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A controlled trial of clobetasol propionate ointment 0.05% in the treatment of experimentally induced Rhus dermatitis
Clinical and laboratory studies A controlled trial of clobetasol propionate ointment 0.05% in the treatment of experimentally induced Rhus dermatitis Hazel J. Vernon, MD, and Elise A. Olsen, MD Durham, North Carolina We studied the effectiveness of clobetasol propionate ointment 0.05% in experimentally induced Rhus dermatitis. Clobetasol rapidly decreased the vesiculation at each treated site, although the effect was most prominent at the site to which clobetasol was applied the earliest, that is, at 12 hours after exposure to Rhus extract. On the basis of this experimental model, c1obetasol propionate ointment 0.05% may be effective therapy for naturally occurring Rhus dermatitis. (J AM ACAD DERMATOL 1990;23:829-32.) Few studies address the efficacy of topical steroids in either naturally acquired or experimentally induced Rhus dermatitis. 1, 2 Kaidbey and Kligman1 developed a model of experimentally induced Rhus dermatitis in which patients with a vesiculobullous reaction had class II to VII topical steroids applied once daily for 5 days. They found that only the more potent topical steroids modified the clinical response. 1 Since these studies were performed, several more potent topical corticosteroid preparations have been released. We developed a model of experimentally induced Rhus dermatitis to study the efficacy of c1obetasol propionate ointment. METHOD Subject selection. Eleven women and nine men, 20 to 40 years of age, with a positive history of Rhus dermatitis and a positive patch test reaction to Rhus oleoresin were selected. No subject was pregnant or nursing, had dermatitis in the study area, bad used topical steroids within 2 weeks, or had taken immunosuppressive agents including systemic steroids within 1 month before the study. None had atopic dermatitis, asthma, allergic rhinitis, an immunologic disorder, or diabetes mellitus. Application of Rhus extraction. Four test sites were selected, two on each forearm (Fig. 1). Two to three drops of Rhus oleoresin 1:50 in absolute alcohol (HollisterStier, Yeadon, Pa.) were applied to saturate each of eight From the Division of Dermatology, Department of Medicine, Duke University Medical Center. Supported in part by a grant from Glaxo, Inc., Research Triangle Park, N.C. Accepted for publication Dec. 29, 1989. Reprint requests: Elise A, Olsen, MD, Box 3294, Duke University Medicnl Center, Durham, NC 27710.
16/1/19371
Finn Chamberfilter paper disks. Thesaturated disks were applied to each test site and secured with Scanpor tape. All sites were rinsed with water 12 hours later. Application of test topical steroid (Fig. 1). In a singleblinded manner with a randomized schema, clobetasol propionate ointment 0.05% was begun at one site immediately after removal of Rhus oleoresin (referred to as CP-12 because clobetasol propionate ointment was begun 12 hours after Rhus application); at a second site 12 hours after removal (24 hours after application and referred to as CP-24); and at a third site 48 hours after the initial application ofextract (CP-48). Enough clobetasol ointment to cover the area completely with a thin film was used. Once clobetasol ointment was begun, it was continued at that site twice daily throughout the study. White petrolatum was placed on each site twice daily until c1obetasol propionate ointment was begun and was continued twice daily on the fourth site (control) for the duration of the study. Evaluations. Evaluations were made on day 1 (approximately 24 hours after application, 12 hours after rinsing off extract) and days 2, 4, 7,10, and 14. Erythema, induration, and pruritus were evaluated on a scale of 0 to 3 (absent, mild, moderate, or severe). Vesiculation was graded on the same 3-point scale; a 3+ reaction was a frank bulla. All evaluations were made by the same investigator. Photographs were taken at each visit Statistical methods. For each aspect of efficacy, means of the scores for the 20 subjects were used to compare the four treatments. Values of p were determined by the Wilcoxon signed-rank test. RESULTS A mild to moderate dermatitis developed in 10 subjects and a moderate to severe dermatitis developed in 10 subjects in response to the Rhus extract. A representative patient is shown in Fig. 2. Vesiculation (Table I). At day 2, only the CP-12
829
Journal of the American Academy of Dermatology
830 Vernon and Olsen
Fig. 1. Rhus extract was applied to all four sites and rinsed off all four sites 12 hours later. Subjects were given an instruction sheet outlining when to begin application of clobetasol ointment at a particular site, with the use of letters A, B, C, and D. A designated the initial application site, 12 hours after application of Rhus extract, immediately after rinsing. B designated the second application site, 24 hours after application of Rhus extract, 12 hours after rinsing. C designated the third application site, 48 hours after application of Rhus extract, 36 hours after rinsing. D designated the control site. Placement of A, B, C, and D, (i.e., right vs left arm, upper vs lower site) was randomized. The investigator was not aware of the placement pattern on any subject.
