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PUVA-cream photochemotherapy for the treatment of localized scleroderma
PUVA-cream photochemotherapy for the treatment of localized scleroderma Marcella Grundmann-Kollmann, MD, Falk Ochsendorf, MD, Thomas M. Zollner, MD, Konstanze Spieth, MD, Evelyn Sachsenberg-Studer, MD, Roland Kaufmann, MD, and Maurizio Podda, MD Frankfurt, Germany Background: The efforts to treat localized scleroderma, including therapies with potentially hazardous side effects, are often unsatisfactory. Recently, PUVA-bath photochemotherapy has been proven highly effective in the treatment of localized scleroderma. Another form of topical PUVA therapy, 8methoxypsoralen (8-MOP) containing cream or gel preparations, has been proven to be as effective as PUVA-bath therapy for palmoplantar dermatoses. Objective: We sought to assess the efficacy of PUVA-cream photochemotherapy in patients with localized scleroderma. Methods: Four patients with localized scleroderma were included in the study. Diagnosis was confirmed by 20 MHz ultrasound assessment as well as pretreatment skin biopsy specimens from lesional skin. PUVAcream therapy was performed 4 times a week; all patients received 30 treatments. Results: PUVA-cream photochemotherapy induced significant clinical improvement or clearance of localized scleroderma in all patients. Clearance was documented by clinical features as well as by 20 MHz ultrasound and histopathologic analysis. Conclusion: PUVA-cream phototherapy can be highly effective in patients with localized scleroderma even if previous therapy was unsuccessful. (J Am Acad Dermatol 2000;43:675-8.)
L
ocalized scleroderma (LS) can severely affect the quality of life and may progress to longlasting induration of the skin and subcutaneous tissues. Numerous treatments have been used with limited success, such as intravenous penicillin, infiltration with glucocorticosteroids, nonsteroidal anti-inflammatory drugs, and immunosuppressive or vasoactive drugs.1 Recently, the successful treatment of LS with PUVAbath therapy and low- or high-dose UVA1 therapy was described.2-4 The results suggest phototherapy with UVA1 as well as methoxsalen bath plus UVA as promising new approaches. However, only a few dermatologists have access to UVA1 therapy because of its high cost. PUVA-bath therapy is an alternative but yields
From the Department of Dermatology, Johann Wolfgang Goethe University. Reprint requests: Marcella Grundmann-Kollmann, MD, Department of Dermatology, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/105503 doi:10.1067/mjd.2000.105503
some disadvantages: It is–especially for dermatologic practitioners–difficult to organize because it requires bath facilities; it also is unsuitable for patients with only solitary LS lesions because the whole body is photosensitized. Therefore methoxsalen-containing cream or gel preparations seem a relevant alternative topical application.5,6 PUVA-cream therapy has been shown to be effective in treating palmoplantar dermatoses.6,7 Therefore we decided to investigate the efficacy of this new variation of topical PUVA therapy in patients with LS.
PATIENTS AND METHODS Four patients with LS (1-3 lesions; diameter, 5-10 cm) were included in our study over 8 weeks after informed consent was obtained. In all patients (2 women, 2 men; age, 32-65 years; duration of disease, 3-7 years) the diagnosis of LS was established according to clinical and histopathologic criteria. In all patients conventional therapy had not resulted in any significant improvement and did not halt progression of disease. No other treatment had been given for at least 6 weeks before initiation of PUVAcream therapy. 675
676 Grundmann-Kollmann et al
J AM ACAD DERMATOL OCTOBER 2000
Fig 1. Patient 1. Pretreatment biopsy specimen shows dermal and subcutaneous sclerosis with entrapment of eccrine glands and blunting of rete ridges.
Fig 2. Patient 1. Ultrasound B-scan of representative sclerotic plaque before therapy.
