Dermatologic Therapy, Vol. 28, 2015, 276–278 Printed in the United States All rights reserved
C 2015 Wiley Periodicals, Inc. V
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE: LETTERS Effective use of photodynamic therapy on the treatment of chronic leg ulcers: a pilot study Luciano Mavilia*, Carlo Cantarella*, Francesca Cicero† & Santo Raffaele Mercuri* *UO Dermatology and Cosmetology, San Raffaele Hospital, Milano, Italy and †Policlinico Universitario, Messina, Italy
Introduction Chronic leg ulcers (CLUs) affect around 1% of adults and 4% of people over the age of 65 all over the world (1). To this day, the proposed treatments are: compression therapy, varicose surgery, endovascular therapies, sclerosing therapy, and surgical ulcer treatment (2). There are two main causes that prevent the healing of ulcers: a vascular insufficiency that causes a lack of oxygen and nutrients (3), and the almost constant presence of a bacterial biofilm that “paralyses” the fibroblasts and the repairing mechanism of epidermal cells (4). Recent studies showed the increased fibroblastic activity of photodynamic therapy (PDT) with the production of neocollagen, the modulation of matrix metallopeptidase MMP1 e MMP3, the production of both vascular endothelial growth factor and Address correspondence and reprint requests to: Carlo Cantarella, MD, UO Dermatology and Cosmetology, San Raffaele Hospital, Milano, Italy, or email: [email protected] [Correction added on 26 February 2016, after first online publication: the authors’ first name and surname have been interchanged.] Funding sources: None. Conflicts of interest: None declared.
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keratinocyte growth factor (5), and its antibacterial effect (6). Considering these studies and according to our experience on how PDT can heal carcinomatous ulcer lesions without or with very little scarring, we report the successful offlabel use of PDT for the treatment of CLUs.
Materials and methods In 3 years, we treated nine patients affected by uncomplicated venous leg ulcers, grade 6 of CEAP classification (1). The inclusion criterion was no use of topical pharmaceutical products for at least 3 months or systemic drugs for at least 6 months. We excluded patients affected by diabetes mellitus undergoing treatment with oral hypoglycemic agents or insulin. The patients were all female with a mean age of 72 years and the ulcers had a mean area of 11 cm2. All patients underwent a 3 mm punch from the side of the lesion in order to exclude a carcinomatous ulcer and an Echo Color Doppler to exclude venous thrombosis. We used a reduced concentration of methyl R ; Galderma), mixaminolevulinate (MAL, MetvixV ing one part of MAL with three parts of moistuR, rizing cream (CetaphilV Galderma), thus
Photodynamic therapy on chronic leg ulcers
Table 1. Characteristics and results of treated patients
Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt. 8 Pt. 9 Mean
Age (years)
VLU mean area (cm2)
No. of treatments
Healing (weeks)
76 66 77 75 74 73 70 67 70 72
11 7 15 13 13 11 10 8 11 11
8 6 10 10 9 8 7 6 8 8
24 18 30 28 28 24 20 20 24 24
FIG. 2. Up: Almost complete healing of the ulcer after five treatments (15 weeks). Down: 12-month follow-up. Complete healing of the ulcer.
Results FIG. 1. A 67 years old woman presenting a chronic leg ulcer on the left tibia.
diluting the concentration of the drug to 4%. The use of a lower concentration of the product, which we already successfully used in the treatment of acne (7), is aimed at minimizing the side effects of PDT. We applied gauze soaked in physiological solution on the ulcer for some minutes. After removing it, we dried the area with dry gauze and then applied the diluted cream in wet-wrap dressing for 45 minutes thus acting only on the ulcer surface. A 630 nm red light (Aktilite CL R ; Galderma) was applied at a dose of 18 J 128V cm2. Following the treatment, the ulcers also were covered with cold water and chamomilesoaked gauzes and aloe vera gel. Patients then performed the same medication at home twice a day for 10 days. Treatments were carried out at 3-week intervals for a mean of eight treatments treatment courses. All patients completed the trial and were monitored up to 1 year after their last treatment course.
