Photodynamic therapy in dermatology: established and new indications

Summary

Photodynamic therapy (PDT) is internationally established as an approved treatment option for in situ forms of keratinocytic skin cancer (actinic keratoses, Bowen's disease, basal cell carcinoma). For these indications, there are standardized treatment protocols using narrow‐spectrum light sources or (artificial) daylight, the use of which is associated with successful healing, a low rate of lesion recurrence, and a very good cosmetic result.

Daylight PDT is superior to conventional PDT in terms of significantly less pain and associated higher patient acceptance.

Newer indications, for which no approval has yet been granted, but which nevertheless have sufficient evidence of efficacy according to the study situation, are inflammatory (lichen sclerosus, acne) and infectious dermatoses (viral warts, cutaneous leishmaniasis, atypical mycobacteriosis). In addition, PDT is increasingly being used in aesthetic dermatology with the aim of skin rejuvenation.

INTRODUCTION

In recent years, photodynamic therapy (PDT) has become increasingly important in dermatology as a minimally invasive therapeutic procedure. To date, comprehensive data on the clinical use of various PDT procedures are available for various conditions including keratinocytic skin cancer and actinic keratoses. Here, the basic principles, modes of action, suitable irradiation devices, approved photosensitizers, as well as in‐label and off‐label indications are described.

Basic principles and mechanisms of PDT

The triplet state of photosensitizer molecules excited by light energy is the initial state for the photochemical reactions. From this state, electron or energy transfer reactions, referred to as type I or type II mechanisms, occur in the presence of suitable substrates and result in the formation of highly reactive oxygen species. In the type I mechanism, the excited photosensitizer molecules act as electron donors or acceptors for substrate or oxygen molecules, thus creating highly reactive radicals. These result in cell damage by oxidation of various biomolecules. ¹ In the type II mechanism, highly reactive singlet oxygen is formed by elevating the energy level of the photosensitizer into the singlet state with transition into the equally excited triplet state and subsequent energy transfer to molecular oxygen. In both reaction types, cellular damage is caused by similar oxidation mechanisms. ² The production of singlet oxygen in the type II mechanism is considered mainly responsible for cytotoxicity and the effect of PDT. ³ Sufficient oxygen, photosensitizer, and light must be present in the tissue at the same time to ensure effectiveness of the photodynamic effect.

PDT is based on photochemical reactions. The photosensitizer molecules are excited by light energy and transfer energy to molecular oxygen. The resulting reactive oxygen species are mainly responsible for cytotoxicity and the effect of PDT.

Radiation sources

Usually, porphyrin molecules serve as photosensitizers showing preferential enrichment in tumor tissue in vivo. They have absorption maxima at several wavelengths: 405 nm (UV to blue), 505 nm (blue), 540 nm (green), 580 nm (yellow), and 635 nm (red). The highest penetration depth into the skin with approximately 2–3 mm is achieved with red light. Apart from non‐coherent broadband radiation sources, long‐pulsed dye lasers, LED systems (especially cold LED red light), and flash lamps can also be used as radiation sources. For a uniform dose equivalent, no significant differences in efficacy of the various radiation sources were found. ⁴ Distinct therapeutic regimens exist for different dermatoses. For inflammatory, infectious, and cosmetic indications, for example, low doses of light and sensitizer with frequent cycles are usually applied. If selective destruction of tumor cells is intended, for example in non‐melanoma skin cancer, one to two cycles with significantly higher light and sensitizer doses are required (high‐dose PDT).

Natural solar radiation may also serve as effective radiation source (daylight PDT). ⁵ For this purpose, artificial radiation sources have been developed that allow for homogenous irradiation of the desired area within closed rooms, thus improving therapy control (Table 1). ⁶

Apart from non‐coherent broadband radiation sources, long‐pulsed dye lasers, LED systems, and flash lamps are potential radiation sources for PDT. Natural solar radiation may also serve as an effective radiation source.

TABLE 1.

Common current PDT approaches.

Conventional PDT (cPDT)

Daylight PDT (DL‐PDT)

Indoor Daylight PDT

Daylight PDT with artificial radiation sources (ADL‐PDT)

Photosensitizers

5‐Aminolevulinic acid (5‐ALA, for example, present in Ameluz^®) and its methyl ester (MAL, for example, present in Metvix^®) are favored as photosensitizers in dermatology due to their selectivity for metabolically active cells, their existence as individual substances, and their small molecular size that facilitates their penetration into the skin after topical application. They are prodrugs that are transformed into the actual photosensitizer molecule protoporphyrin IX (molecule with tetrapyrrole ring) after uptake into the cell.