site had significantly reduced vesiculation over the control site (p < 0.01). By day 4, vesiculation was significantly reduced in both CP-12 (p < 0.01) and CP-24 (p < 0.01) sites. By day 7 and continuing to days 10 and 14 all three clobetasol-treated sites showed a significant reduction of vesiculation when compared with the control site (p < 0.05). Erythema. At day 4, only the CP-12 sites were significantly improved over the control (p < 0.03). By day 7, however, all three clobetasol-treated sites were significantly improved over the control and remained significant at day 10 (p < 0.01). On day 14, the CP-12 and CP-24 sites were significantly improved compared with the control sites. Edema. All three clobetasol-treated sites showed a significant improvement over the control sites at day 7 (p < 0.01). Only CP-12 and CP-24 sites were significantly improved versus the control site at day l4.
Pruritus. Many subjects reported near to total relief of their pruritus soon after application of test medication, with recurrence of the pruritus 10 to 12 hours later. In grading pruritus, the intensity before reapplication was recorded. At day 2, only the CP-12 site had significantly less pruritus than the control site (p = 0.05). The earlier clobetasol treatment was begun, the lower the mean symptom score, although statistical significance could not be shown. Adverse experiences during the study period. On day 10 of the study, five subjects, each with a severe vesicular response to the Rhus extract, had cutaneous reactions remote from the site of exposure, but none was severe enough to require removal from the study. Follow-up. From telephone or direct follow-up, 6 of 10 subjects in the moderate to severe dermatitis group and 3 of 10 subjects in the mild to moderate dermatitis group reported mild to moderate flares of the dermatitis at one or more sites when clobetasol was discontinued. By day 21 after application of extract, the dermatitis had subsided totally or to the intensity seen at the end of the study. DISCUSSION
This study addressed two aspects of therapeutic intervention in Rhus dermatitis: (1) whether superpotent steroids, with c1obetasol propionate ointment as a prototype, can significantly modify the course of Rhus dermatitis. (2) If so, what is the time frame for application after antigen exposure that will lead to an effective response'? We showed that clobetasol propionate ointment, a class I topical steroid, effectively ameliorated the signs and symptoms of experimentally produced Rhus dermatitis. Vesiculation was most affected regardless of whether clobetasol (Temovate) was applied 12 or 48 hours after antigen exposure but was most marked within the first day. Intensity of pruritus, erythema, and edema were also moderated with application ofclobetasol applied within 12 to 48 hours after Rhus exposure. Clearly, there is a time after antigen exposure in which application of even a superpotent steroid is not effective. If we can extrapolate from this experimentally induced Rhus dermatitis, clobetasol propionate ointment may be effective in treating naturally occurring Rhus dermatitis. The earlier after Rhus exposure the medication is applied, the more effective the amelioration of signs and symptoms of Rhus dermatitis. In clinical practice, the application of a
Volume 23 Number 5, Part 1 November 1990
Clobetasol propionate in treatment olRhus dermatitis 831
Fig. 2. Example of progression of experimentally produced allergic contact dermatitis. In this subject, randomization of the time ofapplication of topical steroid after removal of Rhus extract was as shown in upper left panel labeled Day 2. A, Steroid application begun immediately after removal of Rhus extract (i.e., at 12 hours [CP-12]). B, Steroid application begun 12 hours after removal of Rhus extract (Le., at 24 hours [CP-24]). C, Steroid application begun 36 hours after removal of Rhus extract (i.e., at 48 hours [CP-48]). D, Control (white petrolatum) application begun immediately after removal of Rhus extract.
