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A case of cicatricial pemphigoid or cicatricial linear IgA bullous dermatosis
A case of cicatricial pemphigoid or cicatricial linear IgA bullous dermatosis Vijay Kumar, Ph.D., Tomasz Rogozinski, M.D., Charles Yarbrough, M.D., Ernst H. Beutner, Ph.D., and Tadeusz P. Chorzelski, M.D. Buffalo. NY. Huntington. WV, and Warsaw, Poland A case has been described with clinical features of cicatricial pemphigoid, but immunofluorescent (IF) biopsy findings are suggestive of linear IgA bullous dermatosis (LABD), i.e., the presence of IgA deposits with a linear pattern at the basement membrane zone: The patient failed to respond to sulfones and gave a limited response to corticosteroid. These findings suggest that therapy of the type found to be effective in cutaneous forms of LABD, i.e., combinations of low doses of sulfones and corticosteroids, may be . indicated in such cases. (J AM ACAD DERMATOL 2:327-33 I, 1980.)
Cicatricial pemphigoid (also known as benign mucous membrane pemphigoid or ocular pemphigus) is a chronic bullous disease that usually occurs in the sixth or seventh decade of life and is more frequent in women than in men (2: I). The mucous membranes are nearly always involved; oral and conjunctival lesions are the most common, though the nasal and genital mucosa may also be involved. 1 Skin lesions develop in about one third of the cases. Lesions are characterized by the development of subepidermal bullae. These rupture to form ulcers that frequently lead to scarring, as the name implies. Ocular involvement is characterized by conjunctivitis that leads to adhesions, shrinking and eventually obliteration of the conjunctiva, and, in severe cases, to blindness. Histologically, the subepidermal bullae are surrounded by mixed Iymphohistiocytic infiltrates, From the Department of Microbiology, SUNY at Buffalo School of Medicine, Buffalo, the Department of Medicine, Marshall University School of Medicine, Huntington, and the Department of Dermatology, Warsaw Academy of Medicine, Warsaw. Supported in part by grants from the Summerhill Foundation and from the IF Testing Service. Reprint requests to: Dr. Vijay Kumar, Department of Microbiology, SUNY at Buffalo, 219 Sherman Hall, Buffalo, NY 14214/716831-2905.
0190-9622/80/040327+05$00.50/0 © 1980 Am Acad Dcrrnatol
sometimes with the presence of eosinophils and, occasionally, neutrophils.? These changes are not disease-specific. Direct immunofluorescence (IF) studies of skin biopsy specimens reveal linear deposits of complement components and IgG in the basement membrane zone (BMZ).3-12 Sometimes lesser amounts of IgA and IgM are found. Less than 10% of the cases have circulating BMZ antibodies." These immunofluorescent findings are qualitatively similar to those of bullous pemphigoid and distinct from those of linear IgA bullous dermatoses (LABD) (including chronic bullous diseases of childhood). In this report, we describe a case of cicatricial pemphigoid with IgA deposits in the BMZ. CASE REPORT A 69-year-old woman presented in May, 1978, with a history of mouth ulcers that began as a blistering disease in 1974. In 1977, her right conjunctiva was somewhat inflamed, and a burning sensation was present. (Fig. I). The mouth was diffusely involved and showed shallow ulcerations (Fig. 2). Histologic examination of the buccal mucosa revealed liquefaction degeneration of the basal cell layer, with the presence of lymphocytic and plasmacytic infiltrate in the dermis
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Fig. 1. Early changes in the eye of a 69-year-old woman who had LABD variant cicatricial pemphigoid. Note inflammatory changes.