To date, the combination of MAL and red light has been approved worldwide for the treatment of actinic keratoses. In Europe, it is also approved for the therapy of basal cell carcinoma and Bowen's disease. Luxerm^®, also containing MAL as active ingredient, is approved for daylight PDT (DL‐PDT) of actinic keratoses in the head area. Furthermore, an ALA‐containing patch is available for the treatment of AK and actinic cheilitis. ⁷ The currently commercially available formulations in different bases are presented in Table 2.

TABLE 2.

Currently commercially available formulations of photosensitizers.

Trade name / manufacturer	Substance	Incubation time	Indications according to approval
Metvix® (Galderma)	16% ALA methyl ester	3 h 30 min + 2 h	cPDT: AK, Bowen's disease, BCC DL‐PDT: AK ADL‐PDT: AK
Luxerm® (Galderma)	16% ALA methyl ester	30 min + 2 h	DL‐PDT: AK
Alacare® (Photonamic)	ALA methyl ester in patch base	4 h	cPDT: AK
Ameluz® (Biofrontera)	10% ALA nanoemulsion	10 min 30 min + 2 h	cPDT: AK, BCC DL‐PDT: AK
Levulan® Kerastick® (DUSA Pharmaceuticals)	20% ALA hydrochloride	14–18 h	approved in the USA in combination with BLU‐U® light

Abbr.: cPDT, conventional PDT; DL‐PDT, daylight PDT; ADL‐PDT, artificial daylight PDT; AK, actinic keratosis; BCC, basal cell carcinoma; BLU‐U^® light, blue light

5‐Aminolevulinic acid (5‐ALA) and its methyl ester (MAL) are favored as photosensitizers in dermatology. Currently, various formulations in different bases are commercially available.

Advantages and disadvantages of the respective procedures

The major disadvantage of daylight PDT is the dependency on weather conditions and the loss of control, given that the procedure is essentially performed by the patients themselves. ⁷ Due to the weather‐dependency, the procedure is usually not feasible in Germany in winter, given that the temperature‐dependent enzymatic porphyrin formation requires an external temperature of at least 10°C. In rainy weather, the therapy cannot be performed even in summer. ⁸ Moreover, it should also be considered that too much wind (wind chill factor) may compromise the efficacy of PDT due to the decrease in skin temperature. However, seasonal and meteorological conditions play no role in artificial daylight PDT (ADL‐PDT), given that it is performed indoors (Figures 1, 2). The main advantage of both procedures is the painlessness during irradiation. ⁹ , ¹⁰ In contrast, the main disadvantage of conventional PDT is the pain during irradiation (Figure 3). The reason for the different levels of pain is the spread of protoporphyrin IX (PPIX) after intracellular synthesis resulting from the incubation time: In conventional PDT, PPIX is moved by outward transfer into the intercellular space during the three‐hour incubation. There, the sensitizer is taken up by free nerve endings resulting in direct pain activation during subsequent irradiation. ¹¹

FIGURE 1.

Daylight PDT performed on the dorsum of the hands with an artificial radiation source. After curettage of the hyperkeratoses, a one‐hour incubation with 20% 5‐ALA cream is carried out, protected from light. Subsequently, the radiation source is placed at about 40 cm from the skin area to be irradiated.

FIGURE 2.

Application of daylight PDT in the head and face area with an artificial radiation source using the Medisun^® daylight 9000 cabin. Homogeneous exposure is warranted since the radiation sources are located at the same distance from the patient.

FIGURE 3.

Diffuse erythema with partly hemorrhagic crusts a few days after performing a red‐light PDT with 10% 5‐ALA cream.

In daylight or artificial daylight PDT, however, the irradiation is performed simultaneously to PPIX synthesis in the mitochondria of affected keratinocytes. The photodynamic effect is, therefore, exerted directly at the target site and there is no sensitization of adjacent pain‐mediating nerve fibers.

An advantage of conventional PDT is the excellent study situation with established data for each indication. ⁹

An excellent study situation with established data for numerous dermato‐oncological indications is available for the efficacy of conventional (red light) PDT. A disadvantage of this therapy is the sometimes pronounced pain during irradiation.

