- Email: [email protected]
The modern paradigm of phototherapy
The Modern Paradigm of Phototherapy MICHAEL ZANOLLI, MD Abstract. The recognition of medical benefits obtained with suberythemogenic doses of natural sunlight extends back centuries. Modern medical application of phototherapy has been in place for over 100 years. It is the nature of scientific discovery to depend upon the use of new investigational methods or new devices to gain a better understanding of the mechanisms involved with the observed effects. Advancements in the field of photobiology and in the development of delivery systems for light therapy, such as narrow band UVB and laser, has given us additional insight into why and how phototherapy works in regards to treatment of skin disease and conditions of the skin. This discussion will primarily focus on ultraviolet light, photochemotherapy and a brief mention of photodynamic therapy.
P
hototherapy has been used for centuries to treat numerous skin disorders. Most of the insight into the therapeutic benefit of phototherapy gained in previous centuries was related to the observed effects of natural sunlight. Still today, certain areas of the world, such as the Dead Sea, have unique geographic locations recognized as providing effective sites for climatotherapy for psoriasis. Numerous other inflammatory skin diseases, such as atopic dermatitis, and pigment disorders, like vitiligo, benefit from ultraviolet light treatment. Recent advances in the understanding of phototherapy and, more importantly, the application of phototherapy and its specific effects on the cutaneous immune system, have resulted in a renewed interest in the application of ultraviolet (UV) light in dermatology. The development of artificial sources utilizing ultraviolet light for medical purposes began at the beginning of the 20th century. Niels Finsen was awarded the Nobel Prize in 1903 for using ultraviolet light as treatment for a skin disease. He was treating cutaneous mycobacterial infection of the skin with focused delivery of ultraviolet light. Further developments in the 20th century relate to the use of Ultraviolet B (UVB) therapy, primarily for psoriasis, in the mid part of the century. For example, Goeckerman treatment consisting of ultraviolet light in the B region combined with crude coal tar was one of the mainstays of therapy for moderate to severe psoriasis in the United States. In fact, the therapeutic response and duration of remission for this treatment for psoriasis still comprise one of the standards against which new therapies are measured; however, the long-term hospital admissions of 2 to 3 weeks and the many hours of special wrappings on the skin required by the treatment make this procedure very time-consuming, demanding, and expensive to deliver appropriately. Likewise, the Ingram method, From the Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee. Address correspondence to Michael Zanolli, MD, Dermatology Consultants PC, Suite 609 East, 4230 Harding Road, Nashville TN 37205. E-mail address: [email protected]. © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
which uses short-term contact anthralin in combination with ultraviolet B therapy, has also proven to be a very effective treatment for psoriasis, but again requires specialized nursing facilities and day-long care or hospitalization. A more recent change in the paradigm for phototherapy use emerged in the second half of the 20th century from the recognition and implementation of photochemotherapy for treatment of skin diseases. The combination of a photon-absorbing chemical delivered in a systemic manner, followed by delivery of ultraviolet light to the skin, was observed to promote clearing of psoriasis in a high percentage of patients. It is through just such discoveries by keen observation that fundamental change and advancement in a discipline can occur. The paradigm of using ultraviolet light in combination with an endogenous or exogenous chemical to promote a photochemical reaction changed the entire approach for the concept of photochemotherapy and photodynamic therapy. In North America, the leaders in the development of photochemotherapy were Drs. Fitzpatrick and Parish. Their observations of the effects of photochemotherapy on vitiligo and subsequently the notable improvement in psoriasis on the skin of a patient undergoing photochemotherapy led to the further development and application of PUVA treatments. PUVA is one of the best examples of advancement of dermatologic therapy in the last quarter of the 20th century.
Laser Therapy The application of coherent light with the development of laser therapy for medical purposes has made a special impact in dermatology. In the broad sense, this field should be considered an aspect of phototherapy because various wavelengths of electromagnetic spectrum are employed with laser light. Laser therapy, however, is now its own discipline. Lasers are used to treat a variety of problems, such as inhibiting disease processes and altering specific skin structures. Laser ther0738-081X/03/$–see front matter doi:10.1016/j.clindermatol.2003.08.005
Clinics in Dermatology
Y
2003;21:398 – 406
apy has many applications in dermatology that are beyond the scope of this discussion of the use of therapeutic phototherapy. What is important and central to the advancement of phototherapy is the creative approach of fashioning and employing certain wavelengths of laser light to very specific actions and reactions in skin. This is exemplified by the concept of selected photothermolysis promoted by Dr. Rox Anderson.1 Lasers are being developed for their selected effects on specific chromophores in the skin based on the absorption spectrum of molecules in the protein or structures. The targeted action of the laser coupled with a very short duration of energy delivered would help decrease injury to surrounding structures. Application of this concept led to the manufacture of vascular lasers, which effectively treat dermal blood vessels without scarring the skin surface. This was another advancement within the past 20 years that utilized photobiologic and photochemical reactions to effect a change in the pathogenesis and/or normal pathophysiology of a specific biologic or anatomic condition. The development of selected photothermolysis has led to the use of lasers that specifically target hemoglobin as well as pigment, such as melanin, or tattoos and other foreign pigment in the skin. In addition, collagen itself can be made a potential target in an effort to alter and disrupt it so that regeneration of collagen in the superficial dermis will occur. This field is growing and maturing with better designed studies to demonstrate effects of laser light. Rather than trying to discuss application of lasers for cosmetic purposes and/or for selective photothermolysis of benign vascular malformations, I will limit further discussion of the application of laser light to the ultraviolet region of the electromagnetic spectrum and as it applies to the treatment of disease. The principles and standards established by the paradigm shift in the last 20 years, involving selection of a wavelength of light in the UV, visible, or infrared region to effect specific actions in the skin, provide the foundation for further modern advances in phototherapy. Thus, it was not a new discovery that has led to the application of better ultraviolet light therapy for inflammatory diseases. Rather, it was the availability of previous information derived from experiments done in the mid 1970s and early 1980s that provides the basis for the modern use of ultraviolet B light in applications for inflammatory skin diseases mediated by T lymphocytes. Determining the action spectrum for psoriasis provides a means to select the best wavelength of UV light to treat that disease. In 1976, Dr. Turkel Fisher performed a series of experiments using a limited number of individual discontinuous wavelengths of light on plaques of psoriasis.2 Dr. Fisher’s findings indicated a
THE PARADIGM OF PHOTOTHERAPY
399