Histopathologic analysis of lesional skin at the beginning of the study revealed dermal and subcutaneous sclerosis with entrapment of eccrine glands and blunting of rete ridges (Fig 1). Before treatment, 20 MHz ultrasound assessment of sclerotic plaques in all patients revealed a substantially increased skin thickness and skin density (Fig 2) as compared with contralateral unaffected areas. Psoralen cream (final concentration 0.001% 8methoxypsoralen [8-MOP] containing water in oil emulsion (30% H2O) for Fitzpatrick skin types I and II, 0.0025% 8-MOP containing water in oil emulsion (30% H2O) for skin types III and IV) was prepared as previously described.6 To control the final concentration of 8-MOP in the cream and stock solution, high-performance liquid chromatography was performed.8 Four times a week (Monday, Tuesday, Thursday, Friday) 8-MOP cream was applied in an even layer for 1 hour to the LS lesions. Afterward the remaining cream was completely removed by a cotton swab. Minimal phototoxic dose was determined before the first treatment. Application of PUVA cream was followed directly by UVA administration with increasing doses (starting dose 30% of MPD), according to indi-
vidual photosensitivity, up to a maximum single dose of 3.5 J/cm2. The UVA irradiation equipment consisted of a UVA cabin (model 8001, Waldmann, VillingenSchwenningen, Germany) emitting exclusively UVA in the range of 320 to 400 nm, with a peak at 365 nm. Patients were assessed before, after 4 weeks, and at the end of phototherapy by palpation for tethering and thickening of the skin. Furthermore, 20 MHz ultrasound analysis was performed before, after 4 weeks, and at the end of treatment. Before treatment, 20 MHz ultrasound assessment of representative sclerotic plaques in all patients revealed a substantially increased skin thickness and skin density as compared with contralateral unaffected areas (Table I). Ultrasound measurements were performed with a digital 20 MHz scanner (Dermascan, Cortex Technology, Hadsund, Denmark). Histopathologic analysis was performed in a blinded fashion on hematoxylineosin–stained sections from skin biopsy specimens. Pretreatment specimens were taken from sclerotic skin areas (Fig 1). Posttreatment specimens were taken from previously affected areas next to the sites of previous biopsy (Fig 3).
Grundmann-Kollmann et al 677
J AM ACAD DERMATOL VOLUME 43, NUMBER 4
Fig 3. Patient 1. Posttreatment biopsy specimen shows almost normal human skin.
Fig 4. Patient 1. Ultrasound B-scan of the same plaque after 25 PUVA-cream therapy sessions.
Table I. Characteristics of patients with localized scleroderma treated with PUVA-cream therapy Skin thickness (mm) Patient No.
1 2 3 4
Age (y)/Sex
Duration of disease (y)
32/M 47/M 65/F 57/F
3 5 7 7
Pretreatment
Cumulative UVA dose (J/cm2)
Before tx
After tx
Roc Roc, SS Roc, SS Roc
121 77.5 92 67.5
2.2 2.05 1.86 1.90
1.75 1.05 1.00 0.98
Roc, Rocephin (ceftriaxone); SS, systemic glucocorticosteroids; tx, therapy.
RESULTS The therapy was well accepted and completed by all patients. Except for hyperpigmentation in a patient with skin type III, no side effects were observed. All patients had 30 treatments; the mean cumulative UVA dose was 89.5 J/cm2 (range, 67.5-121 J/cm2). According to clinical and ultrasound criteria, sclerotic plaques disappeared or improved markedly in all patients. Palpation revealed a remarkable softening of the sclerotic lesions. These results were confirmed by 20 MHz ultrasound evaluation. Dermal thickness was increased before therapy and decreased into the normal range after therapy (Table I). As shown in Fig 4, there was a marked reduction
in the highly reflective echo-rich bands within the epidermis and subcutis. Similar results were obtained by histopathologic evaluation of biopsy specimens after therapy (Fig 3). The structure of the dermal collagen returned to normal or almost normal human dermis. The single collagen bundles revealed regular thickness and were separated by regular spaces.
DISCUSSION Different types of photochemotherapy have been described for sclerosing skin diseases, such as oral PUVA therapy, PUVA-bath therapy, and low- and highdose UVA1 therapy.