Clinical in‐label indications

PDT is well established for the treatment of actinic keratoses, Bowen's disease, and superficial basal cell carcinoma and integrated in the respective guidelines. It is an approved therapeutic option for these indications. Depending on the country‐specific compensation situation, PDT is performed in outpatient or inpatient settings. In Germany, the approved formulations of aminolevulinic acid (Table 2) may be prescribed to patients with statutory health insurance. There is, however, no adequate settlement item for the outpatient implementation of the treatment. The services are reimbursed for patients with private health insurance or in the context of treatment of an occupational disease (BK5103).

Actinic keratoses

There are numerous studies for conventional PDT of actinic keratosis (AK) with 5‐ALA and MAL demonstrating the effectiveness in thin AKs and AKs of medium thickness (grade I–II according to Olsen) of the face and head area. In this context, response rates of 81%–92% may be achieved three months after single treatment. ⁷ , ¹⁰ , ¹²

Daylight MAL‐PDT (DL‐PDT) is equally effective but significantly less painful than conventional PDT. ⁵ A study investigated the influence of the geographic localization of the treatment on the outcome. It turned out that DL‐PDT can be effectively applied throughout the summer until mid‐September in Reykjavik and Oslo, until late in October in Copenhagen and Regensburg, until mid‐November in Turin, and throughout the year in Israel. ⁸

Compared to the face, PDT is somewhat less effective in acral AK, probably due to the thicker/hyperkeratotic lesions in these localizations. ¹² In a right‐left comparison, however, PDT with 5‐ALA resulted in a statistically significant, higher clearance rate of AK of medium thickness on the upper extremities than topical imiquimod therapy (57.89% vs. 37.03%). In addition, it was preferred by the patients, possibly due to the easier implementation. ¹³

Study data demonstrate the efficacy of conventional PDT both as lesion‐directed and field‐directed therapy. The data suggest that PDT plays an important role in treatment of multiple AKs, especially since it can also be applied repeatedly in case of diffusely sun‐damaged skin. ¹² , ¹⁴ Furthermore, a Cochrane analysis of therapeutic options of AK positioned daylight MAL‐PDT as valuable option for patients with multiple AKs in small and large fields. ¹⁴ Accordingly, PDT is also integrated in the current S3 guideline for the therapy of AK. ⁷ Conventional PDT with 5‐ALA or MAL in AK or field cancerization has, irrespective of the affected skin region, the recommendation grade B and should be offered to patients as a potential therapeutic option. The same is true for daylight MAL‐PDT on face and scalp (but only for immunocompetent individuals). ⁷ , ¹⁵

Actinic cheilitis is a special indication for PDT. ⁷ , ¹⁵ A systematic analysis of conventional PDT in actinic cheilitis evaluated 15 eligible studies. In 62% of the patients, lesions showed complete clinical healing at follow‐up times ranging from three to 30 months. Histological healing was, however, only found in 47% of the patients after 1.5 to 30 months. ¹⁶ Pretreatment of the lips with fractional ablative laser (laser‐assisted PDT) markedly improved the therapeutic outcome. A prospective randomized trial found complete clinical response of 92% of the lesions at a follow‐up of 3 months (compared to 59% after MAL‐PDT alone). Only 8% of the patients experienced recurrence (compared to 50% after MAL‐PDT alone) after 12 months. ¹⁷

Both conventional and daylight PDT are effective in actinic keratosis or field cancerization. In actinic cheilitis, pretreatment of the lips with fractional ablative laser (laser‐assisted PDT) may markedly improve the therapeutic outcome.

Bowen's disease

In many countries (including Germany), conventional MAL‐PDT is approved for the treatment of Bowen's disease. Two cycles one week apart are recommended for optimal therapeutic outcome. ¹⁵ In a Cochrane Review, PDT appeared to be equally effective as 5‐fluorouracil cream and significantly more effective than cryotherapy. The good efficacy is accompanied by the advantage of reduced scar formation. ¹⁸ However, recurrence rates appear to be dependent on the lesion size and have been reported to be almost 20% for large skin lesions with a diameter of more than 3 cm. ¹⁹ , ²⁰

In a recent study, 158 patients with Bowen's disease treated by surgical excision, cryotherapy, PDT, and topical imiquimod were evaluated. Eventually, 121 patients were analyzed. Therapy success was highest after surgical excision of lesions (100%) and lowest after PDT (62.5%). The recurrence rate after initially successful therapy was highest after topical treatment with imiquimod (33.3%). In patients treated with cryotherapy, the occurrence of satellite lesions was observed after initial treatment success (9.09%). ²¹ Despite proven efficacy of conventional MAL‐PDT, Bowen's disease showed the highest clearance rate and lowest recurrence rate after surgical excision. Accordingly, excision in healthy tissue remains the gold standard of treatment.