Table I. Vesiculation scores Control
Day
Mean
I 2 4 7 10 14
0.20 1.25 1.50 1.20 0.72 0.45
I
CP-24
CP-12 (SD)
Mean
(0.34) (1.30) (1.17) (1.08) (0.72) (0.60)
0.20 0.30 0.52 0.28 0.18 0.12
I
(SD)
Mean
(0.34) (0.70)* (0.88)* (0.79)* (0.37)* (0.28)t
0.40 0.85 0.72 0.25 0.18 0.15
1
CP-48 (SD)
Mean
(0.74) (0.99) (0.88)* (0.50)* (0.29)* (0.24)t
0.40 1.32 1.18 0.62 0.40 0.15
1
(SD)
(0.79) (1.38) (1.23) (0.86)* (0.42)t (0.24)t
SD. Standard deviation. For explanation of CP-12, CP-24, and CP-48, see text. "p < 0.01 for treatment versus control (Wilcoxon signed-rank test). tp < 0.05 for treatment versus control (Wilcoxon signed-rank test).
superpotent steroid to an area exposed to Rhus, but without clinical rash, would probably only be useful or prudent in those subjects with known Rhus exposure over a defined limited body surface area (e.g., the wrists above gloves in an exposed gardener). The
broader implications here are that applications of a superpotent steroid at the earliest stage of the allergic reaction (i.e., pruritus or erythema that may develop in 6 to 24 hours) may effectively moderate the expected rash. To prevent a rebound flare, treatment
Journal of the American Academy of Dermatology
Vernon and Olsen may need to be continued more than 2 weeks, but perhaps a less potent steroid could be substituted for c1obetasol propionate ointment at that time. We thank Eldred E. Giefer of Glaxo, Inc., Research Triangle Park, North Carolina, for performing the statistical computations.
REFERENCES 1. Frank L, Stritzler C, Kaufman J. Hydrocortisone (com2.
pound F) free alcohol and hydrocortisone acetate for topical uses. Arch Dermatol 1955;71:117-20. Kaidbey KH, Kligman AM. Assay oftopical corticosteroids, efficacy of suppression of experimental Rhus dermatitis in humans. Arch Dermatol 1976;112:808-13.
Clinical association of autoantibodies to fibrillarin with diffuse scleroderma and disseminated telangiectasia Gunter Kurzhals, MD,a Michael Meurer, MD,a Thomas Krieg, MD,a and Georg Reimer, MDb Munich and Erlangen, Federal Republic of Germany Circulating autoantibodies against a variety ofnuclear and nucleolar antigens are characteristic serologic findings in systemic scleroderma. Some of these antibodies correlate with clinical subsets of the disease. We describe three patients with systemic scleroderma and high autoantibody titers against U3 ribonucleoprotein-associated fibrillarin, a recently identified 34 leD nucleolar protein. These patients showed a progressive course with multiple organ and diffuse skin involvement with disseminated telangiectasia. (J AM ACAD DERMATOL 1990;23:832-6.)