678 Grundmann-Kollmann et al
Successful treatment of LS with oral PUVA therapy has been reported; however, it is limited by side effects due to systemic resorption of psoralens. PUVA-bath therapy, in which patients are immersed in an 8-MOP dilute bath water solution immediately followed by UVA irradiation, has been developed to avoid unwanted effects due to systemic effects of psoralens. It has been shown to be highly effective in patients with LS.2 Thus it seemed likely that other variations of topical PUVA therapy also may be of benefit for patients with LS. Our preliminary data suggest that PUVA-cream therapy may be effective for patients with LS. Like PUVA-bath therapy, PUVA-cream therapy induces a homogeneous skin sensitivity to UVA; a great advantage is that selected body regions can be excluded from the therapy. Therefore PUVA-cream therapy is a promising therapeutic alternative to PUVA-bath therapy for patients with solitary or few LS lesions. These results underscore the importance of testing variations of accepted therapies to achieve benefits for both patients and dermatologists. Although the mechanisms by which UVA phototherapy induces regression of sclerosis need to be elucidated, induction of collagenase activity as shown by Scharffetter et al9 is likely to be involved. The number of patients treated in this study is too small to make judgments on the overall efficacy of PUVA-cream photochemotherapy for LS, and we cannot draw any conclusions on the percentage of patients responding to PUVA-cream photochemother-
J AM ACAD DERMATOL OCTOBER 2000
apy. However, our initial results indicate that PUVAcream photochemotherapy is a treatment protocol favorably accepted by patients, which could develop into an important alternative to PUVA-bath therapy for patients with few lesions of LS. REFERENCES 1. Rowell NR, Goodfield M. The connective tissue diseases. In: Champion RH, Burton JL, Ebling F, editors. Textbook of dermatology. Oxford: Blackwell Scientific; 1992. p. 2163-94. 2. Kerscher M, Volkenandt M, Meurer M, Lehmann P, Plewig G, Röcken M. Treatment of localised scleroderma with PUVA bath photochemotherapy. Lancet 1994;343:1233. 3. Kerscher M, Dirschka T, Volkenandt M. Treatment of localised scleroderma by UVA1 phototherapy. Lancet 1995;346:1166. 4. Stege H, Berneburg M, Humke S, Klammer M, Grewe M, GretherBeck S, et al. High-dose UVA1 radiation therapy of localized scleroderma. J Am Acad Dermatol 1997;36:938-44. 5. De Rie MA, Eendenburg van JP, Versnick AC, Stolk LML, Bos JD, Westerhof W. A new psoralen containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema. Br J Dermatol 1995;132:964-9. 6. Stege H, Berneburg M, Ruzicka T, Krutmann J. Cream-PUVAPhototherapy. Hautarzt 1997;48:89-93. 7. Grundmann-Kollmann M, Behrens S, Peter RU, Kerscher M. Treatment of severe recalcitrant dermatoses of the palms and soles with PUVA-bath versus PUVA-cream therapy. Photodermatol Photoimmunol Photomed 1999;15:87-9. 8. Susanto F, Humfeld S, Reinauer H, Meschig R. High performance liquid chromatography measurement of 8-methoxsypsoralen in plasma. Chromatographia 1986;21:443-6. 9. Scharffetter K, Wlascheg M, Hogg A, Bolsen K, Schothorst A, Goerz G, et al. UVA irradiation induces collagenase in human dermal fibroblasts in vitro and in vivo. Arch Dermatol Res 1991;283:506-11.
L
ocalized scleroderma (LS) can severely affect the quality of life and may progress to longlasting induration of the skin and subcutaneous tissues. Numerous treatments have been used with limited success, such as intravenous penicillin, infiltration with glucocorticosteroids, nonsteroidal anti-inflammatory drugs, and immunosuppressive or vasoactive drugs.1 Recently, the successful treatment of LS with PUVAbath therapy and low- or high-dose UVA1 therapy was described.2-4 The results suggest phototherapy with UVA1 as well as methoxsalen bath plus UVA as promising new approaches. However, only a few dermatologists have access to UVA1 therapy because of its high cost. PUVA-bath therapy is an alternative but yields
From the Department of Dermatology, Johann Wolfgang Goethe University. Reprint requests: Marcella Grundmann-Kollmann, MD, Department of Dermatology, Johann Wolfgang Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/105503 doi:10.1067/mjd.2000.105503
some disadvantages: It is–especially for dermatologic practitioners–difficult to organize because it requires bath facilities; it also is unsuitable for patients with only solitary LS lesions because the whole body is photosensitized. Therefore methoxsalen-containing cream or gel preparations seem a relevant alternative topical application.5,6 PUVA-cream therapy has been shown to be effective in treating palmoplantar dermatoses.6,7 Therefore we decided to investigate the efficacy of this new variation of topical PUVA therapy in patients with LS.