In many countries (including Germany), conventional MAL‐PDT is approved for the treatment of Bowen's disease. Two cycles one week apart are recommended for optimal therapeutic outcome.

Basal cell carcinoma

Conventional PDT with 5‐ALA or MAL may be used effectively for the therapy of superficial basal cell carcinoma (BCC). In a prospective study, clinical response rates of 92%–97% were achieved after conventional MAL‐PDT with two sessions one week apart. However, 9% of the initially cleared lesions recurred after one year. ²² Moreover, horizontal tumor diameters of more than 10 mm are accompanied by higher recurrence rates. ²³ Accordingly, conventional PDT with 5‐ALA or MAL is mentioned as suitable for the therapy of thin BCCs in the current S2k guideline, primarily if surgical excision is contraindicated. ²⁴

The use of PDT in lesions thicker than 2 to 3 mm, pigmented BCC, or sclerodermiform variants is contraindicated, given that the destruction of tumor cells is insufficient. Moreover, tumors should not be localized in the centrofacial H‐zone, because preferential deeper invasion is observed in this localization. ¹⁵

Conventional PDT with 5‐ALA or MAL is effective in small (< 10 mm in diameter) superficial BCC and an option if contraindications for surgical excision exist.

New off‐label indications

Apart from the classical dermato‐oncological PDT indications, there are several relatively new fields of application. For instance, PDT achieved resolution of refractory common warts and condylomata acuminata. Moreover, experience reports on successful therapy of atypical mycobacteriosis and cutaneous leishmaniasis are available. In addition, PDT is used in aesthetic medicine resulting in improved skin texture and reduction of small wrinkles by stimulation of dermal neocollagenesis. It must be taken into account, however, that these are off‐label therapies.

INFECTIOUS DISEASES

Common and plantar warts

Although numerous therapeutic options are available for viral warts and spontaneous regression is often observed, they may be refractory to therapy at certain localizations (for example, plantar or periungual) and result in a high degree of psychological strain in affected patients. ²⁵ Numerous case reports and clinical studies exist on the therapy of viral warts by PDT. Generally, classical red‐light PDT with 20% 5‐ALA is used for this purpose. ²⁶ , ²⁷ , ²⁸ Successful therapies after three to six treatment cycles at one‐week intervals have been described. A meta‐analysis performed in 2022 showed that PDT is statistically significantly more effective for the therapy of palmar and plantar warts than placebo or the use of various laser systems and cryotherapy. ²⁹

In general, effectiveness has also been described for red‐light PDT with MAL, but complete lesion clearance was observed slightly less often than after application of 5‐ALA. This has been attributed to the deeper penetration of 5‐ALA into the tissue. ³⁰ The mode of action of PDT in viral warts is probably based on activation of the immune system by induction of necrosis and apoptosis of keratinocytes ³¹ and subsequent infiltration of CD4⁺ and CD8⁺ T cells. ³² Strong local inflammatory reactions and pain have been described as the most common side effects of PDT in common warts. ²⁶ , ²⁷ , ²⁸

Red‐light PDT with 20% 5‐ALA has proven its effectiveness against common warts. Usually, three to six sessions at one‐week intervals are required for complete lesion clearance.

Condylomata acuminata

Given the high affinity of 5‐ALA to keratinocytes infected with human papilloma virus, PDT can also be used in condylomata acuminata. ³³ There are several clinical studies comparing the efficacy of PDT with other therapies. ³⁴ , ³⁵ , ³⁶ , ³⁷ Although MAL has been used in individual reports, ³³ effective therapy with 20% 5‐ALA in combination with red light (632.8 nm) has been reported in the vast majority of cases. ³⁵ , ³⁶ Similar to the therapy of common warts, several PDT cycles at one‐week intervals have been described in literature, with three sessions usually sufficient for an optimal response. ³⁵ , ³⁶ Overall, the efficacy of PDT in condylomata acuminata was similar to that of treatment with CO₂ laser, electrocautery, or topical trichloroacetic acid – provided sufficient keratolysis is achieved and all viral particles are removed. ²⁹ , ³⁴ Recurrence rates appear to be significantly lower after PDT, which can be explained by the local activation of the immune system by PDT. ³² Because of the inhomogeneity of available studies, PDT is only recommended as second‐line therapy in the current European guideline for the management of genital warts. ³⁸ Although good tolerability of PDT in condylomata acuminata has been described in literature, the procedure‐related pain should be considered as limitation for the feasibility of the therapy in the genital region. In addition, the illumination of the affected areas in the anogenital region is challenging and reinfections due to concomitant involvement of the anal mucosa are common. ³⁹

PDT in condylomata acuminata shows similar efficacy as other procedures, although it is associated with markedly fewer recurrences. Due to the strong pain, however, it is only of limited use for this indication in daily clinical practice.

