 16-19(1968). 18 T anenbaum , M. H. and Becker , S. W .: Scarring from corticosteroid therapy. Archs Derm. 89: 560 (1964). 19 T ouraine , M. R .; F ournet , M. et B elaich , S.: Les atrophies cutanées au cours de la corticothérapie genérale; in J adassohn and Schirren 13th Congr. Int. Dermatologiae, vol. 1, pp. 153-156 (Springer, Berlin 1968).
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/5/2018 7:11:50 PM
Mrs. Dr. E. F ulop , Department of Dermatology, Semmelweis Medical University, Maria u. 41,1085 Budapest (Hungary)