PATIENTS AND METHODS Four patients with LS (1-3 lesions; diameter, 5-10 cm) were included in our study over 8 weeks after informed consent was obtained. In all patients (2 women, 2 men; age, 32-65 years; duration of disease, 3-7 years) the diagnosis of LS was established according to clinical and histopathologic criteria. In all patients conventional therapy had not resulted in any significant improvement and did not halt progression of disease. No other treatment had been given for at least 6 weeks before initiation of PUVAcream therapy. 675
676 Grundmann-Kollmann et al
J AM ACAD DERMATOL OCTOBER 2000
Fig 1. Patient 1. Pretreatment biopsy specimen shows dermal and subcutaneous sclerosis with entrapment of eccrine glands and blunting of rete ridges.
Fig 2. Patient 1. Ultrasound B-scan of representative sclerotic plaque before therapy.
Histopathologic analysis of lesional skin at the beginning of the study revealed dermal and subcutaneous sclerosis with entrapment of eccrine glands and blunting of rete ridges (Fig 1). Before treatment, 20 MHz ultrasound assessment of sclerotic plaques in all patients revealed a substantially increased skin thickness and skin density (Fig 2) as compared with contralateral unaffected areas. Psoralen cream (final concentration 0.001% 8methoxypsoralen [8-MOP] containing water in oil emulsion (30% H2O) for Fitzpatrick skin types I and II, 0.0025% 8-MOP containing water in oil emulsion (30% H2O) for skin types III and IV) was prepared as previously described.6 To control the final concentration of 8-MOP in the cream and stock solution, high-performance liquid chromatography was performed.8 Four times a week (Monday, Tuesday, Thursday, Friday) 8-MOP cream was applied in an even layer for 1 hour to the LS lesions. Afterward the remaining cream was completely removed by a cotton swab. Minimal phototoxic dose was determined before the first treatment. Application of PUVA cream was followed directly by UVA administration with increasing doses (starting dose 30% of MPD), according to indi-
vidual photosensitivity, up to a maximum single dose of 3.5 J/cm2. The UVA irradiation equipment consisted of a UVA cabin (model 8001, Waldmann, VillingenSchwenningen, Germany) emitting exclusively UVA in the range of 320 to 400 nm, with a peak at 365 nm. Patients were assessed before, after 4 weeks, and at the end of phototherapy by palpation for tethering and thickening of the skin. Furthermore, 20 MHz ultrasound analysis was performed before, after 4 weeks, and at the end of treatment. Before treatment, 20 MHz ultrasound assessment of representative sclerotic plaques in all patients revealed a substantially increased skin thickness and skin density as compared with contralateral unaffected areas (Table I). Ultrasound measurements were performed with a digital 20 MHz scanner (Dermascan, Cortex Technology, Hadsund, Denmark). Histopathologic analysis was performed in a blinded fashion on hematoxylineosin–stained sections from skin biopsy specimens. Pretreatment specimens were taken from sclerotic skin areas (Fig 1). Posttreatment specimens were taken from previously affected areas next to the sites of previous biopsy (Fig 3).
Grundmann-Kollmann et al 677
J AM ACAD DERMATOL VOLUME 43, NUMBER 4
Fig 3. Patient 1. Posttreatment biopsy specimen shows almost normal human skin.
Fig 4. Patient 1. Ultrasound B-scan of the same plaque after 25 PUVA-cream therapy sessions.
Table I. Characteristics of patients with localized scleroderma treated with PUVA-cream therapy Skin thickness (mm) Patient No.
1 2 3 4
Age (y)/Sex
Duration of disease (y)
32/M 47/M 65/F 57/F
3 5 7 7
Pretreatment
Cumulative UVA dose (J/cm2)
Before tx
After tx
Roc Roc, SS Roc, SS Roc
121 77.5 92 67.5
2.2 2.05 1.86 1.90
1.75 1.05 1.00 0.98
Roc, Rocephin (ceftriaxone); SS, systemic glucocorticosteroids; tx, therapy.