wavelength of 313 nm was more effective for clearing of psoriasis than other wavelengths within the UVB region and some wavelengths in the UVA region. This work is very important in determining the action spectrum for psoriasis. Building on this information, Dr. John Parish conducted research that provided a more extensive array of wavelengths, including UVC, UVB, and UVA, to help delineate those wavelengths most effective in treating psoriasis.3 This work confirmed the findings previously reported by Dr. Fisher and helped demonstrate the most effective wavelengths for treating psoriasis, which exist somewhere between the range of 310 and 315 nm. There are beneficial therapeutic effects on plaques of psoriasis from other wavelengths, although not to the same degree. It is important to note that wavelengths in the UVC region can also clear psoriasis; however, because these wavelengths are much more likely in low dose to produce an erythema response, they were not tolerated well by the subjects. Although this information has been available since the early 1980s, it was not really applied in the use of conventional phototherapy because the fluorescent tubes designed for delivery of this wavelength were not yet being manufactured. Accordingly, there was an appreciable delay in the further development of narrow-band UVB for treatment of psoriasis. That problem has now been overcome because the proper phosphor on the linings of ultraviolet lamps necessary for delivery of narrow-band UVB therapy is being manufactured and is available. The shift to narrow-band UVB that has occurred in Europe over the past 10 years, which is occurring in North America over the past 4 years, has focused on applying this important therapy for inflammatory skin disease. Modifications utilizing UVB with delivery systems for localized areas of the skin with peak emissions of UV light in the therapeutic region between 310 and 315 nm are now being advocated for a number of diseases. Another area within phototherapy that is undergoing a transformation involves application of the longer wavelengths of light within the UVA region. The region of UVA is now subdivided into UVA-1 (340-400 nm) and UVA-2 (320-340 nm.). Specialized devices with high output delivery of UVA-1 have had an important impact on selective diseases within the field of dermatology. The physics and interaction of skin with wavelengths of light permit these longer wavelengths to have deeper penetration into the dermis, which otherwise would not be reached by UVB wavelengths. Further discussion of UVA-1 and its potential impact on the use of ultraviolet light therapy in the decades ahead will receive special consideration.
400 ZANOLLI
Clinics in Dermatology
Mechanisms
the primary effects of therapeutic ultraviolet light intervention in skin diseases to be an immune modifying treatment. This very significant review helps put into perspective the multitude of effects on the cutaneous immune system that have been reported. The effects of ultraviolet light outlined fall into two main categories and include direct effects through injury to certain cell types, as well as indirect effects through production of other chemicals that might help shift a balance of cytokine production. The acute effects relate to direct damage to membranes or induction of cytoplasmic transcription factors, DNA damage, and isomerization of urocanic acid. The second major category, subacute changes, relate to alteration of the presentation and processing of antigenic stimulation through antigen-presenting cells and T cells. The majority of information about these effects refers to known effects of ultraviolet light on Langerhans’s cells with observed altered function of Langerhans cells. The changes occurred despite the presence of the cells, which were not induced to undergo apoptosis.
Many biologic effects of ultraviolet light, visible light, and wavelengths of laser light that extend into the infrared are observable. This does not necessarily mean, however, that the mechanism mediating the therapeutic effect has been sufficiently defined. The first principle of photochemistry is that only absorbed light can cause a photochemical change. The perspective of the new paradigm requires identifying the target of the photobiologic effect of phototherapy. The main areas of phototherapy that have briefly been introduced in the first section are UVB therapy, photochemotherapy (including photodynamic therapy), UVA-1 therapy, and therapeutic interventions with various wavelengths of laser light. These different therapeutic alternatives may have some mechanisms in common, such as the production of oxidants in the skin and in the mitochondrial membranes. However, there are differences in the chromophores, the targets for the photons of energy contained in each of these different therapeutic modalities. There has been an increase in the understanding of the effects of UVB therapy over the past 10 to 15 years. In the past, it was clear that UVB therapy helped clear psoriasis, with the majority of patients having a good to excellent therapeutic response. More recently, with the existence of better markers for cells, such as T cells and antigen-presenting cells in the epidermis, the effects of UVB light have been more clearly defined. This is especially true for narrow-band UVB therapy. Observed effects of narrow-band UVB therapy and how it influences T lymphocytes in the skin have been reported by numerous authors. In North America, the clinical trials that help define the therapeutic efficacy of narrow-band UVB as compared to broad-band UVB and PUVA demonstrate the effect of narrow-band UVB on T cells and antigen-presenting cells in the epidermis and superficial dermis.4 T lymphocyte and antigenpresenting cells appear to be more susceptible to the effects of UVB therapy than do keratinocytes. Loss of cell markers and preferential apoptosis occurs at lower doses than are necessary to cause the same effect in keratinocytes.5 Previously, one of the major mechanisms to identify effects of ultraviolet light therapy on cell types was that used to identify apoptosis through light microscopy studies; however, lower doses of ultraviolet light may be also effective in treating psoriasis, and it is clear that one does not have to use erythemogenic doses of narrow-band UVB therapy to produce the same grade or better clearing than with erythemogenic doses of UVB.6 A review with further insight into mechanisms of ultraviolet light in skin has helped clarify some of the many effects that have been observed.7 This is especially important for understanding the effects on the human immune system and thereby recognizing one of
Y
2003;21:398 – 406
Photochemotherapy Photochemotherapy remains one of the most effective forms of phototherapy for treatment of psoriasis and many other skin disorders. The combination of a psoralen molecule and ultraviolet light has been given the eponym PUVA. In the context of photochemotherapy, the use of topically applied, naturally occurring compounds with natural sunlight has been known for centuries to produce both therapeutic and phototoxic reactions. The Egyptians used topical psoralen and molecules for treatment of pigmentary disorders. It was not until the modern use of photochemotherapy with specific psoralen molecules, such as 8 methoxypsoralen, that the true potential for this modality of therapy was realized. El Mofty is credited with the first modern medical use of photochemotherapy, using it not just as extracts but as a molecule applied topically. Further development of systemic photochemotherapy occurred when ingestion of psoralen, initially used to treat vitiligo, was found to have profound effects on psoriasis.8 Ever since the early 1970s, photochemotherapy has been a demonstrably effective treatment for psoriasis, with more than 80% of individuals expected to obtain good to excellent results. Another significant feature of this form of therapy is that the duration of remissions following treatment typically extends months rather than weeks as with standard broadband UVB therapy. An additional benefit of the use of PUVA is its effectiveness in dark-skinned as well as lighter-skinned individuals. This benefit contrasts with the traditional broadband UVB therapy, which is not as effective in darker-skinned individuals such as those from African
Clinics in Dermatology
Y
2003;21:398 – 406
decent. Dermatologists can use PUVA in many other dermatologic disorders with good results.
