PHOTODYNAMIC THERAPY OF ACNE

Acne is one of the most common skin conditions in the world. A number of studies have shown that photodynamic therapy (PDT) is safe and effective for both inflammatory and non-inflammatory acne and can significantly improve skin conditions in this disease. The effectiveness of PDT against acne is mainly due to a decrease in the amount of sebum produced by the sebaceous glands due to a decrease in their activity as a result of direct photodynamic damage to the sebaceous glands, eradication of Cutibacterium acnes, and a decrease in the level of hyperkeratosis. Compared with systemic drug therapy, PDT treatment of severe acne has the following advantages: fast results, high efficiency, high selectivity, no systemic adverse reactions and drug resistance


Epidemiology
Acne affects approximately 600 million people worldwide every year, making it the eighth most common skin disease in the world [1]. Acne occurs in 70-75% of prepubertal children up to 12 years of age (usually at 9-11 years of age). Up to 80-85% of teenagers and young adults suffer from acne. In older age groups, the percentage decreases, but still, almost one in ten adults over 25 suffers from acne [2]. Although acne is not a life-threatening disease, serious psychological consequences have been reported in various studies in patients, which can affect sociability, cause phobias, and lead to depressive symptoms [1].

Etiology and pathogenesis
Acne can occur against the background of seborrhea, which is characterized by a change in the chemical composition of sebum and increased secretion of sebum by the sebaceous glands. As a result, acne occurs in areas of the skin that are richest in sebaceous glands [2]. Acne pathogenesis involves four main mechanisms: follicular hyperkeratosis (epithelial proliferation with thickening of the stratum corneum of the sebaceous gland channels), increased secretion of sebum, C. acnes colonization, and localized inflammation [3]. It is believed that it is the colonization of C. acnes that plays a key role in the development of acne [3]. C. acnes is a Gram-positive, anaerobic, slow growing bacterium that metabolizes triglycerides and produces cytokines that induce inflammatory responses [3,4].
The Leeds acne severity score takes into account acne lesions on the face, back, and chest and classifies them as inflammatory or non-inflammatory. Leeds scores range from 0 (least severe) to 10 (most severe). There are modified Leeds scales, the maximum score for which is 12 [5,6]. The Pillsbury Acne Rating Scale ranks acne severity from 1 (least severe) to 4 (most severe) [7,8].

Acne therapy
Traditional acne therapy includes topical and systemic antibiotics, such as tetracyclines and isotretinoin, as well as retinoids [1]. The use of antibiotics is significantly limited by the growth of antibiotic resistance in C. acnes, and the use of retinoids is limited by their serious side effects associated with teratogenicity, spontaneous abortion, skin irritation, cheilitis, photosensitivity, arthralgia, hypertriglyceridemia, inflammatory bowel disease, pancreatitis, and depression [3,9]. Acne therapy is very long. Thus, according to Cunliffe et al., for complete resolution of mild to moderate acne, 3-4 years of treatment are required, and in the case of severe acne, 8-12 years may be required. According to Cunliffe, in 7% of patients with disease manifestation in adolescence, the manifestations of the disease can last up to 45-50 years [10]. Long-term use of antibiotics can cause a variety of side effects, including dysbiosis and an increased chance of infection with opportunistic pathogens. Longterm use of isotretinoin can cause dry skin and mucous membranes, increase blood lipid levels, and lead to impaired liver function, depression, and suicidal tendencies. In addition, this drug has a teratogenic effect and cannot be recommended in women of childbearing age [11]. The topical application of these drugs may cause skin irritation. It is also important that their use requires adherence to a clear regimen of administration, and in real clinical practice there is often a violation of the rules of admission by the patient.
Low efficacy, side effects, and duration of treatment with antibiotics and retinoids are prerequisites for finding new, safe, and effective ways to treat acne. In this context, various safe and effective physiotherapy procedures are becoming a new trend in the treatment of acne. One of the possible alternative methods of treatment can be photodynamic therapy (PDT) [1,11].

PDT in the treatment of acne
PDT is used for various tumor and precancerous skin pathologies [12,13,14]. A number of studies have shown that PDT is safe and effective in both inflammatory and non-inflammatory acne and can significantly improve skin conditions in this disease. Moreover, since the reactive oxygen species produced by PDT do not have any specific molecular target, PDT makes it possible to easily bypass drug resistance in microorganisms, which gives this therapy an advantage over antibiotic treatment. The effectiveness of PDT against acne is mainly due to a decrease in the amount of sebum produced by the sebaceous glands due to a decrease in their activity as a result of direct photodynamic damage to the sebaceous glands, eradication of C. acnes and a decrease in the level of hyperkeratosis [1,15].