Systemic scleroderma is a generalized disease of connective tissue that involves mainly the skin, the gastrointestinal tract, the lungs, the heart, and the kidneys. 1 Circulating antibodies against a variety of nuclear and nucleolar antigens can be detected in more than 95% ofpatients. 2-4 Some antibody specificities correlate with defined clinical subsets of the disease and have proved to be of diagnostic and prognostic significance. For example, anti-Sc1-70 antibodies directed against the nuclear/nucleolar enzyme DNA topoisomerase 1 are associated with diffuse scleroderma and multiple organ involvement. s On the other hand, anticentromere antibodies are characteristic of the CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome From the Department of Dermatology, Ludwig-Maximilians-UniversHiit Munchen,' and the Department of Dermatology, Friedrich-ALexander-Universitat Erlangen-Nurnberg.b Accepted for publication Jan. 17,1990. Reprint requests: Michael Meurer, MD, DermatoLogische Klinik und Poliklinik, Ludwig-Maximilians-Universitat Miinchen, Frauenlobstr. 9-11, D-8000 Milnchen 2, FRG. 16/1/19464
832
and of acroscleroderma with limited cutaneous and internal organ involvement. 6 More recently, a variety of nucleolar proteins within RNA-protein complexes have been identified as targets of autoantibodies in scleroderma patients. These nucleolar antigens include RNA polymerase 1,7 the Pm-Scl particle,8 U3 ribonucleoprotein CD3RNP)-associated fibrillarin, and 7-2 RNP.9 Antibodies directed against the Pm-Scl antigen identify a group of scleroderma patients with concomitant myositis. 10 The clinical significance of the other antinucleolar antibodies is less clear. We present evidence that antibodies against the D3-RNA-associated nucleolar protein fibrillarin may characterize a subset of patients with diffuse scleroderma and widespread telangiectasia. CASE REPORTS
Case 1 A 43-year-old white man had had Raynaud's disease for 8 years and diffuse scleroderma for 4 years. Recently, dysphagia and dyspnea on exertion developed. He had had psoriasis for 20 years. On examination, edema and swelling of the fingers and toes were present. Cutaneous
16/1/19371
Finn Chamberfilter paper disks. Thesaturated disks were applied to each test site and secured with Scanpor tape. All sites were rinsed with water 12 hours later. Application of test topical steroid (Fig. 1). In a singleblinded manner with a randomized schema, clobetasol propionate ointment 0.05% was begun at one site immediately after removal of Rhus oleoresin (referred to as CP-12 because clobetasol propionate ointment was begun 12 hours after Rhus application); at a second site 12 hours after removal (24 hours after application and referred to as CP-24); and at a third site 48 hours after the initial application ofextract (CP-48). Enough clobetasol ointment to cover the area completely with a thin film was used. Once clobetasol ointment was begun, it was continued at that site twice daily throughout the study. White petrolatum was placed on each site twice daily until c1obetasol propionate ointment was begun and was continued twice daily on the fourth site (control) for the duration of the study. Evaluations. Evaluations were made on day 1 (approximately 24 hours after application, 12 hours after rinsing off extract) and days 2, 4, 7,10, and 14. Erythema, induration, and pruritus were evaluated on a scale of 0 to 3 (absent, mild, moderate, or severe). Vesiculation was graded on the same 3-point scale; a 3+ reaction was a frank bulla. All evaluations were made by the same investigator. Photographs were taken at each visit Statistical methods. For each aspect of efficacy, means of the scores for the 20 subjects were used to compare the four treatments. Values of p were determined by the Wilcoxon signed-rank test. RESULTS A mild to moderate dermatitis developed in 10 subjects and a moderate to severe dermatitis developed in 10 subjects in response to the Rhus extract. A representative patient is shown in Fig. 2. Vesiculation (Table I). At day 2, only the CP-12
829
Journal of the American Academy of Dermatology
830 Vernon and Olsen
Fig. 1. Rhus extract was applied to all four sites and rinsed off all four sites 12 hours later. Subjects were given an instruction sheet outlining when to begin application of clobetasol ointment at a particular site, with the use of letters A, B, C, and D. A designated the initial application site, 12 hours after application of Rhus extract, immediately after rinsing. B designated the second application site, 24 hours after application of Rhus extract, 12 hours after rinsing. C designated the third application site, 48 hours after application of Rhus extract, 36 hours after rinsing. D designated the control site. Placement of A, B, C, and D, (i.e., right vs left arm, upper vs lower site) was randomized. The investigator was not aware of the placement pattern on any subject.
site had significantly reduced vesiculation over the control site (p < 0.01). By day 4, vesiculation was significantly reduced in both CP-12 (p < 0.01) and CP-24 (p < 0.01) sites. By day 7 and continuing to days 10 and 14 all three clobetasol-treated sites showed a significant reduction of vesiculation when compared with the control site (p < 0.05). Erythema. At day 4, only the CP-12 sites were significantly improved over the control (p < 0.03). By day 7, however, all three clobetasol-treated sites were significantly improved over the control and remained significant at day 10 (p < 0.01). On day 14, the CP-12 and CP-24 sites were significantly improved compared with the control sites. Edema. All three clobetasol-treated sites showed a significant improvement over the control sites at day 7 (p < 0.01). Only CP-12 and CP-24 sites were significantly improved versus the control site at day l4.