Newer Developments in Photochemotherapy The application of different psoralen molecules with potentially fewer acute side effects has been one of the most recent advancements in photochemotherapy. 5 Methoxypsoralen (5 MOP) is the compound that has been utilized more in European countries. It is a naturally occurring psoralen that can be ingested. One of the most frequent complaints with PUVA therapy has been with acute gastrointestinal side effect, which can be a cause for patients’ discontinuation of therapy in certain cases. Significantly, 5 MOP has fewer acute gastrointestinal side effects such as nausea and vomiting, than does 8 MOP. 5 MOP has been shown to be effective in clinical trials, although a slightly higher dose is needed for efficacy.9 Oral ingestion of 1.2 to 1.6 mg per kg is needed for the same efficacy as has been obtained with 8 MOP. The absorption through the gastrointestinal tract occurs at approximately the same rate such that the timing of the UVA delivery with 5 MOP is within 1 to 1.5 hours after ingestion. Psoralens are ingested very readily from the gastrointestinal tract, and after absorption in the proximal small bowel, direct transport to the liver by the hepatic venus circulation occurs. The psoralens demonstrate a saturable first pass effect in the liver, which causes a rapid rise in blood levels once the capacity for liver metablism of the molecule has been saturated. As a result, the delivery of psoralens must be consistent with regards to the dose, the food ingested with psoralen, and the timing before the delivery of UV light. Alterations in one of these three variables may result in more of a phototoxic reaction because of variability in the blood levels of the psoralen at the time of UV light delivery. Further advancement in treatments using different psoralen molecules should strive to decrease the possibility of long-term side effects. The most important long-term side effect demonstrated with the use of PUVA therapy has been the development of cutaneous malignancies, which occurred after cumulative highdose therapy extended over time. For example, patients having had more than 200 PUVA treatments are at increased risk for developing squamous cell carcinomas. This is especially an important consideration with regard to the areas of male genitalia, which is more prone to having squamous cell carcinoma in relation to PUVA therapy.10 This effect from PUVA seems to be due to a cumulative dose. There is an induction period for the development of squamous cell carcinomas, which appears to be 10-15 years. Evidence reported from the North American cohort of PUVA patients followed over the past 25 years dem-
THE PARADIGM OF PHOTOTHERAPY
401
onstrates an increased frequency of development of melanoma in certain groups.11 It is important that patients having a Type I Fitzpatrick or Type II Fitzpatrick response to ultraviolet light not receive excessive exposures to photochemotherapy. In addition to patients with Type I or Type II skin being at increased risk, patients who have received greater than 200 PUVA treatment are also likely to have an increased chance of developing melanoma. Finally, patients who have received a high number of treatments and experienced a 15- to 20-year latency period should be followed because of a possible increased incidence of melanoma. A component of the theoretic basis for such incidence of squamous cell carcinoma in the high-dose group of PUVA patients are the photobiologic effects of PUVA on DNA. Psoralen molecules can enter the nucleus of cells and intercalate between DNA base pairs. With absorption of a photon of light, a covalent bond is formed with adjacent pyrimidine bases, producing a cyclobutane ring. If a second photon of light is absorbed by the psoralen molecule when it already has had formation of a cyclobutane ring, a DNA cross-link is formed across the strands of DNA base pairs. Theoretically, this is the prime basis for repetitive errors in DNA and plays a role in formation of squamous cell carcinoma. The influence of the direct DNA damage in the pathogenesis of malignancy may be either a direct effect on the keratinocytes or indirect through abnormalities in the altered immunologic surveillance of the skin. One of the directions for continued refinement of photochemotherapy in the future, as well as one of the new paradigms associated with photochemotherapy itself, is development of other psoralen molecules that do not form bifunctional adducts, which provide a basis for the DNA cross-linking. One such class of psoralens is the methylangelicins.12 This type of psoralen only forms monofunctional adducts, and although long-term studies are needed, there is clearly a theoretical basis that monofunctional adducts would be less likely to promote cutaneous malignancies as compared to bifunctional adducts.
Narrow-band UVB The introduction of narrow-band UVB was made possible through the development of the proper fluorescent tubes that can deliver UVB therapy in a conventional manner. The initial studies demonstrating the efficacy of narrow-band UVB therapy for treatment of psoriasis were done by colleagues in Europe.13,14 Additional studies have been done over the past decade, which demonstrate the comparative efficacy of broad-band UVB and narrow-band UVB therapies as well as NBUVB and PUVA. North American studies demon-
402 ZANOLLI
strating the superiority of narrow-band UVB over conventional UVB have also been completed.4 When compared with PUVA therapy, narrow-band UVB treatments are not quite as effective in clearing psoriasis, although the improvement scores are very similar. The most marked difference between narrowband UVB and PUVA therapy lies in the duration of remission once good to excellent clearing is obtained, which occurs in more than 70% of individuals.15 Studies investigating the possible mechanism of actions of narrow-band UVB have demonstrated apoptosis of T cells in the epidermis and superficial dermis without apparent keratinocyte alteration.5 The availability of narrow-band UVB is finally increasing in North America. Our European colleagues have had the availability of narrow-band UVB fluorescent tubes for the past 10 years, and in Europe, it has become the treatment of choice within the UVB spectrum (personal communication). Because of its effectiveness in treating psoriasis, narrow-band UVB therapy is now gaining much more acceptance and is more frequently used in North America. The standardized protocols and methodologies used in the Unted States and Europe appear to be similar. However, the initial dose of narrow-band UVB continues to be variable from one center relative to another. The most accurate starting dose of narrow-band UVB is between 50% and 75% of the measured minimal erythema dose (MED). An important feature of treatment is the accurate detemination of the MED due to the marked variation in response to this narrow wavelength. To evaluate this accurately and determine the initial treatment dose, effort should be taken to obtain the MED. Protocols are available with the starting point estimated by skin type, but the range of the dose within each skin type varies. Without the MED, the initial treatments may greatly underestimate the more effective doses needed to advance treatments in the early stages of therapy. Significantly, advancement of therapy can easily occur by increasing the dose by 10% to 20% of the MED each treatment, with a treatment frequency of three times a week.6,16 As with broad-band UVB therapy, narrow-band UVB therapy is not limited to use of psoriasis itself. Numerous applications of this modality of therapy have been used in atopic dermatitis, vitiligo, cutaneous T cell lymphoma, lichen planus, pruritus, and as a preventative treatment for photodermatoses.