Fig. 2. Diffuse involvement of the oral mucosa of the same patient as shown in Fig. 1. Note shallow ulcerations. that suggested a possible diagnosis of lichen planus (Fig. 3). The occurrence of conjunctivitis and oral lesions was more suggestive of cicatricial pemphigoid. In July, 1978, a 4-mm punch biopsy of buccal mucosa was taken for direct IF, and blood was drawn for serum studies for epithelial antibodies. Prior to that time, the patient was given symptomatic treatment with a mouthwash containing nystatin and tetracycline. On the basis of the clinical findings, the patient was placed on 20 mg of prednisone per day for 2 weeks, but failed
to respond. Treatment with I gm of sulfasalazine (Azulfidine) four times daily for 1 week, then 500 mg daily for 2 weeks, also failed to yield a response. Because of failure to respond to sulfasalazine, the patient was again started on 20 mg of prednisone per day for 3 weeks, but with no effect, and it was discontinued. After a lag of 3 weeks, the patient was placed on a regimen of 60 mg of prednisone per day for 10 days, off for 10 days, then on for 10 days. Due to the lack of response to prednisone and the patient's complaints of
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April, 1980
Fig, 3, Histology of oral biopsy specimen stained with hematoxylin and eosin . Note
liquefaction of the basal layer and the mononuclear cell infiltrate (predominantly lymphocyte) of the lamina propria. (x400.) headache and confusion, prednisone was discontinued . Two weeks later, the patient started to develop new ulcers, and hence was started on 40 mg of prednisone every other day for I month. On a dosage of 40 mg of prednisone on alternate days, the patient continued to have oral lesions but noted slight improvement. She elected to discontinue treatment, is taking no medication at this time, and is exhibiting oral ulcerations in most of her mouth.
Methods for IF studies The biopsy specimen was received in Michel's transport medium in ambi ent temperature. Standard direct and indirect IF technics were employed as described by Beutner et al.! " The characteristics of the conjugates used were as follows: anti-IgG molar F/P = 4 .0, antibody content, 8 Vlml, dilution, 1:32; anti-IgA molar F/P = 3.4,2 VI ml , dilution, 1:4; anti-IgM molar F/P = 4.2 , 2 Vlml, dilution, 1:4; anti fibrin molar F/P = 0 .9,2 Vlml, dilution, I : 8; anti-C3 component of complement, molar F/P = 2.4,2 Ulml, dilution, 1: 8 . Indirect IF tests were performed on the patient's serum. Serial doubling dilu tions of the patient's serum starting at I : 10dilution were
tested on 4-p. sections of monkey esophagus with the use of the same anti-IgG conjugate as for the direct IF studies. RESULTS
Direct IF studies of the biopsy specimen taken at the border of an ulcerative lesion of the buccal mucosa revealed the presence of IgA deposits with a linear pattern in the BMZ area (Fig. 4). Serum studies revealed no significant antibodies. Antinuclear antibodies were detected to a titer of 40; these are within normal limits for 69-year-old women under the test conditions used. Histologically, the patient presented with a subepidermal separation of the epithelium from the underlying fibrous connective tissue with a lymphocytic infiltrate. In addition, the epithelium showed a sawtooth rete ridge formation with liquefaction degeneration of the basal cell layer. Based on these findings, a histologic diagnosis of erosive lichen planus was made. However, the differentiation between intraoral erosive lichen
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Journal of the American Academy of Dermatology
Fig. 4. Direct IF stain for IgA of oral biopsy specimen. The anti-IgA conjugate with a molar F/P ratio of 3.4 diluted to contain 1f.l Uzrnl of antibody for direct IF staining (corresponding approximately to 25 p.g of antibody protein per milliliter). Note the specific fluorescence in the BMZ. (X400.)