Cutaneous leishmaniasis

Several case reports and clinical studies describe the successful application of PDT in cutaneous leishmaniasis. ⁴⁰ , ⁴¹ , ⁴² , ⁴³ Different photosensitizing agents (for example, 5‐ALA, MAL, curcumin, or hypericin) and various wavelengths have been used for this indication. In a placebo‐controlled trial, red‐light PDT (633 nm) with 10% 5‐ALA applied in four cycles at weekly intervals proved to be very effective in the treatment of small lesions (< 2 cm in diameter) caused by Leishmania major. Moreover, the procedure was significantly more effective than topical therapy with a cream containing 15% paromomycin and 12% methylbenzethonium chloride, as well as placebo. ⁴⁰ Furthermore, daylight PDT and PDT with green light (543–548 nm) have been described as effective. ⁴¹ , ⁴² , ⁴³ Treatments were also performed at weekly intervals, and five to seven sessions were required to achieve complete clearance of the lesions. The exact mode of action of PDT in cutaneous leishmaniasis is not yet known, especially against the background that leishmanias have no enzymes for heme synthesis. The available in vitro data show that the accumulated dose of protoporphyrin IX in amastigotes is too low to neutralize them during PDT. It is, therefore, assumed that complex immunological reactions result in clearance of the lesions. ⁴⁴

Given that in leishmaniasis of the “New World” the increased risk of visceral and mucocutaneous involvement must be considered, systemic therapy should be prioritized in these cases according to the guidelines. ⁴⁵ Even in these cases, however, PDT may be used as adjuvant procedure to accelerate the clearance of lesions. In contrast, PDT may be used as monotherapy in leishmaniasis of the “Old World”.

Red‐light, green‐light, or daylight PDT with 10% 5‐ALA present a suitable therapeutic option for the treatment of leishmaniasis of the “Old World”. Usually, five to seven sessions at one‐week intervals are required to achieve complete clearance of the lesions.

Atypical mycobacteriosis

Atypical mycobacterioses of the skin are caused by nontuberculous mycobacteria and often require long‐term anti‐tuberculous therapy. ⁴⁶ Therefore, alternative therapies should be established. It has been shown that red‐light PDT with 5‐ALA can kill nontuberculous mycobacteria, such as Mycobacterium marinum or Mycobacterium abscessus, in vitro by formation of reactive oxygen species. ⁴⁷ , ⁴⁸ Similar results have been obtained in animal experiments in mice. ⁴⁹ In addition, individual case reports on successful 5‐ALA or MAL‐PDT of atypical mycobacteriosis of the skin exist. Clearance has been achieved after several sessions. ⁵⁰ , ⁵¹ , ⁵² Another therapeutic approach is the combination of PDT and oral antibiotics. This results in faster resolution of skin changes and allows for a reduced duration of antibiotic therapy. ⁵³ , ⁵⁴ , ⁵⁵

The treatment of lupus vulgaris with light, for which Niels Ryberg Finsen was awarded the Nobel Prize 120 years ago, is also based on the photodynamic effect. Mycobacterium species produce endogenous porphyrins that are inactivated by irradiation with Finsen lamps. ⁵⁶

5‐ALA or MAL‐PDT with red light result in vitro in elimination of nontuberculous mycobacteria and present an effective therapeutic option of atypical mycobacterioses of the skin. In combination with oral anti‐tuberculous therapy, duration of the required antibiotic therapy can be reduced by repeated PDT.

Onychomycosis

Several experience reports on the therapy of onychomycosis by PDT are available. ⁵⁷ The aim is to kill the fungi via formation of singlet oxygen, which, however, requires efficient incubation of the pathogen with the photosensitizer. For this purpose, gradual detachment of the hyperkeratotic nail portions by topical agents containing 40% urea or even atraumatic nail avulsion may be helpful. ⁵⁸

While the application of various photosensitizers, for example, 5‐ALA, MAL, and methylene blue, has been described for the treatment of onychomycosis, they were usually investigated in small studies with up to 40 participants and variable success rates of 18% to 90%. ⁵⁹ In a recent Cochrane Review of topical therapies for onychomycosis also no obvious advantage of a specific PDT variant was identified. ⁶⁰ Whether the fungicidal effect includes fungal spores seems doubtful. Therefore, the risk of reinfection is high. Given the heterogeneity of the data, the current S1 guideline on onychomycosis provides neither a positive nor a negative recommendation for the implementation of PDT in this indication. ⁶¹

The data on the efficacy of PDT in onychomycoses are very heterogeneous. The current German S1 guideline on onychomycosis contains neither a positive nor a negative recommendation for PDT.