Variations in UVB, Including Excimer Laser and Delivery of Localized UVB Successful application of narrow-band UVB in treating psoriasis has renewed interest in UVB treatment for inflammatory dermatosis. Newer variations in delivery of UVB may be helpful for treatment of psoriasis and
Clinics in Dermatology
Y
2003;21:398 – 406
other phototherapy responsive dermatosis. Current development of delivery systems for localized light is being refined due to the insight into the more pronounced effects of 310 to 315 nm UV light on activated T cells and antigen-presenting cells in the epidermis and superficial dermis. The two main variations in traditional UVB and even in narrow-band UVB are the application of 308 nm laser light in the form of the EXTRAC laser and a localized delivery system for a light source with a broad region of UVB emission. Both of these devices have been approved for use in treating psoriasis and have applications for the diseases traditionally treated with UVB phototherapy such as vitiligo. There are ongoing investigations that will provide further conformation on their efficacy and other aspects of treatment. The use of laser light at 308 nm for treatment of psoriasis has been under investigation for the past 6 years. An early report regarding a limited number of patients indicated that use of high energy laser light at multiples of the minimal erythema doses produces a phototoxic reaction locally.17. This report showed clearing of areas within larger plaques of psoriasis where the laser light was delivered. Although the reaction at the site provoked a marked amount of redness, at times blistering, after the initial healing of this superficial phototoxic reaction, there was persistence of normal skin for many weeks. This result promoted additional investigation into the use of this laser device for localized plaques of psoriasis.18 The methods used very high multiples of the minimal erythema dose and produced clearing of the psoriasis with a very low number of treatments. Because the initial reports were enthusiastically received, a larger size study was done on a very limited area of psoriasis at minimal erythema doses within the 4 to 6 MED range. Patients’ own self assessment of the approach to treatment was very positive.19 In this study, standardization of the protocols and the delivery of the ultraviolet light matured with treatments at twice a week using the lower MEDs for 10 weeks. A good to excellent response in 70% of the subjects was reported in this multicenter trial. The duration of remission and the potential for a lower number of treatments required for a clinical response remain some of the most desirable effects of the use of high intensity laser light for treatment of psoriasis. Further investigations using more tolerable MEDs and larger patient sample sizes to focus on the duration and durability of the remission are currently ongoing. The EXTRAC laser option is available worldwide for treatment of resistant localized plaques of psoriasis. One limitation of the laser device is that its current spot size is only 3.2 cm2 so multiple doses would be required if a large surface area is to be treated at one setting. The application has been primarily used for treatment of a
Clinics in Dermatology
Y
2003;21:398 – 406
limited surface area where resistant plaques of psoriasis persist. The more recent advent of a device having a limited wavelength range than that of the fluorescent UVB tube has occurred through the efforts of the Lumenins company with development of a device called B CLEAR. This device also takes advantage of the action spectrum for treating psoriasis, such that it has a peak admission between 310 and 315 nm, although its range extends below 300 and above 320 nm. The light source for this device is a filamentous element that produces an incoherent source of UV light delivered through fiberoptics to a hand held mechanism for final delivery to the skin surface. However, because the spot size is approximately 16 mm in diameter, the B CLEAR device is used for localized treatment of limited plaques of psoriasis. As with a laser application of specific wavelengths of light in treating psoriasis, the delivery of this light to the skin is done in multiples of the minimal erythema dose, producing more redness and direct effect at the targeted site. Both of these systems have the added benefit of limiting skin exposure to UV light, as compared to whole body irradiance in a booth or by a panel of fluorescent lamps. Larger, longer term reports regarding the use devices such as the EXTRAC laser and the B CLEAR system or modifications for their delivery are currently underway.
Ultraviolet A-1 (UVA-1) The UVA-1 region (340 to 400 nm) of the UV spectrum is less likely to promote a sunburn reaction. Photons of light contained within this region have less energy and are less likely to be absorbed by DNA than UVB wavelengths. Formation of thymidine dimers and resultant long-term alteration of DNA replication are less likely to occur. Understanding some of the benefits of this longer wave ultraviolet light, as compared to the more high energy UVB, is important. One significant benefit is deeper penetration of UVA light into the dermis, especially the longer wave UVA-1 region, thereby enabling the longer wavelengths to reach further into the skin for its site of action. In contrast, UVB is primarily absorbed in the epidermis with a very small percentage of UVB light penetrating into the upper reticular dermis. Its primary action is therefore on epidermal cells whether keratinacytes or mediators of inflammation such as lymphocytes or antigen-presenting cells.20 UVA-1 as compared to UVB, penetrates deeper into the dermis because of shifting of the main chromophore for this longer wavelength to the absorption spectrum of proteins, rather than DNA.20 Knowledge of this theoretical benefit led to further experimentation into the use of UVA-1 as a therapeutic modality. In particular, the two main categories of in-
THE PARADIGM OF PHOTOTHERAPY
403
vestigation, especially in the early reports, focused on treatment of atopic dermatitis and connective tissue disease.21 Over this past decade since the demonstration of the efficacy of UVA-1 for treatment of atopic dermatitis in particular, there has been more interest in the possible mechanisms of action for this modality, especially since it was previously thought to be fairly innocuous, low-energy light. For example, observation by light microscopy of treated skin with atopic dermatitis shows apoptosis of T cells deeper in the middermis when UVA-1 therapy has been used. These findings help generate a direction concerning the underlying mechanisms for UVA-1 treatment.22 These investigations demonstrated evidence of singlet oxygen-induced human T helper cell apoptosis as a basic mechanism of UVA radiation phototherapy. Understanding the basic mechanisms and applications of known effects in skin is necessary to thoughtfully apply new modalities of treatment. The fact that high doses of UVA-1 have beneficial effects on atopic dermatitis is clear; however, identifying the mechanism of action can make it possible to apply a modality of treatment to other diseases in a more selective manner rather than just relying on just trial and error. Because high-dose UVA-1 therapy requires a specialized delivery system, its use internationally has remained limited. The initial methods for therapeutic delivery required 130 mj/cm2 UVA-1 radiation twice a week. This is produced by the UVASUN 30,000 BIOMED system, manufactured by Mutzhis in Munic, Germany. This device produces a very high irradiance and requires a special air-cooling system to prevent overheating of the subject being treated. Although relatively expensive as compared with routine UVB, narrow-band UVB, or PUVA phototherapy equipment, UVA-1 delivery systems are not necessarily expensive when compared with the cost of the majority of laser devices. More recent manufacture of a localized delivery system for UVA-1 has occurred with the availability of a UVA-1 unit by Daavlin Corporation for use in the United States. The application for UVA-1 therapy and investigations concerning its mechanism of action will continue to provide a basis for this ongoing development of therapeutic ultraviolet light treatments. It will be interesting to see whether other diseases previously resistant to treatment with systemic agents or phototherapy, such as resistant hand dermatitis, scleroderma, or other connective tissue diseases, can and will be treated with the developing new methods of UVA-1 therapy.