All the patients healed from ulcers completely in a mean of 24 weeks. All the patients reported a slight but bearable sensation of heat during light application, followed by variable degrees of erythema, which disappeared within 5–7 days. No relapse of the treated ulcers was reported. No cases of infection were reported (Table 1; FIG. 1 and 2).
Discussion and conclusion PDT allowed healing of CLUs through the inflammation induced, improving the oxygenation of ulcer tissue with a reduction in healing time and improving scarring results. In particular, PDT is able to free ulcers from the microorganisms that form the biofilm which slows the natural healing process of the wounds (8). Further studies are needed to assess the role of PDT in the treatment of CLUs.
References 1. Vasudevan B. Venous leg ulcers: Pathophysiology and classification. Indian Dermatol Online J 2014: 5(3): 366–370.
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Luciano et al. 2. Kahle B, Hermanns HJ, Gallenkemper G. Evidence-based treatment of chronic leg ulcers. Dtsch Arztebl Int 2011: 108(14): 231–237. 3. Labropoulos N, Wang ED, Lanier ST, Khan SU. Factors associated with poor healing and recurrence of venous ulceration. Plast Reconstr Surg 2012: 129(1): 179– 186. 4. Lantis JC 2nd, Marston WA, Farber A, et al. The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. J Vasc Surg 2013: 58(2): 433–439. 5. Devirgiliis V, Panasiti V, Fioriti D, et al. Antibacterial activity of methyl aminolevulinate photodynamic therapy in
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the treatment of a cutaneous ulcer. Int J Immunopathol Pharmacol 2011: 24(3): 793–795. 6. Mavilia L, Malara G, Moretti G, Lo Re M, Puglisi Guerra A. Photodynamic therapy of acne using methyl aminolaevulinate diluted to 4% together with low doses of red light. Br J Dermatol 2007: 157(4): 810–811. 7. Beidler SK, Douillet CD, Berndt DF, Keagy BA, Rich PB, Marston WA. Multiplexed analysis of matrix metalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. Wound Repair Regen 2008: 16(5): 642–648. 8. Cappugi P, Campolmi P, Mavilia L, Prignano F, Rossi R. Topical 5-aminolevulinic acid and photodynamic therapy in dermatology: a minireview. J Chemother 2001: 13(5): 494–502.
C 2015 Wiley Periodicals, Inc. V
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE: LETTERS Effective use of photodynamic therapy on the treatment of chronic leg ulcers: a pilot study Luciano Mavilia*, Carlo Cantarella*, Francesca Cicero† & Santo Raffaele Mercuri* *UO Dermatology and Cosmetology, San Raffaele Hospital, Milano, Italy and †Policlinico Universitario, Messina, Italy
Introduction Chronic leg ulcers (CLUs) affect around 1% of adults and 4% of people over the age of 65 all over the world (1). To this day, the proposed treatments are: compression therapy, varicose surgery, endovascular therapies, sclerosing therapy, and surgical ulcer treatment (2). There are two main causes that prevent the healing of ulcers: a vascular insufficiency that causes a lack of oxygen and nutrients (3), and the almost constant presence of a bacterial biofilm that “paralyses” the fibroblasts and the repairing mechanism of epidermal cells (4). Recent studies showed the increased fibroblastic activity of photodynamic therapy (PDT) with the production of neocollagen, the modulation of matrix metallopeptidase MMP1 e MMP3, the production of both vascular endothelial growth factor and Address correspondence and reprint requests to: Carlo Cantarella, MD, UO Dermatology and Cosmetology, San Raffaele Hospital, Milano, Italy, or email: [email protected] [Correction added on 26 February 2016, after first online publication: the authors’ first name and surname have been interchanged.] Funding sources: None. Conflicts of interest: None declared.
276
keratinocyte growth factor (5), and its antibacterial effect (6). Considering these studies and according to our experience on how PDT can heal carcinomatous ulcer lesions without or with very little scarring, we report the successful offlabel use of PDT for the treatment of CLUs.