Aesthetic indication: skin rejuvenation

It has been shown that PDT stimulates the neogenesis of collagen in the dermis and normalizes the architecture of the epidermis by necrosis of atypical keratinocytes. ⁶² This improves roughness, skin elasticity, skin complexion, and superficial pigment changes. Small wrinkles may also recede. However, telangiectasias, sebaceous gland hyperplasia, and deep wrinkles remain unaffected. ⁶³

Various photosensitizers and light sources have been tested with respect to skin rejuvenation. The results of clinical trials suggest the potential use of conventional PDT, but also PDT with blue light, daylight, and various laser systems (Table 3). In case of co‐existing actinic skin damage, however, approved PDT standard protocols should be used. ⁵⁹ , ⁶³ Pretreatment with fractional laser prior to application of the photosensitizer or post‐treatment with microneedling may improve penetration of the photosensitizer into the epidermis and increase the efficacy of PDT by synergistic effects on collagen synthesis. ⁶⁴

TABLE 3.

Overview of off‐label indications for photodynamic therapy with corresponding photosensitizers and light sources/wavelengths.

Diagnosis	Photosensitizer	Light source	Therapy frequency
Common warts	20% 5‐ALA	‐Red light	Once a week, 3–6 sessions
Condylomata acuminata	20% 5‐ALA	‐Red light	Once a week, approximately 3 sessions
Cutaneous leishmaniasis	10% 5‐ALA 16% MAL	‐Red light ‐Green light ‐Daylight	Once a week, 5–7 sessions
Atypical mycobacteriosis	10–20% 5‐ALA 16% MAL	‐Red light	3–5 sessions at weekly to monthly intervals
Acne vulgaris	20% 5‐ALA 16% MAL	‐Red light	2 sessions 2 weeks apart, repeated during the disease course, if necessary
Lichen sclerosus	5–20% 5‐ALA	‐Red light	2–6 sessions at intervals of 2 weeks
Skin rejuvenation	5–20% 5‐ALA 16% MAL	‐Red light ‐Blue light ‐Daylight ‐pulsed dye laser ‐high‐energy flashlamp (IPL)	2–3 sessions at intervals of 4 weeks

Usually, two to three PDT sessions at intervals of 4 weeks each are needed for optimal cosmetic outcome, although 3 to 6 months are required before the treatment becomes fully effective. Especially the treatment areas of face, neck, décolleté, and dorsum of the hand may be considered for cosmetic indications. ⁶⁴ For the combination with additional aesthetic treatments, such as injections of hyaluronic acid or botulinum toxin, a time interval of at least two weeks before or after PDT treatment should be observed. ⁶⁴

PDT may be used with the goal of skin rejuvenation. It improves roughness, skin elasticity, skin complexion, and pigment changes, as well as small wrinkles. However, telangiectasias, sebaceous gland hyperplasia, and deep wrinkles remain unaffected.

INFLAMMATORY DERMATOSES

Acne vulgaris

PDT with 5‐ALA or MAL has a transient antimicrobial and anti‐inflammatory effect. Moreover, PDT with red light may cause inhibition or even destruction of sebaceous glands. ⁶⁵ These effects result in improvement of acne.

There is no established PDT protocol for use in acne. Most studies on application of PDT in facial acne have been performed with red light (635 nm). After incubation for three hours, red‐light PDT with 16% MAL resulted in marked improvement of inflammatory lesions compared to placebo (no treatment or placebo PDT). Two sessions 2 weeks apart were performed. ⁶⁶ , ⁶⁷ In a comparative study on 15 patients with facial acne, the efficacy of 20% 5‐ALA compared to 16% MAL cream was examined in a half‐side test after incubation for three hours. Both substances showed similar efficacy. ⁶⁸

Individual clinical studies could show advantages of red‐light PDT for acne therapy compared to standard therapy (doxycycline 100 mg/d and 0.1% topical adapalene gel) and in combination with a systemic therapy (minocycline). ⁶⁹ , ⁷⁰

Outdoor daylight PDT with 16% MAL cream was also effective in moderate to severe facial acne both as monotherapy and in combination with laser pretreatment. ⁷¹ There are, however, markedly fewer experience reports for daylight PDT in acne than for red‐light PDT.