Specialized Use of Visible Light Phototherapy for Treatment of Inflammatory Acne Nontraditional application of ultraviolet light therapy is entering into the main stream of therapy for diseases
404 ZANOLLI
such as acne vulgaris. It is a common observation that acne tends to improve in the summer. There was speculation as to why this occurs. The observation that the primary bacteria of acne (proprionibacterium acnes) has a fluorescence within the visible light region and may be susceptible to different wavelengths of light was made in the late 1990s. The application of both blue wavelengths of light at 415 nm and red wavelengths of light at 660 nm for the treatment of acne was done in a study of over 100 patients.23 The treatment was done with twice-a-week therapy with a combination of the two light sources and compared with benzoyl peroxide. Visible light therapy was a superior treatment with no significant short term adverse effects. Additional investigation into this line of therapy was done using a higher intensity but only a single region of light around the blue region (415 nm). This investigation reported a 64% reduction in the severity of acne with twice a week therapy for five weeks.24 A devise is available in the United States and approved for treatment of acne vulgaris using blue light with a peak emission at 415 nm. The equipment is manufactured by Lumenis and has been demonstrated as a useful adjunctive therapy for inflammatory acne. This is an example of application of phototherapy with a known specific mechanism based on known characteristics of proprionibacterium acne. Both studies report the presence of staphylococcal bacteria which was not irradicated by the use of this ultraviolet light. This new application of therapeutic light in the visible range penetrates deeper into the dermis to reach its site of action. It has minimal potential for photochemical reactions of collagen or other structural chromophores in the skin.
Photodynamic Therapy The concept of using an exogenous chemical followed by delivery of energy in the form of light is not new to dermatologists. Photochemotherapy with PUVA is the best example in our discipline. Photodynamic therapy can be used with a systemic delivery of an exogenous photosensitizer or by topical application of a molecule to produce accumulation of porphyrins in the skin. Advancement of topical photodynamic therapy has occurred since its demonstrated practical use in 1990 using aminolevulonic acid (ALA) as the photosensitizer.25 Currently, topical PDT has been brought to the level of office based treatment. The only approved indication for use of topical PDT in North America is actinic keratosis. However, reports of efficacy in non melanoma cutaneous malignancies exist,26-28 as well as a review of this application in skin conditions other than malignancies.29 Systemic administration of photosenitizers has been used primarily for treatment of solid tumors such as
Clinics in Dermatology
Y
2003;21:398 – 406
gastrointestinal and bronchopulmonary malignancies.30 Previously, Photofrin II has been used as the primary porphyrin for systemic administration. The major disadvantage of this type of delivery system is the long duration of skin photosensitivity following administration of Photofrin II systemically. This can be as long as 2 to 3 weeks in some cases. Systemically administered 5-ALA is not tolerated well by subjects due to gastrointestinal effects. In addition, an increase in hepatic amino transferases and prolonged photosensitivity occurs. More recent interest in systemically administered porphyrin derivatives relate to use of Verteporfin which has a shorter half life and thus a much shorter duration of photosensitivity.31 The use of 5-ALA has facilitated the development of topical PDT. ALA applied topically is metabolized by epidermal cells into protoporphyrin IX (PpIX), which is a molecule sensitive to a broad range of light starting at the Soret band (around 400 nm), at 415 nm, and through the red region of the visible spectrum. The photochemical reaction between PpIX and absorbed photons produces singlet oxygen along with other reactive oxygen species and free radicals. The direct effects of these oxidative molecules causes localized membrane damage to cellular and mitochondrial membranes. An advantage of topical PDT is the preferential accumulation of PpIX in skin tumors helping to localize its effects.32 Another advantage is the rapid loss of photosensitivity within 24 hours.33 Topical application of 5-ALA up to 0.2 g/cm2 does not lead to measurable blood levels of 5-ALA in serum.34 The accumulation of 5-ALA in diseased skin is thought to be multifactorial. Localized areas of accumulation of the effects of 5-ALA can be identified by fluorescence clearly evident within areas of actinic keratosis and tumors. The factors of altered stratum corneum and porphyrin levels in tumors most likely contribute to the increased uptake.35 Porphyrins absorb light in the visible wavelength range, and multiple devices can be used for delivery of the photons of energy. The basic principles for this aspect of therapy relate to use of a wavelength providing the best penetration of the skin appropriate for the location of disease or tumor to be treated. For example, actinic keratosis occur in the epidermis, while nodular basal cell carcinomas would be both in the epidermis and dermis. A shorter wavelength of light may be more appropriate for actinic keratosis to help limit potential for deeper dermal side effects. In contrast, a longer wavelenght of light would be more desirable for the dermal component of a nodular basal cell carcinoma. Only direct clinical trials are able to answer this question appropriately. The development of the approved methods for treatment of actinic keratosis with topical photodynamic therapy has resulted in the Luvulan® PDT process. The elements of this step-wise treatment are:
Clinics in Dermatology
Y
2003;21:398 – 406
1. Application of a 20% ALA solution to actinic keratosis using a topical applicator (Kerastick™) 2. The patient returns the following day for delivery of the light dose. 3. The specialized light source emits light at a peak emission at 415 nm. The duration of the light treatment is 15 minutes. Aspects of treatment which reinforce the principles of PDT threapy are the selection of the photosensitizer and the wavelength of the light. The selection of the blue light near the Soret band is efficacious for a photochemical reaction with PpIX. The rational use of the shorter wavelength was due to the superficial nature of the actinic keratosis. The most common side effect is a smarting reaction at the time of the treatment which is usually mild and tolerated by the patient. Although, occasionally the treatments must be interrupted to provide analgesia for the patient. The benefit is the one time treatment procedure and multiple lesions being treated simultaneously. Further development and refinement of PDT for multiple applications in dermatology will occur in the years ahead. Variations in the active molecule used to promote increased levels of a photosensitive chromophore in the target site of the skin together with comparison trials vs. conventional therapy will help define increased clinical advantages of PDT.