planus and cicatricial pemphigoid cannot be made purely on the basis of histologic findings. COMMENTS
Direct IF studies in cicatricial pemphigoid usually revealed the presence of C3 deposits, sometimes associated with the presence of IgG and, to a lesser extent, other immunoglobulins. These findings are comparable to those seen in bullous pemphigoid. In our case, however, direct IF stud-
ies of the biopsy specimen revealed the presence of linear IgA deposits in the BMZ without the presence of C3 deposits. Such IgA deposits point to a diagnosis of LABD.14-16 Some experts in the field are of the opinion that it is of value to perform immunoelectron microscopic studies in patients such as the one described in this report. Immunoelectron microscopic studies are of help in determining whether the immune deposits occur in the lamina lucida (as
Volume 2 Number 4 April, 1980
in bullous pemphigoid) or in the basal lamina, as reported in cicatricial pemphigoid and, notably, in some but not all cases of LABD. In our opinion, the classification of LABD into two types in such cases as the one described in this report is open to question for two reasons. One is that, while some reports on LABD suggest the existence of the two ultrastructural variants.P-" others reveal both localizations in a single case.!" The second is that the only ultrastructural localizations of immune deposits that have been reported in cicatricial pemphigoid are of the basal lamina type and not in the lamina lucida, as found in bullous pemphigoid. We are of the opinion that these differences need to be clarified before ultrastructural localization of immune deposits can be used in the classification of such cases as the one described in this report. Our findings suggest that the case described in this report is a cicatricial variant of LABD. If this is true, it may be expected that such cases respond to combined therapy with low doses of sulfones (or sulfapyridine) and corticosteroids, since such responses usually occur in the cutaneous form of LABD:15 This remains to be proved in our case. LABD patients commonly give only limited responses to sulfones or to corticosteroids when given alone. It is noteworthy that this also held true in the case described in this report.
Cicatricial pemphigoid
6.
7.
8. 9.
10.
11.
12.
13.
14.
15.
REFERENCES 1. Moschella SL, Pillsbury DM, Hurley HJ Jr, editors; Dermatology. Philadelphia. 1975, W. B. Saunders Co., 1751 pp. 2. Lever WF, Schaumberg-Lever G, editors; Histopathology of the skin, ed. 5. Philadelphia, 1975, J. B. Lippincott Co., 793 pp. 3. Bean SF, Waisman M, Michel B, Thomas CI, Knox JM, Levine M; Cicatricial pemphigoid; Immunofluorescent studies. Arch Derrnatol 106: 195-199, 1972. 4. Bean SF; Cicatricial pemphigoid. Arch Dcrmatol J 10: 552-555, 1974. 5. Bean SF, Michel B: Cicatricial pemphigoid, ill Beumer EH, Chorzelski TP, Bean SF, Jordon RE; Irnrnu-
16.
17.
331
nopathology of the skin: Labeled antibody studies, ed. I. Stroudsburg, PA, 1973, Dowden, Hutchinson & Ross Inc., pp. 55-63. ' Bean SF, Rogers RS III, Jordon RE, Furey NL, Michel B: Cicatricial pemphigoid, ill Beumer EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 257-263. Michel B: Localized chronic pemphigoid of BrunstingPerry; Its relationship to bullous pemphigoid, ill Beutner EJ:I, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 265-27 J. Dantzig P; Circulating antibodies in cicatricial pemphigoid. Arch Derrnatol 108:264-266, 1973. Frank H, Beetz HM; Fluorescienzmikroskopischer Nachweis von Igfl-Ablagerungen bei vemarbendem Pemphigoid. Hautarzt 25:201-202, 1974. Griffith MR, Fukuyama K, Tuffanelli D, Silverman S, Jr: Immunofluorescent studies in mucous membrane pemphigoid. Arch Derrnatol 109:195-199, 1974. Heydenreich G, From E, Diederichsen H: Some unusual findings obtained by the immunofluorescence method in bullous pemphigoid and benign mucous membrane pemphigoid. Acta Dcrm Venereol (Stockh) 52:201-204, 1972. Tagami H, Imamura S; Benign mucous membrane pemphigoid. Demonstration of circulating and tissue bound membrane antibodies. Arch Dermatol 109:711-713, 1974. Beutner EH, Nisengard RJ, Kumar V: Defined immunofluorescence: Basic concepts and their application to clinical immunodermatology, ill Beumer EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 29-75. Jablonska S, Chorzelski TP; Transitional forms between dermatitis herpetiformis and bullous pemphigoid. Br J Dermatol 83: n. 1973. Chorzelski TP, Jablonska S, Beutner EH: Linear IgA bullous dermatosis. Adult form of linear IgA bullous dermatosis, Part I, ill Beutner EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 316-319. Bean SF, Furey NL, Chorzelski TP, Jablonska S: Linear IgA bullous dermatosis. Childhood form of linear IgA bullous dermatosis (benign chronic bullous disease of childhood), Part 2, ill Beutner EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 320-323. Yaoita H, Hertz KC, Katz SI; Dermatitis herpetiformis. Immunoelectronmicroseopic and ultrastructural studies of a patient with linear deposition of IgA. J Invest Derrnatol 67:691-695, 1976.