PDT results in marked reduction of inflammatory lesions in moderate to severe acne vulgaris and may, therefore, be performed as alternative of conventional systemic therapies, if, for example, systemic therapy is not desired by the patient.

Lichen sclerosus

In recent years, several case series and small studies on the therapy of vulvar lichen sclerosus with PDT in adult patients with insufficient response to standard therapies have been published in scientific journals. In the vast majority of cases, PDT was performed with 5‐ALA at concentrations between 5% and 20% after an incubation time of 2 to 6 hours. ⁷² Depending on the protocol, the number of sessions ranged from one to ten and the intervals between treatments from 1 to 15 weeks, although in most studies the individual PDT sessions were performed at intervals of 2 weeks. ⁷² , ⁷³ In most cases, red‐light PDT was performed. In one study, PDT was performed with green light with the intention to reduce the peri‐interventional pain. ⁷⁴ Overall, PDT was effective in adult women with respect to the distressing symptoms (especially pruritus) and clinical lesions of vulvar lichen sclerosus and improved the quality of life. In a prospective randomized trial on 40 patients, four sessions of red‐light PDT with 5‐ALA at intervals of 2 weeks were more effective than daily local therapy with 0.05% clobetasol propionate for 8 weeks. ⁷⁵

Red‐light PDT with 5‐ALA has been described as effective in vulvar lichen sclerosus in adult patients with insufficient response to standard therapies. Patients should be informed in detail about the side effects of the procedure (such as pain, redness, and swelling).

CONCLUSION

PDT has been an integral component of dermatological practice for years. Apart from established, approved oncological indications, such as actinic keratoses, Bowen's disease, and basal cell carcinoma, numerous infectious and chronic inflammatory dermatoses can be treated successfully and at low risk off‐label by PDT. In addition to conventional PDT, the markedly less painful daylight PDT has been established for years. Comparable to conventional PDT with red light, it is associated with very good cosmetic results. With artificial daylight PDT (ADL‐PDT), a variant applicable throughout the year and regardless of weather conditions has recently become available for actinic keratoses.

CONFLICT OF INTEREST STATEMENT

R.M.S. received grants from Almirall, Biofrontera, Dr. Wolff Group, Galderma, Leo Pharma, Novartis, and photonamic for clinical studies, honoraria for advisor and lecturer activities from Abbvie, Almirall, Eli Lilly, Galderma, Janssen, and Leo Pharma, and is Vice‐President of the EURO‐PDT Society.

CME‐Questions – Lernerfolgskontrolle

1. Welche Aussage zu den Grundlagen und Mechanismen der photodynamischen Therapie trifft zu?

   1. Die Photosensibilisatormoleküle können auch in Abwesenheit von Licht in den angeregten Triplett‐Zustand übergehen.
   2. Reaktive Sauerstoffspezies gelten als hauptverantwortlich für die Zytotoxizität der PDT.
   3. Zusätzlich zu dem Singulett‐Sauerstoff wird im Gewebe Singulett‐Jod gebildet, welches ebenfalls eine wichtige Rolle bei der PDT spielt.
   4. Im Rahmen der PDT werden drei Zytotoxizitätsmechanismen unterschieden: Typ‐I‐Mechanismus, Typ‐IIA‐Mechanismus und Typ‐IIB‐Mechanismus.
   5. Die Bildung von reaktiven Sauerstoffspezies findet insbesondere im Golgi‐Apparat statt.
2. Welche Aussage bezüglich der Strahlenquellen im Rahmen der PDT trifft zu?

   1. Porphyrinmoleküle haben ein Absorptionsmaximum bei einer einzigen Wellenlänge, die bei etwa 405 nm liegt
   2. Grünlicht weist die höchste Eindringtiefe in das Gewebe auf.
   3. Die Eindringtiefe des Rotlichts in die Haut liegt bei etwa 2–3 mm.
   4. Sonnenstrahlung ist die wirksamste Strahlenquelle für PDT.
   5. Mit dem Begriff „konventionelle PDT“ ist eine PDT mit Blaulicht gemeint.
3. Welche Aussage zur Durchführung der Outdoor‐Tageslicht‐PDT trifft zu?