Conclusions Phototherapy has been used for decades as an effective treatment of skin disorders. Its use continues today and is one of the safest approaches to help modify the cutaneous immune system. Overuse of this modality, especially when an exogenous photosensitiser is used, does have greater risk for side effects. As with other therapies, appropriate use and rotation of therapy when the limit of safe treatment approaches is part of the expertise a dermatologist has when considering the available treatment options. Today, a new paradigm is available when considering the application of the various forms of phototherapy. Significant improvements have been realized by delivery of UVB in the narrow-band range, which is most effective for diminishing the effects of T lymphocytes and antigen-presenting cells. In addition, the direct introduction of a molecule like 5-ALA can be used to target specific tumor cells. These are just a few examples that demonstrate how we can use phototherapy in a more focused, effective manner. The insight of known mechanisms of actions and observable photochemical reactions helps us to better use phototherapy without the added risk of potent immunosuppression of the systemic immune system. The decades ahead will allow more precise use of photodynamic therapy for
THE PARADIGM OF PHOTOTHERAPY
405
cutaneous malignancies and reveal the best combinations of the new biologic therapies with either full body or localized delivery of narrow band UVB to best help our patients.
References 1. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220:524 –7. 2. Fisher T. UV light treatment of psoriasis. Acta Derm Venereol 1976;56:473–9. 3. Parrish JA, Jaenicke KF, Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981;76:359 –62. 4. Walters IB, Burack LH, Coven TR, et al. Suberythemogenic narrow band UVB is markedly more effective than conventional UVB treatment of psoriasis vulgaris. J Am Acad Dermatol 1999;40:893–900. 5. Ozawa M, Ferenczi K, Kikuchi T, et al. 312 nm UV induces apoptosis of T cells. J Exp Med 1999;189:711–8. 6. Hofer A, Fink–Puches R, Kerl H, et al. Comparison of phototherapy with near vs. far erythemogenic doses of narrow-band ultraviolet B in patients with psoriasis. Br J Dermatol 1998;138:96 –100. 7. Duthie MS, Kimber I, Norval M. The effects of ultraviolet radiation on the human immune system. Br J Dermatol 1999;140:995–1009. 8. Parrish JA, Fitzpatrick TB, Tanenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med, 1974;291:1207–11. 9. Tanew A, Ortel B, Rappersberger K, et al. 5-methoxypsoralen for photochemotherapy. J Am Acad Dermatol 1988; 18:333–8. 10. Photochemotherapy Follow Up Study Group, Stern RS, Laird N. The carcinogenic risks of treatments for severe psoriasis. Cancer 1994;73:2759 –64. 11. Stern RS, Nichols KP, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997;336:1041–5. 12. Cristofolini M, Recchia G, Goie S, et al. 6-Methylangelicins: new monofunctional photochemotherapeuitc agents for psoriasis. Br J Dermatol 1990;122:513–24. 13. Green C, Ferguson J, Lakshmipathi T, Johnson BE. 311Nm. UVB phototherapy—an effective treatment for psoriasis. Br J Dermatol 1988;119:691–696. 14. Larko O. Treatment of psoriasis with new UVB lamp. Acta Derm Venereol 1989;69:357–9. 15. Tanew A, Radakovic–Fijan S, Schemper M, et al. Narrow band UVB phototherapy versus photochemotherapy in the treatment of chronic plaque psoriasis. Arch Dermatol 1999;135:519 –24. 16. Dawes RS, Wainwright NJ, Cameron H, Ferguson J. Narrowband ultraviolet B phototherapy for chronic plaque psoriasis: three times or five times weekly treatment? Br J Dermatol 1998;138:833–9. 17. Asawanonda P, Anderson RR, Chang Y, Taylor CR. 308 nm excimer laser for the treatment of psoriasis: a doseresponse study. Arch Dermatol 2000;136:619 –24. 18. Trehan M, Taylor CR. High-dose 308 nm laser for the treatment of psoriasis. J Am Acad Dermatol 2002;46:732–7.
406 ZANOLLI
19. Feldman SR, Mellen BG, Housman TS, et al. Efficacy of the 308 nm excimer laser for treatment of psoriasis: results of a multicenter study. J Am Acad Dermatol 2002;46: 900 –6. 20. Anderson RR, Parish JA. The optics of even skin. J Invest Dermatol 1981;77:13–9. 21. Krutmann J, Cjeck W, Diepgen T, et al. High-dose UVA-1 therapy in the treatment of patients with atopic dermatitis. J Am Acad Dermatol 1992;26:225–30. 22. Morita A, Werfel P, Stege H, et al. J Exp Med. 1997;186: 1763–8. 23. Papgeorgiou P, Katsambas A, Chu A. Phototherapy with blue 415 nm and red 660 nm light in the treatment of acne vulgaris. British J Dermatol 2000;142:973–8. 24. Kawada A, Aragane Y, Kameyama H, et al. Acne phototherapy with a high intensity enhanced narrowband blue light source: an open study and in vitro investigation. J Dermatol 2002;30:129 –35. 25. Kennedy JC, Puttier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol 1990;6:143–8. 26. Morton CA, Mackie RM, Whitehurst C, et al. Photodynamic therapy for basal cell carcinoma: effects of tumor thickness and duration of photosensitizer application on response. Arch Dermatol 1998;134:248 –9.
Clinics in Dermatology
Y
2003;21:398 – 406
27. Morton CA, Whitehurst C, Moseley H, et al. Comparison of photodynamic therapy with cryotherapy in the treatmen of Bowen’s disease. Br J Dermatol 1996;135:766 –71. 28. Fritsch C. Goerz G, Ruzicka T. Photodynamic therapy in dermatology. Arch Dermatol 1998;134:207–14. 29. Ibbotson SH. Topical 5 amino levulonic acid photodynamic therapy for the treatment of skin conditions other than non melanoma skin cancers. Br J Dermatol 2002;146: 178 –88. 30. Pass HI. Photodynamic therapy in oncology: mechanisms and clinical use. J Natl Cancer Inst 1993;85:443–56. 31. Houle JM, Strong HA. Duration of skin photosensitivity and incidence of photosensitivity reactions after administration of verteporfin. Retina 2002;22:691–97. 32. Dougherty TJ. Photosensitizers: therapy and detection of malignant tumors. Photochem Photobiol 1987;45:879 –89. 33. Divaris D, Kennedy JC, Pottier RH. Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5 ALA correlates with localized protoporphyrin IX fluorescence. Am J Pathol 1990;136:891–7. 34. Fritsch C, Verwohlt B, Bolsen K, et al. Influence of topical photosynamic therapy with 5ALA on porphyrin metabolism. Arch Dermatol Res 1996;288:517–21. 35. Peng Q, Berg K, Moon J, et al. 5ALA acid-based photodynamic therapy: principles and experimental research. Photochem Photobiol 1997;65:235–51.
