Review Article Skin Appendage Disord 2016;2:166–176 Received: September 28, 2016 DOI: 10.1159/000453273 Accepted: November 7, 2016 Published online: December 8, 2016 Photodynamic Therapy and Skin Appendage Disorders: A Review Matteo Megna Gabriella Fabbrocini Claudio Marasca Giuseppe Monfrecola Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples , Italy Key Words Introduction Photodynamic therapy · Hidradenitis suppurativa · Acne · Sebaceous hyperplasia · Onychomycosis Photodynamic therapy (PDT) is a noninvasive treat- ment that utilizes light treatment along with an applica- tion of a photosensitizing agent in the presence of mo- Abstract lecular oxygen [1–3] . The scientific basis of PDT has Photodynamic therapy (PDT) is a noninvasive treatment that been recognized since 1900; Oscar Raab and Herman utilizes light treatment along with application of a photosen- von Tappeiner were first to report the concept of cell sitizing agent. In dermatology, PDT is commonly used and death being induced by the interaction of light and chem- approved for the treatment of oncological conditions such icals [4–5] . Shortly afterwards, von Tappeiner and Je- as actinic keratosis, Bowen disease and superficial basal cell sionek [6] performed the first medical application in der- carcinoma. In the last 2 decades however, PDT has also been matology, using a combination of topical eosin and white used for the treatment of several nonneoplastic dermato- light to treat skin tumors. Nevertheless, numerous stud- logical diseases. The present review summarizes published ies have then concentrated on the potential role of pho- data on PDT application in skin appendage disorders. Our tosensitizing agents such as porphyrins and their deriva- literature review shows that: (a) PDT may be a suitable treat- tives for detection and treatment of different tumors [7] , ment for acne, folliculitis decalvans, hidradenitis suppurati- clinical therapeutic applications of PDT in dermatology va, nail diseases, and sebaceous hyperplasia; (b) there is a were performed only 70 years later [6, 7]. Particularly, in lack of agreement on PDT features (type, concentrations and 1978, Dougherty [8] reported the first large series of pa- incubation period of used substances, number and frequen- tients with primary or secondary skin tumors success- cy of PDT sessions, optimal parameters of light sources, and fully treated with PDT (treatment with a hematoporphy- patient characteristics [e.g., failure to previous treatments, rin derivative followed by exposure to red light from a disease severity, body surface area involved, etc.] which xenon arc lamp). Nowadays, PDT use in dermatology should guide PDT use in these diseases); (c) further research involves light sources such as laser, intense pulsed light, is needed to establish international guidelines helping der- light-emitting diodes, blue light, red light, and many oth- matologists to choose PDT for the right patient at the right er visible lights including natural sunlight [1–3] ; as re- time. © 2016 S. Karger AG, Basel gards photosensitizers, the common employed agents © 2016 S. Karger AG, Basel Matteo Megna, MD 2296–9195/16/0024–0166$39.50/0 Section of Dermatology, Department of Clinical Medicine and Surgery University of Naples Federico II E-Mail [email protected] Via Pansini 5, IT–80131 Naples (Italy) www.karger.com/sad E-Mail mat24 @ libero.it are 5-aminolevulinic acid (ALA), a naturally occurring Acne intermediate in the heme biosynthetic pathway, and its methyl ester named methyl aminolevulinate (MAL) [1– Acne is one of the most common skin diseases, possi- 3] . Particularly, ALA and MAL have no intrinsic photo- bly affecting up to 80% of young people [13] . Acne is not sensitizing effect; efficacy is due to their tissue metabo- only an aesthetic concern as it can leave disfiguring scars lization, by heme pathway enzymes, to the potent photo- which may cause significant psychological distress [14] . sensitizer protoporphyrin IX together with interaction It is an inflammatory disease of the pilosebaceous unit, with molecular oxygen and light exposure [7, 9] . These and it is well known that follicular hyperkeratosis, Propi- substances are applied to the skin, causing the skin to be- onibacterum acnes colonization, and sebum secretion come more susceptible, or receptive, to light. Particular- play a major role in acne pathogenesis [15]. PDT with ly, the agent is applied to the desired cutaneous area and ALA may be a suitable treatment for acne since ALA is allowed to be absorbed for a particular length of time. metabolized to protoporphyrin IX, a photosensitizer that After the photosensitizing agent is removed, a light treat- can also accumulate in pilosebaceous units [16–18] . Stud- ment is administered. Generally, PDT involves the light ies have shown that ALA-induced protoporphyrin IX flu- activation of a photosensitizer to create cytotoxic oxygen orescence is greater in an acne lesion than in the sur- species and free radicals that selectively destroy rapidly rounding skin area, being also correlated with P. acnes proliferating cells [1–10] . Indeed, it has become an estab- colonization of sebaceous follicles [18] . Indeed, P. acnes lished treatment modality for oncological conditions like can produce porphyrins, and topical ALA can cause pref- actinic keratosis, Bowen disease, and superficial basal cell erential accumulation of porphyrins in P. acnes [18, 19] . carcinoma [11] . PDT has however also been found to be Therefore, topical ALA-PDT can impact acne treatment effective for the treatment of several nonneoplastic der- in different ways such as direct photodynamic injury of matological diseases like photo-aged skin, leishmaniasis, sebaceous glands with inhibition of sebum production, hidradenitis suppurativa (HS), sebaceous hyperplasia, photodynamic killing of P. acnes and reduction of follicu- acne vulgaris, etc. [1] . In addition to antitumor activities, lar obstruction through changing keratinocytes shedding experimental studies on PDT have demonstrated a vari- and hyperkeratosis [18] . Therefore, ALA-PDT is able to ety of antimicrobial, anti-inflammatory and immune inhibit multiple pathogenetic factors of acne [18] . It is modulation effects as well as evidence of influence on important to note that a transient acneiform eruption, keratinocytes, fibroblasts, mast cells, sebaceous glands, similar to the one due to systemic retinoid, may occur 3–4 and hair follicles [12] . This review focuses on off-label days after the first ALA-PDT treatment. In addition, both use of PDT in skin appendage disorders such as acne, HS, ALA-PDT and MAL-PDT, which may be often painful, sebaceous hyperplasia and nail diseases, analyzing the may also cause inflammatory side effects, and/or residual published body of evidence and studies regarding PDT photosensitivity [18] . ALA-PDT treatment was first re- in this class of diseases. ported as a possible therapy for acne patients in 2000 by Hongcharu et al. [18] who showed a greater, longer and more sustained efficacy in patients receiving 4 versus 1 Material and Methods PDT treatment session (50 vs. 30% reduction of acne) and significant reduction of sebum output. Improvements We searched for English-language literature regarding PDT usually started 3 weeks after PDT first session. Almost at treatment for skin appendages disorders such as acne, HS, seba- ceous hyperplasia, folliculitis decalvans (FD) and nail diseases in the same time, other authors showed ALA-PDT efficacy the following databases through September 20, 2016: PubMed, in acne treatment, reporting also that improvements last- Embase, The Cochrane Library, Google Scholar, EBSCO and Sco- ed for at least 6 months and that 1 PDT session may be pus. The following key words were used: “photodynamic therapy,” not enough [20, 21] . Nevertheless, almost 16 years have “treatment,” “acne,” “hidradenitis suppurativa,” “nail diseases,” passed since the first studies on ALA-PDT in acne thera- “onychomycosis,” “sebaceous hyperplasia,” “folliculitis decal- vans,” “5-aminolevulinic acid,” and “methyl aminolevulinate.” py; there is still no consensus on how to perform PDT for Only studies including full details about used photosensitizer, in- acne treatment, and its use still remains an off-label op- cubation time, light source, and treatment session duration were tion for acne patients [22] . Despite numerous studies on analyzed in the present review. PDT in acne (mainly mild to severe acne on the face but also acne lesions on the back and acne conglobata) [1, 18, 20, 21, 23–42] ( Table 1 ), they are generally difficult to compare because of the lack of controls, qualitative non- Photodynamic Therapy and Adnexal Skin Appendage Disord 2016;2:166–176 167 Disorders DOI: 10.1159/000453273 Table 1. Studies on PDT use in acne First author [Ref.] Patients, Photo- Incuba- Light source Treatment session and n sensitizer tion time duration 2 Hongcharu [18] 22 20% ALA 3 h Broadband light (550 – 700 nm) at 150 J/cm 4 sessions at 1-week interval Itoh [20] 1 20% ALA 4 h Pulsed excimer dye laser (635 nm) at 5 J/cm2 1 session Itoh [21] 13 20% ALA 4 h Polychromatic visible light (600 – 700 nm) 1 session at 13 J/cm2 Wiegell [23] 21 16% MAL 3 h Red light at 37 J/cm2 2 sessions at 2-week interval Wiegell [24] 15 20% ALA 3 h Red light at 37 J/cm2 1 session or 16% MAL Horfelt [25] 30 16% MAL 3 h Red light (635 nm) at 37 J/cm2 2 sessions at 2-week interval Kimura [26] 51 ALA 4 h Polychromatic