RESULTS The therapy was well accepted and completed by all patients. Except for hyperpigmentation in a patient with skin type III, no side effects were observed. All patients had 30 treatments; the mean cumulative UVA dose was 89.5 J/cm2 (range, 67.5-121 J/cm2). According to clinical and ultrasound criteria, sclerotic plaques disappeared or improved markedly in all patients. Palpation revealed a remarkable softening of the sclerotic lesions. These results were confirmed by 20 MHz ultrasound evaluation. Dermal thickness was increased before therapy and decreased into the normal range after therapy (Table I). As shown in Fig 4, there was a marked reduction
in the highly reflective echo-rich bands within the epidermis and subcutis. Similar results were obtained by histopathologic evaluation of biopsy specimens after therapy (Fig 3). The structure of the dermal collagen returned to normal or almost normal human dermis. The single collagen bundles revealed regular thickness and were separated by regular spaces.
DISCUSSION Different types of photochemotherapy have been described for sclerosing skin diseases, such as oral PUVA therapy, PUVA-bath therapy, and low- and highdose UVA1 therapy.
678 Grundmann-Kollmann et al
Successful treatment of LS with oral PUVA therapy has been reported; however, it is limited by side effects due to systemic resorption of psoralens. PUVA-bath therapy, in which patients are immersed in an 8-MOP dilute bath water solution immediately followed by UVA irradiation, has been developed to avoid unwanted effects due to systemic effects of psoralens. It has been shown to be highly effective in patients with LS.2 Thus it seemed likely that other variations of topical PUVA therapy also may be of benefit for patients with LS. Our preliminary data suggest that PUVA-cream therapy may be effective for patients with LS. Like PUVA-bath therapy, PUVA-cream therapy induces a homogeneous skin sensitivity to UVA; a great advantage is that selected body regions can be excluded from the therapy. Therefore PUVA-cream therapy is a promising therapeutic alternative to PUVA-bath therapy for patients with solitary or few LS lesions. These results underscore the importance of testing variations of accepted therapies to achieve benefits for both patients and dermatologists. Although the mechanisms by which UVA phototherapy induces regression of sclerosis need to be elucidated, induction of collagenase activity as shown by Scharffetter et al9 is likely to be involved. The number of patients treated in this study is too small to make judgments on the overall efficacy of PUVA-cream photochemotherapy for LS, and we cannot draw any conclusions on the percentage of patients responding to PUVA-cream photochemother-
J AM ACAD DERMATOL OCTOBER 2000
apy. However, our initial results indicate that PUVAcream photochemotherapy is a treatment protocol favorably accepted by patients, which could develop into an important alternative to PUVA-bath therapy for patients with few lesions of LS. REFERENCES 1. Rowell NR, Goodfield M. The connective tissue diseases. In: Champion RH, Burton JL, Ebling F, editors. Textbook of dermatology. Oxford: Blackwell Scientific; 1992. p. 2163-94. 2. Kerscher M, Volkenandt M, Meurer M, Lehmann P, Plewig G, Röcken M. Treatment of localised scleroderma with PUVA bath photochemotherapy. Lancet 1994;343:1233. 3. Kerscher M, Dirschka T, Volkenandt M. Treatment of localised scleroderma by UVA1 phototherapy. Lancet 1995;346:1166. 4. Stege H, Berneburg M, Humke S, Klammer M, Grewe M, GretherBeck S, et al. High-dose UVA1 radiation therapy of localized scleroderma. J Am Acad Dermatol 1997;36:938-44. 5. De Rie MA, Eendenburg van JP, Versnick AC, Stolk LML, Bos JD, Westerhof W. A new psoralen containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema. Br J Dermatol 1995;132:964-9. 6. Stege H, Berneburg M, Ruzicka T, Krutmann J. Cream-PUVAPhototherapy. Hautarzt 1997;48:89-93. 7. Grundmann-Kollmann M, Behrens S, Peter RU, Kerscher M. Treatment of severe recalcitrant dermatoses of the palms and soles with PUVA-bath versus PUVA-cream therapy. Photodermatol Photoimmunol Photomed 1999;15:87-9. 8. Susanto F, Humfeld S, Reinauer H, Meschig R. High performance liquid chromatography measurement of 8-methoxsypsoralen in plasma. Chromatographia 1986;21:443-6. 9. Scharffetter K, Wlascheg M, Hogg A, Bolsen K, Schothorst A, Goerz G, et al. UVA irradiation induces collagenase in human dermal fibroblasts in vitro and in vivo. Arch Dermatol Res 1991;283:506-11.