P
hototherapy has been used for centuries to treat numerous skin disorders. Most of the insight into the therapeutic benefit of phototherapy gained in previous centuries was related to the observed effects of natural sunlight. Still today, certain areas of the world, such as the Dead Sea, have unique geographic locations recognized as providing effective sites for climatotherapy for psoriasis. Numerous other inflammatory skin diseases, such as atopic dermatitis, and pigment disorders, like vitiligo, benefit from ultraviolet light treatment. Recent advances in the understanding of phototherapy and, more importantly, the application of phototherapy and its specific effects on the cutaneous immune system, have resulted in a renewed interest in the application of ultraviolet (UV) light in dermatology. The development of artificial sources utilizing ultraviolet light for medical purposes began at the beginning of the 20th century. Niels Finsen was awarded the Nobel Prize in 1903 for using ultraviolet light as treatment for a skin disease. He was treating cutaneous mycobacterial infection of the skin with focused delivery of ultraviolet light. Further developments in the 20th century relate to the use of Ultraviolet B (UVB) therapy, primarily for psoriasis, in the mid part of the century. For example, Goeckerman treatment consisting of ultraviolet light in the B region combined with crude coal tar was one of the mainstays of therapy for moderate to severe psoriasis in the United States. In fact, the therapeutic response and duration of remission for this treatment for psoriasis still comprise one of the standards against which new therapies are measured; however, the long-term hospital admissions of 2 to 3 weeks and the many hours of special wrappings on the skin required by the treatment make this procedure very time-consuming, demanding, and expensive to deliver appropriately. Likewise, the Ingram method, From the Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee. Address correspondence to Michael Zanolli, MD, Dermatology Consultants PC, Suite 609 East, 4230 Harding Road, Nashville TN 37205. E-mail address: [email protected]. © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
which uses short-term contact anthralin in combination with ultraviolet B therapy, has also proven to be a very effective treatment for psoriasis, but again requires specialized nursing facilities and day-long care or hospitalization. A more recent change in the paradigm for phototherapy use emerged in the second half of the 20th century from the recognition and implementation of photochemotherapy for treatment of skin diseases. The combination of a photon-absorbing chemical delivered in a systemic manner, followed by delivery of ultraviolet light to the skin, was observed to promote clearing of psoriasis in a high percentage of patients. It is through just such discoveries by keen observation that fundamental change and advancement in a discipline can occur. The paradigm of using ultraviolet light in combination with an endogenous or exogenous chemical to promote a photochemical reaction changed the entire approach for the concept of photochemotherapy and photodynamic therapy. In North America, the leaders in the development of photochemotherapy were Drs. Fitzpatrick and Parish. Their observations of the effects of photochemotherapy on vitiligo and subsequently the notable improvement in psoriasis on the skin of a patient undergoing photochemotherapy led to the further development and application of PUVA treatments. PUVA is one of the best examples of advancement of dermatologic therapy in the last quarter of the 20th century.
Laser Therapy The application of coherent light with the development of laser therapy for medical purposes has made a special impact in dermatology. In the broad sense, this field should be considered an aspect of phototherapy because various wavelengths of electromagnetic spectrum are employed with laser light. Laser therapy, however, is now its own discipline. Lasers are used to treat a variety of problems, such as inhibiting disease processes and altering specific skin structures. Laser ther0738-081X/03/$–see front matter doi:10.1016/j.clindermatol.2003.08.005
Clinics in Dermatology
Y
2003;21:398 – 406
apy has many applications in dermatology that are beyond the scope of this discussion of the use of therapeutic phototherapy. What is important and central to the advancement of phototherapy is the creative approach of fashioning and employing certain wavelengths of laser light to very specific actions and reactions in skin. This is exemplified by the concept of selected photothermolysis promoted by Dr. Rox Anderson.1 Lasers are being developed for their selected effects on specific chromophores in the skin based on the absorption spectrum of molecules in the protein or structures. The targeted action of the laser coupled with a very short duration of energy delivered would help decrease injury to surrounding structures. Application of this concept led to the manufacture of vascular lasers, which effectively treat dermal blood vessels without scarring the skin surface. This was another advancement within the past 20 years that utilized photobiologic and photochemical reactions to effect a change in the pathogenesis and/or normal pathophysiology of a specific biologic or anatomic condition. The development of selected photothermolysis has led to the use of lasers that specifically target hemoglobin as well as pigment, such as melanin, or tattoos and other foreign pigment in the skin. In addition, collagen itself can be made a potential target in an effort to alter and disrupt it so that regeneration of collagen in the superficial dermis will occur. This field is growing and maturing with better designed studies to demonstrate effects of laser light. Rather than trying to discuss application of lasers for cosmetic purposes and/or for selective photothermolysis of benign vascular malformations, I will limit further discussion of the application of laser light to the ultraviolet region of the electromagnetic spectrum and as it applies to the treatment of disease. The principles and standards established by the paradigm shift in the last 20 years, involving selection of a wavelength of light in the UV, visible, or infrared region to effect specific actions in the skin, provide the foundation for further modern advances in phototherapy. Thus, it was not a new discovery that has led to the application of better ultraviolet light therapy for inflammatory diseases. Rather, it was the availability of previous information derived from experiments done in the mid 1970s and early 1980s that provides the basis for the modern use of ultraviolet B light in applications for inflammatory skin diseases mediated by T lymphocytes. Determining the action spectrum for psoriasis provides a means to select the best wavelength of UV light to treat that disease. In 1976, Dr. Turkel Fisher performed a series of experiments using a limited number of individual discontinuous wavelengths of light on plaques of psoriasis.2 Dr. Fisher’s findings indicated a
THE PARADIGM OF PHOTOTHERAPY
399
wavelength of 313 nm was more effective for clearing of psoriasis than other wavelengths within the UVB region and some wavelengths in the UVA region. This work is very important in determining the action spectrum for psoriasis. Building on this information, Dr. John Parish conducted research that provided a more extensive array of wavelengths, including UVC, UVB, and UVA, to help delineate those wavelengths most effective in treating psoriasis.3 This work confirmed the findings previously reported by Dr. Fisher and helped demonstrate the most effective wavelengths for treating psoriasis, which exist somewhere between the range of 310 and 315 nm. There are beneficial therapeutic effects on plaques of psoriasis from other wavelengths, although not to the same degree. It is important to note that wavelengths in the UVC region can also clear psoriasis; however, because these wavelengths are much more likely in low dose to produce an erythema response, they were not tolerated well by the subjects. Although this information has been available since the early 1980s, it was not really applied in the use of conventional phototherapy because the fluorescent tubes designed for delivery of this wavelength were not yet being manufactured. Accordingly, there was an appreciable delay in the further development of narrow-band UVB for treatment of psoriasis. That problem has now been overcome because the proper phosphor on the linings of ultraviolet lamps necessary for delivery of narrow-band UVB therapy is being manufactured and is available. The shift to narrow-band UVB that has occurred in Europe over the past 10 years, which is occurring in North America over the past 4 years, has focused on applying this important therapy for inflammatory skin disease. Modifications utilizing UVB with delivery systems for localized areas of the skin with peak emissions of UV light in the therapeutic region between 310 and 315 nm are now being advocated for a number of diseases. Another area within phototherapy that is undergoing a transformation involves application of the longer wavelengths of light within the UVA region. The region of UVA is now subdivided into UVA-1 (340-400 nm) and UVA-2 (320-340 nm.). Specialized devices with high output delivery of UVA-1 have had an important impact on selective diseases within the field of dermatology. The physics and interaction of skin with wavelengths of light permit these longer wavelengths to have deeper penetration into the dermis, which otherwise would not be reached by UVB wavelengths. Further discussion of UVA-1 and its potential impact on the use of ultraviolet light therapy in the decades ahead will receive special consideration.