Photodynamic therapy of acne
Таблица Сводные данные результативности применения фотодинамической терапии у больных акне Filonenko E.V., Ivanova-Radkevich V.I. Photodynamic therapy of acne BIOMEDICAL PHOTONICS Т. 12, № 2/2023 possibility of using PDT for the treatment of warts and acne, with 5-amnolevulinic acid (5-ALA) being listed as the most widely used PDT drug. The recommendations also contained an indication of the possibility of using both coherent and incoherent light sources for PDT [16]. By 2008 [17], PDT for the treatment of acne, warts, and cutaneous leishmaniasis was rated clinical recommendation level IB (strength of recommendation B, quality of evidence I). In the latest edition of the European Clinical Guidelines for Local PDT, severe acne remains indicated as an indication for PDT with an IB level [11]. Guo et al., based on almost 20 years of experience in the clinical use of PDT for the treatment of severe acne, conclude that, compared with systemic drug therapy, the treatment of severe acne with PDT has the following advantages: fast results, high efficiency, high selectivity, no systemic adverse reactions, drug resistance, and low recurrence rate [1]. Picone et al. [18] also indicate that the undoubted advantage of PDT for the treatment of acne is the absence of scars after treatment.
Interestingly, low concentrations of the photosensitizer, short incubation time, and low light doses (about 13 J/cm 2 ) under blue light irradiation provide short-term antimicrobial and immunomodulatory effects, while higher light doses (up to 150 J/cm 2 ) of red light additionally cause destruction of the sebaceous glands. An additional effect of all PDT modes, leading to a decrease in follicle obstruction and a decrease in sebum secretion, is an increase in epidermal renewal [4].
In recent years, several large clinical studies have been conducted on the efficacy and safety of PDT in the treatment of acne using 5-ALA and 5-ALA methyl ester (ME-ALA) (Table). Even though there were no reports on the use of chlorin derivatives for PDT in patients with acne in clinical practice, in vitro and in vivo studies using chlorins also showed satisfactory results [19]. Phthalocyanines, to the best of our knowledge, have not yet been investigated for the treatment of this skin pathology.
We searched for published results of studies on the clinical efficacy of PDT in acne patients over the past 10 years using the Pubmed database. We included in the analysis only studies conducted with the participation of 10 or more patients, in which PDT was performed in mono mode using standard sources and irradiation modes. Selected clinical cases of interest are further described below. The analysis made it possible to identify 9 studies that present data obtained in total in the treatment of 368 patients with acne (Table). Most studies have used 5% of 5-ALA as an application for 1-4 hours for PDT. In one study, the concentration of 5-ALA was lower -3.6%. Three studies used ME-ALA for PDT at a standard concentration of 16% or a lower concentration of 4%. For irradiation, red light was most often used. Light doses ranged from 15 to 120 J/cm 2 . All studies have shown an overall improvement in acne after PDT.
The main task in the development of the PDT method in the field of acne treatment at the moment is the search for regimens that reduce pain and the development of local reactions in the area of irradiation while maintaining the high treatment efficiency achieved in previous studies.
A number of studies demonstrate a significant reduction in the intensity of pain during an irradiation session and other adverse events while maintaining high treatment efficiency during low-intensity PDT. For example, in a study by Chen et al., [21] PDT with a light dose of 120 J/cm 2 and a power density of 10 mW/cm 2 caused significant pain, burning, erythrema, and edema that persisted up to 4 days after PDT in 28% of patients and temporary pigmentation in 12% of patients. Liu et al. [3] reported the development of adverse events (moderate pain, erythrema, and edema lasting up to 5 days) in 92% of patients after PDT with a light dose of 127 J/ cm 2 and a power density of 105 mW/cm 2 . In a study by Calzavara-Pinton et al. [22], the light dose was reduced to 37 J/cm 2 at a power density of 10 mW/cm 2 . The authors of the study did not report significant pain sensations or other adverse events. Only 4% of patients with skin type IV developed areas of hyperpigmentation at the treatment site.