Pruritus. Many subjects reported near to total relief of their pruritus soon after application of test medication, with recurrence of the pruritus 10 to 12 hours later. In grading pruritus, the intensity before reapplication was recorded. At day 2, only the CP-12 site had significantly less pruritus than the control site (p = 0.05). The earlier clobetasol treatment was begun, the lower the mean symptom score, although statistical significance could not be shown. Adverse experiences during the study period. On day 10 of the study, five subjects, each with a severe vesicular response to the Rhus extract, had cutaneous reactions remote from the site of exposure, but none was severe enough to require removal from the study. Follow-up. From telephone or direct follow-up, 6 of 10 subjects in the moderate to severe dermatitis group and 3 of 10 subjects in the mild to moderate dermatitis group reported mild to moderate flares of the dermatitis at one or more sites when clobetasol was discontinued. By day 21 after application of extract, the dermatitis had subsided totally or to the intensity seen at the end of the study. DISCUSSION
This study addressed two aspects of therapeutic intervention in Rhus dermatitis: (1) whether superpotent steroids, with c1obetasol propionate ointment as a prototype, can significantly modify the course of Rhus dermatitis. (2) If so, what is the time frame for application after antigen exposure that will lead to an effective response'? We showed that clobetasol propionate ointment, a class I topical steroid, effectively ameliorated the signs and symptoms of experimentally produced Rhus dermatitis. Vesiculation was most affected regardless of whether clobetasol (Temovate) was applied 12 or 48 hours after antigen exposure but was most marked within the first day. Intensity of pruritus, erythema, and edema were also moderated with application ofclobetasol applied within 12 to 48 hours after Rhus exposure. Clearly, there is a time after antigen exposure in which application of even a superpotent steroid is not effective. If we can extrapolate from this experimentally induced Rhus dermatitis, clobetasol propionate ointment may be effective in treating naturally occurring Rhus dermatitis. The earlier after Rhus exposure the medication is applied, the more effective the amelioration of signs and symptoms of Rhus dermatitis. In clinical practice, the application of a
Volume 23 Number 5, Part 1 November 1990
Clobetasol propionate in treatment olRhus dermatitis 831
Fig. 2. Example of progression of experimentally produced allergic contact dermatitis. In this subject, randomization of the time ofapplication of topical steroid after removal of Rhus extract was as shown in upper left panel labeled Day 2. A, Steroid application begun immediately after removal of Rhus extract (i.e., at 12 hours [CP-12]). B, Steroid application begun 12 hours after removal of Rhus extract (Le., at 24 hours [CP-24]). C, Steroid application begun 36 hours after removal of Rhus extract (i.e., at 48 hours [CP-48]). D, Control (white petrolatum) application begun immediately after removal of Rhus extract.
Table I. Vesiculation scores Control
Day
Mean
I 2 4 7 10 14
0.20 1.25 1.50 1.20 0.72 0.45
I
CP-24
CP-12 (SD)
Mean
(0.34) (1.30) (1.17) (1.08) (0.72) (0.60)
0.20 0.30 0.52 0.28 0.18 0.12
I
(SD)
Mean
(0.34) (0.70)* (0.88)* (0.79)* (0.37)* (0.28)t
0.40 0.85 0.72 0.25 0.18 0.15
1
CP-48 (SD)
Mean
(0.74) (0.99) (0.88)* (0.50)* (0.29)* (0.24)t
0.40 1.32 1.18 0.62 0.40 0.15
1
(SD)
(0.79) (1.38) (1.23) (0.86)* (0.42)t (0.24)t
SD. Standard deviation. For explanation of CP-12, CP-24, and CP-48, see text. "p < 0.01 for treatment versus control (Wilcoxon signed-rank test). tp < 0.05 for treatment versus control (Wilcoxon signed-rank test).