Cicatricial pemphigoid (also known as benign mucous membrane pemphigoid or ocular pemphigus) is a chronic bullous disease that usually occurs in the sixth or seventh decade of life and is more frequent in women than in men (2: I). The mucous membranes are nearly always involved; oral and conjunctival lesions are the most common, though the nasal and genital mucosa may also be involved. 1 Skin lesions develop in about one third of the cases. Lesions are characterized by the development of subepidermal bullae. These rupture to form ulcers that frequently lead to scarring, as the name implies. Ocular involvement is characterized by conjunctivitis that leads to adhesions, shrinking and eventually obliteration of the conjunctiva, and, in severe cases, to blindness. Histologically, the subepidermal bullae are surrounded by mixed Iymphohistiocytic infiltrates, From the Department of Microbiology, SUNY at Buffalo School of Medicine, Buffalo, the Department of Medicine, Marshall University School of Medicine, Huntington, and the Department of Dermatology, Warsaw Academy of Medicine, Warsaw. Supported in part by grants from the Summerhill Foundation and from the IF Testing Service. Reprint requests to: Dr. Vijay Kumar, Department of Microbiology, SUNY at Buffalo, 219 Sherman Hall, Buffalo, NY 14214/716831-2905.
0190-9622/80/040327+05$00.50/0 © 1980 Am Acad Dcrrnatol
sometimes with the presence of eosinophils and, occasionally, neutrophils.? These changes are not disease-specific. Direct immunofluorescence (IF) studies of skin biopsy specimens reveal linear deposits of complement components and IgG in the basement membrane zone (BMZ).3-12 Sometimes lesser amounts of IgA and IgM are found. Less than 10% of the cases have circulating BMZ antibodies." These immunofluorescent findings are qualitatively similar to those of bullous pemphigoid and distinct from those of linear IgA bullous dermatoses (LABD) (including chronic bullous diseases of childhood). In this report, we describe a case of cicatricial pemphigoid with IgA deposits in the BMZ. CASE REPORT A 69-year-old woman presented in May, 1978, with a history of mouth ulcers that began as a blistering disease in 1974. In 1977, her right conjunctiva was somewhat inflamed, and a burning sensation was present. (Fig. I). The mouth was diffusely involved and showed shallow ulcerations (Fig. 2). Histologic examination of the buccal mucosa revealed liquefaction degeneration of the basal cell layer, with the presence of lymphocytic and plasmacytic infiltrate in the dermis
327
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Kumar et al
Journal of the American Academy of Dermatology
Fig. 1. Early changes in the eye of a 69-year-old woman who had LABD variant cicatricial pemphigoid. Note inflammatory changes.
Fig. 2. Diffuse involvement of the oral mucosa of the same patient as shown in Fig. 1. Note shallow ulcerations. that suggested a possible diagnosis of lichen planus (Fig. 3). The occurrence of conjunctivitis and oral lesions was more suggestive of cicatricial pemphigoid. In July, 1978, a 4-mm punch biopsy of buccal mucosa was taken for direct IF, and blood was drawn for serum studies for epithelial antibodies. Prior to that time, the patient was given symptomatic treatment with a mouthwash containing nystatin and tetracycline. On the basis of the clinical findings, the patient was placed on 20 mg of prednisone per day for 2 weeks, but failed
to respond. Treatment with I gm of sulfasalazine (Azulfidine) four times daily for 1 week, then 500 mg daily for 2 weeks, also failed to yield a response. Because of failure to respond to sulfasalazine, the patient was again started on 20 mg of prednisone per day for 3 weeks, but with no effect, and it was discontinued. After a lag of 3 weeks, the patient was placed on a regimen of 60 mg of prednisone per day for 10 days, off for 10 days, then on for 10 days. Due to the lack of response to prednisone and the patient's complaints of
Volume 2 Number 4
Cicatricial pemphigoid
329
April, 1980
Fig, 3, Histology of oral biopsy specimen stained with hematoxylin and eosin . Note
liquefaction of the basal layer and the mononuclear cell infiltrate (predominantly lymphocyte) of the lamina propria. (x400.) headache and confusion, prednisone was discontinued . Two weeks later, the patient started to develop new ulcers, and hence was started on 40 mg of prednisone every other day for I month. On a dosage of 40 mg of prednisone on alternate days, the patient continued to have oral lesions but noted slight improvement. She elected to discontinue treatment, is taking no medication at this time, and is exhibiting oral ulcerations in most of her mouth.