   1. Tageslicht‐PDT kann in Deutschland in den Wintermonaten bei wolkenfreiem Himmel jederzeit durchgeführt werden.
   2. Im Sommer kann die Therapie auch an einem Regentag erfolgen.
   3. Ausschließlich geeignet für die Tageslicht‐PDT ist ein Aufenthalt in der prallen Mittagssonne.
   4. Die geeignete Außentemperatur für eine Tageslicht‐PDT liegt bei über 10°C.
   5. Wind hat keinen Einfluss auf die Outdoor‐Tageslicht‐PDT.
4. Welche Aussage ist zutreffend? Für die Therapie der aktinischen Keratosen …

   1. bei immunkompetenten Patienten ist sowohl die konventionelle als auch die Tageslicht‐PDT zugelassen.
   2. ist eine konventionelle PDT zugelassen, während die Tageslicht‐PDT eine Off‐Label‐Therapie darstellt.
   3. sollten zwei Sitzungen einer konventionellen PDT im Abstand von einer Woche durchgeführt werden.
   4. ist eine PDT eine Zweitlinientherapie, falls eine operative Sanierung nicht in Frage kommt.
   5. kann eine Grünlicht‐PDT hilfreich sein, wenn die konventionelle PDT nicht effektiv war.
5. Welche Wirkung einer PDT wird bei der Indikation der Hautverjüngung erwartet?

   1. Teleangiektasien und Talgdrüsenhyperplasien gehen zurück.
   2. Kleine Fältchen und Hautrauigkeiten werden verbessert.
   3. Größere Falten sprechen zu etwa 65% auf die PDT an.
   4. Seborrhoische Keratosen werden durch PDT verringert.
   5. Xanthelasmen können in über 50% der Fälle mittels Rotlicht‐PDT therapiert werden.
6. Welche Hauttumoren können mittels konventioneller PDT erfolgreich behandelt werden?

   1. Dermatofibrosarcoma protuberans
   2. Keratoakanthom
   3. Superfizielles Basalzellkarzinom
   4. Malignes Melanom mit einer Tumordicke kleiner als 0,3 mm
   5. Invasives Plattenepithelkarzinom
7. Welche Aussage zur PDT bei Virus‐bedingten Erkrankungen trifft zu?

   1. Photosensibilisatormoleküle haben eine hohe Affinität zu den durch HPV infizierten Keratinozyten.
   2. Bei EBV‐assoziierten Exanthemen kann PDT den Juckreiz effektiv lindern.
   3. PDT kann bei Condylomata acuminata, aber nicht bei Verrucae vulgares effektiv sein.
   4. Bei COVID‐19‐assoziierten Hautveränderungen zeigt eine Rotlicht‐PDT eine hohe Wirksamkeit.
   5. PDT wird erfolgreich bei einem Ikterus im Rahmen einer Virushepatitis eingesetzt.
8. Welche Aussage zur PDT bei Leishmaniose ist zutreffend?

   1. Es handelt sich um eine für diese Indikation zugelassene Therapie.
   2. Auch Belichtung in Abwesenheit eines Photosensibilisators ist effektiv.
   3. PDT ist insbesondere bei der Leishmaniose der Neuen Welt zu bevorzugen.
   4. Mehrere Therapiesitzungen sind in der Regel notwendig.
   5. Die Wirkung beruht auf der direkten Abtötung der Parasiten.
9. Für folgende Indikation besteht für die konventionelle PDT keine Zulassung:

   1. einzelne aktinische Keratosen
   2. oberflächliches Basalzellkarzinom
   3. Lichen sclerosus
   4. mehrere aktinische Keratosen
   5. Bowen's disease
10. Welche entzündliche Dermatose kann erfolgreich mit PDT off‐label behandelt werden?

    1. Lichen ruber planus
    2. Folliculitis decalvans
    3. Acne vulgaris
    4. Lupus erythematodes
    5. Dyshidrosiformes Hand‐ und Fußekzem

• Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 28. Februar 2025.

  Die richtige Lösung zum Thema “Die fünfte Auflage der WHO‐Klassifikation – Was ist neu für kutane Lymphome?” in Heft 9/2024 ist: 1e, 2d, 3d, 4e, 5c, 6c, 7c, 8b, 9d, 10b

  Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter https://www.akademie-dda.de/mitglieder.php.

Balakirski G, Lehmann P, Szeimies R‐M, Hofmann SC. Photodynamic therapy in dermatology: established and new indications. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2024;22:1651–1662. 10.1111/ddg.15464