superpotent steroid to an area exposed to Rhus, but without clinical rash, would probably only be useful or prudent in those subjects with known Rhus exposure over a defined limited body surface area (e.g., the wrists above gloves in an exposed gardener). The
broader implications here are that applications of a superpotent steroid at the earliest stage of the allergic reaction (i.e., pruritus or erythema that may develop in 6 to 24 hours) may effectively moderate the expected rash. To prevent a rebound flare, treatment
Journal of the American Academy of Dermatology
Vernon and Olsen may need to be continued more than 2 weeks, but perhaps a less potent steroid could be substituted for c1obetasol propionate ointment at that time. We thank Eldred E. Giefer of Glaxo, Inc., Research Triangle Park, North Carolina, for performing the statistical computations.
REFERENCES 1. Frank L, Stritzler C, Kaufman J. Hydrocortisone (com2.
pound F) free alcohol and hydrocortisone acetate for topical uses. Arch Dermatol 1955;71:117-20. Kaidbey KH, Kligman AM. Assay oftopical corticosteroids, efficacy of suppression of experimental Rhus dermatitis in humans. Arch Dermatol 1976;112:808-13.
Clinical association of autoantibodies to fibrillarin with diffuse scleroderma and disseminated telangiectasia Gunter Kurzhals, MD,a Michael Meurer, MD,a Thomas Krieg, MD,a and Georg Reimer, MDb Munich and Erlangen, Federal Republic of Germany Circulating autoantibodies against a variety ofnuclear and nucleolar antigens are characteristic serologic findings in systemic scleroderma. Some of these antibodies correlate with clinical subsets of the disease. We describe three patients with systemic scleroderma and high autoantibody titers against U3 ribonucleoprotein-associated fibrillarin, a recently identified 34 leD nucleolar protein. These patients showed a progressive course with multiple organ and diffuse skin involvement with disseminated telangiectasia. (J AM ACAD DERMATOL 1990;23:832-6.)
Systemic scleroderma is a generalized disease of connective tissue that involves mainly the skin, the gastrointestinal tract, the lungs, the heart, and the kidneys. 1 Circulating antibodies against a variety of nuclear and nucleolar antigens can be detected in more than 95% ofpatients. 2-4 Some antibody specificities correlate with defined clinical subsets of the disease and have proved to be of diagnostic and prognostic significance. For example, anti-Sc1-70 antibodies directed against the nuclear/nucleolar enzyme DNA topoisomerase 1 are associated with diffuse scleroderma and multiple organ involvement. s On the other hand, anticentromere antibodies are characteristic of the CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome From the Department of Dermatology, Ludwig-Maximilians-UniversHiit Munchen,' and the Department of Dermatology, Friedrich-ALexander-Universitat Erlangen-Nurnberg.b Accepted for publication Jan. 17,1990. Reprint requests: Michael Meurer, MD, DermatoLogische Klinik und Poliklinik, Ludwig-Maximilians-Universitat Miinchen, Frauenlobstr. 9-11, D-8000 Milnchen 2, FRG. 16/1/19464
832
and of acroscleroderma with limited cutaneous and internal organ involvement. 6 More recently, a variety of nucleolar proteins within RNA-protein complexes have been identified as targets of autoantibodies in scleroderma patients. These nucleolar antigens include RNA polymerase 1,7 the Pm-Scl particle,8 U3 ribonucleoprotein CD3RNP)-associated fibrillarin, and 7-2 RNP.9 Antibodies directed against the Pm-Scl antigen identify a group of scleroderma patients with concomitant myositis. 10 The clinical significance of the other antinucleolar antibodies is less clear. We present evidence that antibodies against the D3-RNA-associated nucleolar protein fibrillarin may characterize a subset of patients with diffuse scleroderma and widespread telangiectasia. CASE REPORTS
Case 1 A 43-year-old white man had had Raynaud's disease for 8 years and diffuse scleroderma for 4 years. Recently, dysphagia and dyspnea on exertion developed. He had had psoriasis for 20 years. On examination, edema and swelling of the fingers and toes were present. Cutaneous