Methods for IF studies The biopsy specimen was received in Michel's transport medium in ambi ent temperature. Standard direct and indirect IF technics were employed as described by Beutner et al.! " The characteristics of the conjugates used were as follows: anti-IgG molar F/P = 4 .0, antibody content, 8 Vlml, dilution, 1:32; anti-IgA molar F/P = 3.4,2 VI ml , dilution, 1:4; anti-IgM molar F/P = 4.2 , 2 Vlml, dilution, 1:4; anti fibrin molar F/P = 0 .9,2 Vlml, dilution, I : 8; anti-C3 component of complement, molar F/P = 2.4,2 Ulml, dilution, 1: 8 . Indirect IF tests were performed on the patient's serum. Serial doubling dilu tions of the patient's serum starting at I : 10dilution were
tested on 4-p. sections of monkey esophagus with the use of the same anti-IgG conjugate as for the direct IF studies. RESULTS
Direct IF studies of the biopsy specimen taken at the border of an ulcerative lesion of the buccal mucosa revealed the presence of IgA deposits with a linear pattern in the BMZ area (Fig. 4). Serum studies revealed no significant antibodies. Antinuclear antibodies were detected to a titer of 40; these are within normal limits for 69-year-old women under the test conditions used. Histologically, the patient presented with a subepidermal separation of the epithelium from the underlying fibrous connective tissue with a lymphocytic infiltrate. In addition, the epithelium showed a sawtooth rete ridge formation with liquefaction degeneration of the basal cell layer. Based on these findings, a histologic diagnosis of erosive lichen planus was made. However, the differentiation between intraoral erosive lichen
330
Kumar et al
Journal of the American Academy of Dermatology
Fig. 4. Direct IF stain for IgA of oral biopsy specimen. The anti-IgA conjugate with a molar F/P ratio of 3.4 diluted to contain 1f.l Uzrnl of antibody for direct IF staining (corresponding approximately to 25 p.g of antibody protein per milliliter). Note the specific fluorescence in the BMZ. (X400.)
planus and cicatricial pemphigoid cannot be made purely on the basis of histologic findings. COMMENTS
Direct IF studies in cicatricial pemphigoid usually revealed the presence of C3 deposits, sometimes associated with the presence of IgG and, to a lesser extent, other immunoglobulins. These findings are comparable to those seen in bullous pemphigoid. In our case, however, direct IF stud-
ies of the biopsy specimen revealed the presence of linear IgA deposits in the BMZ without the presence of C3 deposits. Such IgA deposits point to a diagnosis of LABD.14-16 Some experts in the field are of the opinion that it is of value to perform immunoelectron microscopic studies in patients such as the one described in this report. Immunoelectron microscopic studies are of help in determining whether the immune deposits occur in the lamina lucida (as
Volume 2 Number 4 April, 1980
in bullous pemphigoid) or in the basal lamina, as reported in cicatricial pemphigoid and, notably, in some but not all cases of LABD. In our opinion, the classification of LABD into two types in such cases as the one described in this report is open to question for two reasons. One is that, while some reports on LABD suggest the existence of the two ultrastructural variants.P-" others reveal both localizations in a single case.!" The second is that the only ultrastructural localizations of immune deposits that have been reported in cicatricial pemphigoid are of the basal lamina type and not in the lamina lucida, as found in bullous pemphigoid. We are of the opinion that these differences need to be clarified before ultrastructural localization of immune deposits can be used in the classification of such cases as the one described in this report. Our findings suggest that the case described in this report is a cicatricial variant of LABD. If this is true, it may be expected that such cases respond to combined therapy with low doses of sulfones (or sulfapyridine) and corticosteroids, since such responses usually occur in the cutaneous form of LABD:15 This remains to be proved in our case. LABD patients commonly give only limited responses to sulfones or to corticosteroids when given alone. It is noteworthy that this also held true in the case described in this report.