Pain sensations are also reduced with the use of 5-ALA and ME-ALA at lower concentrations than usual. For example, in a study by Dessinioti et al. [24] ME-ALA cream was used for PDT with a concentration 4 times lower than the standard (4%). Side effects were limited to mild transient erythema at the treatment sites and lasted several hours. Edema, pustules, crusting, or persistent erythema were not observed. Patients did not report pain. At the same time, the effectiveness of treatment was quite high -immediately after 2 courses of PDT, the number of acne foci decreased by an average of 35% from the initial level.
Many researchers note that the use of high concentrations of 5-ALA for acne PDT causes significant side effects. For example, Pollock et al. [27] reported on the use of 5-ALA in 10 patients with acne at a concentration of 20% with application for 3 hours. Despite the rather sparing irradiation regimen (15 J/cm 2 , 25 mW/cm 2 ), patients experienced significant pain during the irradiation session and erythrema. The effectiveness of the treatment was even lower than when using lower concentrations of 5-ALA: after the second course of treatment, a statistically significant decrease in the number of inflammatory foci of acne was observed in the treatment area compared to the baseline, but not in comparison with the control areas. As a result of the treatment, no statistically significant amount of C. acnes or the level of sebum secretion was obtained.
Some researchers recommend shortening the application time of 5-ALA as a way to reduce the intensity of Filonenko E.V., Ivanova-Radkevich V.I. Photodynamic therapy of acne BIOMEDICAL PHOTONICS Т. 12, № 2/2023 pain during irradiation. Thus, the results of one recent small-scale study in which 5% 5-ALA cream was used in patients with acne showed that a reduction in the application time from 90 to 30 minutes led to an almost complete absence of pain during irradiation in patients with the same effectiveness of treatment [28]. Chinese dermatologists also give the results of studies demonstrating that PDT with a 5-ALA concentration of 3-5% and a shorter application time (30 min) can effectively improve the condition of moderate to severe acne vulgaris with minimal pain and other adverse reactions [29].
The use of a ventilator, air cooling, and possible short breaks in irradiation may also be used to reduce treatment-related pain during PDT. Local anesthesia can usually be used before and after PDT [30].
A separate promising area of application of PDT in patients with acne is PDT after ineffective acne treatment by other methods, in particular, after an exacerbation of the disease during isotretionine treatment. Despite the fact that no large-scale studies of the effectiveness of PDT in this group of patients have been conducted, several interesting clinical cases have been described in the literature. Thus, Liu J. et al. [31] report the successful treatment of a patient with acne flare-ups after treatment with isotretionin. Acne exacerbation develops in a small proportion of patients at the start of oral isotretinoin. Clinically, it usually manifests as painful, ulcerated, and hemorrhagic lesions. Traditional therapy in this case is the ingestion of corticosteroids. However, in some patients, such therapy can also be accompanied by side effects, such as metabolic disorders, suppression of immune function, and other effects. The authors report a young man with acne exacerbation after taking isotreti-noin, who was treated with PDT (2-hour application of 5% 5-ALA, irradiation 633±6 mm, 42 mW/cm 2 , 75.6 J/ cm 2 , 7 cycles). The result of the treatment was rated as a complete cleansing of the skin with an excellent cosmetic result). Picone et al. [18] report another case of successful treatment of acne exacerbation while taking isotretionine. PDT was performed in a patient with ulcerative and hemorrhagic lesions from acne on the face and trunk with an exacerbation of the disease after the start of treatment with isotretinoin, which did not respond to systemic prednisolone in combination with topical application of clindamycin and disinfectants. The patient underwent 6 courses of PDT with ME-ALA (application of 16% ointment) with red light irradiation (630 nm, light dose 39 J/cm 2 ). At a 6-month follow-up, the patient showed no active lesions, only scarring, and no side effects were reported during and after each treatment session.

Conclusion
In recent years, the method of acne treatment, PDT, has been actively developed, demonstrating high efficiency and a satisfactory safety profile. For acne PDT, 5-ALA and ME-ALA are used. Both drugs show high efficacy in both inflammatory and non-inflammatory lesions, in mild, moderate, and severe forms of acne, as well as after ineffective acne treatment by other methods, in particular after an exacerbation of the disease during treatment with isotretionine. The main direction in the development of PDT in acne patients is the search and development of low-intensity PDT schemes to minimize pain and local reactions to radiation.