Materials and methods In 3 years, we treated nine patients affected by uncomplicated venous leg ulcers, grade 6 of CEAP classification (1). The inclusion criterion was no use of topical pharmaceutical products for at least 3 months or systemic drugs for at least 6 months. We excluded patients affected by diabetes mellitus undergoing treatment with oral hypoglycemic agents or insulin. The patients were all female with a mean age of 72 years and the ulcers had a mean area of 11 cm2. All patients underwent a 3 mm punch from the side of the lesion in order to exclude a carcinomatous ulcer and an Echo Color Doppler to exclude venous thrombosis. We used a reduced concentration of methyl R ; Galderma), mixaminolevulinate (MAL, MetvixV ing one part of MAL with three parts of moistuR, rizing cream (CetaphilV Galderma), thus
Photodynamic therapy on chronic leg ulcers
Table 1. Characteristics and results of treated patients
Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt. 8 Pt. 9 Mean
Age (years)
VLU mean area (cm2)
No. of treatments
Healing (weeks)
76 66 77 75 74 73 70 67 70 72
11 7 15 13 13 11 10 8 11 11
8 6 10 10 9 8 7 6 8 8
24 18 30 28 28 24 20 20 24 24
FIG. 2. Up: Almost complete healing of the ulcer after five treatments (15 weeks). Down: 12-month follow-up. Complete healing of the ulcer.
Results FIG. 1. A 67 years old woman presenting a chronic leg ulcer on the left tibia.
diluting the concentration of the drug to 4%. The use of a lower concentration of the product, which we already successfully used in the treatment of acne (7), is aimed at minimizing the side effects of PDT. We applied gauze soaked in physiological solution on the ulcer for some minutes. After removing it, we dried the area with dry gauze and then applied the diluted cream in wet-wrap dressing for 45 minutes thus acting only on the ulcer surface. A 630 nm red light (Aktilite CL R ; Galderma) was applied at a dose of 18 J 128V cm2. Following the treatment, the ulcers also were covered with cold water and chamomilesoaked gauzes and aloe vera gel. Patients then performed the same medication at home twice a day for 10 days. Treatments were carried out at 3-week intervals for a mean of eight treatments treatment courses. All patients completed the trial and were monitored up to 1 year after their last treatment course.
All the patients healed from ulcers completely in a mean of 24 weeks. All the patients reported a slight but bearable sensation of heat during light application, followed by variable degrees of erythema, which disappeared within 5–7 days. No relapse of the treated ulcers was reported. No cases of infection were reported (Table 1; FIG. 1 and 2).
Discussion and conclusion PDT allowed healing of CLUs through the inflammation induced, improving the oxygenation of ulcer tissue with a reduction in healing time and improving scarring results. In particular, PDT is able to free ulcers from the microorganisms that form the biofilm which slows the natural healing process of the wounds (8). Further studies are needed to assess the role of PDT in the treatment of CLUs.
References 1. Vasudevan B. Venous leg ulcers: Pathophysiology and classification. Indian Dermatol Online J 2014: 5(3): 366–370.
277
Luciano et al. 2. Kahle B, Hermanns HJ, Gallenkemper G. Evidence-based treatment of chronic leg ulcers. Dtsch Arztebl Int 2011: 108(14): 231–237. 3. Labropoulos N, Wang ED, Lanier ST, Khan SU. Factors associated with poor healing and recurrence of venous ulceration. Plast Reconstr Surg 2012: 129(1): 179– 186. 4. Lantis JC 2nd, Marston WA, Farber A, et al. The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. J Vasc Surg 2013: 58(2): 433–439. 5. Devirgiliis V, Panasiti V, Fioriti D, et al. Antibacterial activity of methyl aminolevulinate photodynamic therapy in
278
the treatment of a cutaneous ulcer. Int J Immunopathol Pharmacol 2011: 24(3): 793–795. 6. Mavilia L, Malara G, Moretti G, Lo Re M, Puglisi Guerra A. Photodynamic therapy of acne using methyl aminolaevulinate diluted to 4% together with low doses of red light. Br J Dermatol 2007: 157(4): 810–811. 7. Beidler SK, Douillet CD, Berndt DF, Keagy BA, Rich PB, Marston WA. Multiplexed analysis of matrix metalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. Wound Repair Regen 2008: 16(5): 642–648. 8. Cappugi P, Campolmi P, Mavilia L, Prignano F, Rossi R. Topical 5-aminolevulinic acid and photodynamic therapy in dermatology: a minireview. J Chemother 2001: 13(5): 494–502.