Cicatricial pemphigoid
6.
7.
8. 9.
10.
11.
12.
13.
14.
15.
REFERENCES 1. Moschella SL, Pillsbury DM, Hurley HJ Jr, editors; Dermatology. Philadelphia. 1975, W. B. Saunders Co., 1751 pp. 2. Lever WF, Schaumberg-Lever G, editors; Histopathology of the skin, ed. 5. Philadelphia, 1975, J. B. Lippincott Co., 793 pp. 3. Bean SF, Waisman M, Michel B, Thomas CI, Knox JM, Levine M; Cicatricial pemphigoid; Immunofluorescent studies. Arch Derrnatol 106: 195-199, 1972. 4. Bean SF; Cicatricial pemphigoid. Arch Dcrmatol J 10: 552-555, 1974. 5. Bean SF, Michel B: Cicatricial pemphigoid, ill Beumer EH, Chorzelski TP, Bean SF, Jordon RE; Irnrnu-
16.
17.
331
nopathology of the skin: Labeled antibody studies, ed. I. Stroudsburg, PA, 1973, Dowden, Hutchinson & Ross Inc., pp. 55-63. ' Bean SF, Rogers RS III, Jordon RE, Furey NL, Michel B: Cicatricial pemphigoid, ill Beumer EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 257-263. Michel B: Localized chronic pemphigoid of BrunstingPerry; Its relationship to bullous pemphigoid, ill Beutner EJ:I, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 265-27 J. Dantzig P; Circulating antibodies in cicatricial pemphigoid. Arch Derrnatol 108:264-266, 1973. Frank H, Beetz HM; Fluorescienzmikroskopischer Nachweis von Igfl-Ablagerungen bei vemarbendem Pemphigoid. Hautarzt 25:201-202, 1974. Griffith MR, Fukuyama K, Tuffanelli D, Silverman S, Jr: Immunofluorescent studies in mucous membrane pemphigoid. Arch Derrnatol 109:195-199, 1974. Heydenreich G, From E, Diederichsen H: Some unusual findings obtained by the immunofluorescence method in bullous pemphigoid and benign mucous membrane pemphigoid. Acta Dcrm Venereol (Stockh) 52:201-204, 1972. Tagami H, Imamura S; Benign mucous membrane pemphigoid. Demonstration of circulating and tissue bound membrane antibodies. Arch Dermatol 109:711-713, 1974. Beutner EH, Nisengard RJ, Kumar V: Defined immunofluorescence: Basic concepts and their application to clinical immunodermatology, ill Beumer EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 29-75. Jablonska S, Chorzelski TP; Transitional forms between dermatitis herpetiformis and bullous pemphigoid. Br J Dermatol 83: n. 1973. Chorzelski TP, Jablonska S, Beutner EH: Linear IgA bullous dermatosis. Adult form of linear IgA bullous dermatosis, Part I, ill Beutner EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 316-319. Bean SF, Furey NL, Chorzelski TP, Jablonska S: Linear IgA bullous dermatosis. Childhood form of linear IgA bullous dermatosis (benign chronic bullous disease of childhood), Part 2, ill Beutner EH, Chorzelski TP, Bean SF; Immunopathology of the skin, ed. 2. New York, 1979, John Wiley & Sons, Inc., pp. 320-323. Yaoita H, Hertz KC, Katz SI; Dermatitis herpetiformis. Immunoelectronmicroseopic and ultrastructural studies of a patient with linear deposition of IgA. J Invest Derrnatol 67:691-695, 1976.