400 ZANOLLI
Clinics in Dermatology
Mechanisms
the primary effects of therapeutic ultraviolet light intervention in skin diseases to be an immune modifying treatment. This very significant review helps put into perspective the multitude of effects on the cutaneous immune system that have been reported. The effects of ultraviolet light outlined fall into two main categories and include direct effects through injury to certain cell types, as well as indirect effects through production of other chemicals that might help shift a balance of cytokine production. The acute effects relate to direct damage to membranes or induction of cytoplasmic transcription factors, DNA damage, and isomerization of urocanic acid. The second major category, subacute changes, relate to alteration of the presentation and processing of antigenic stimulation through antigen-presenting cells and T cells. The majority of information about these effects refers to known effects of ultraviolet light on Langerhans’s cells with observed altered function of Langerhans cells. The changes occurred despite the presence of the cells, which were not induced to undergo apoptosis.
Many biologic effects of ultraviolet light, visible light, and wavelengths of laser light that extend into the infrared are observable. This does not necessarily mean, however, that the mechanism mediating the therapeutic effect has been sufficiently defined. The first principle of photochemistry is that only absorbed light can cause a photochemical change. The perspective of the new paradigm requires identifying the target of the photobiologic effect of phototherapy. The main areas of phototherapy that have briefly been introduced in the first section are UVB therapy, photochemotherapy (including photodynamic therapy), UVA-1 therapy, and therapeutic interventions with various wavelengths of laser light. These different therapeutic alternatives may have some mechanisms in common, such as the production of oxidants in the skin and in the mitochondrial membranes. However, there are differences in the chromophores, the targets for the photons of energy contained in each of these different therapeutic modalities. There has been an increase in the understanding of the effects of UVB therapy over the past 10 to 15 years. In the past, it was clear that UVB therapy helped clear psoriasis, with the majority of patients having a good to excellent therapeutic response. More recently, with the existence of better markers for cells, such as T cells and antigen-presenting cells in the epidermis, the effects of UVB light have been more clearly defined. This is especially true for narrow-band UVB therapy. Observed effects of narrow-band UVB therapy and how it influences T lymphocytes in the skin have been reported by numerous authors. In North America, the clinical trials that help define the therapeutic efficacy of narrow-band UVB as compared to broad-band UVB and PUVA demonstrate the effect of narrow-band UVB on T cells and antigen-presenting cells in the epidermis and superficial dermis.4 T lymphocyte and antigenpresenting cells appear to be more susceptible to the effects of UVB therapy than do keratinocytes. Loss of cell markers and preferential apoptosis occurs at lower doses than are necessary to cause the same effect in keratinocytes.5 Previously, one of the major mechanisms to identify effects of ultraviolet light therapy on cell types was that used to identify apoptosis through light microscopy studies; however, lower doses of ultraviolet light may be also effective in treating psoriasis, and it is clear that one does not have to use erythemogenic doses of narrow-band UVB therapy to produce the same grade or better clearing than with erythemogenic doses of UVB.6 A review with further insight into mechanisms of ultraviolet light in skin has helped clarify some of the many effects that have been observed.7 This is especially important for understanding the effects on the human immune system and thereby recognizing one of
Y
2003;21:398 – 406
Photochemotherapy Photochemotherapy remains one of the most effective forms of phototherapy for treatment of psoriasis and many other skin disorders. The combination of a psoralen molecule and ultraviolet light has been given the eponym PUVA. In the context of photochemotherapy, the use of topically applied, naturally occurring compounds with natural sunlight has been known for centuries to produce both therapeutic and phototoxic reactions. The Egyptians used topical psoralen and molecules for treatment of pigmentary disorders. It was not until the modern use of photochemotherapy with specific psoralen molecules, such as 8 methoxypsoralen, that the true potential for this modality of therapy was realized. El Mofty is credited with the first modern medical use of photochemotherapy, using it not just as extracts but as a molecule applied topically. Further development of systemic photochemotherapy occurred when ingestion of psoralen, initially used to treat vitiligo, was found to have profound effects on psoriasis.8 Ever since the early 1970s, photochemotherapy has been a demonstrably effective treatment for psoriasis, with more than 80% of individuals expected to obtain good to excellent results. Another significant feature of this form of therapy is that the duration of remissions following treatment typically extends months rather than weeks as with standard broadband UVB therapy. An additional benefit of the use of PUVA is its effectiveness in dark-skinned as well as lighter-skinned individuals. This benefit contrasts with the traditional broadband UVB therapy, which is not as effective in darker-skinned individuals such as those from African
Clinics in Dermatology
Y
2003;21:398 – 406
decent. Dermatologists can use PUVA in many other dermatologic disorders with good results.
Newer Developments in Photochemotherapy The application of different psoralen molecules with potentially fewer acute side effects has been one of the most recent advancements in photochemotherapy. 5 Methoxypsoralen (5 MOP) is the compound that has been utilized more in European countries. It is a naturally occurring psoralen that can be ingested. One of the most frequent complaints with PUVA therapy has been with acute gastrointestinal side effect, which can be a cause for patients’ discontinuation of therapy in certain cases. Significantly, 5 MOP has fewer acute gastrointestinal side effects such as nausea and vomiting, than does 8 MOP. 5 MOP has been shown to be effective in clinical trials, although a slightly higher dose is needed for efficacy.9 Oral ingestion of 1.2 to 1.6 mg per kg is needed for the same efficacy as has been obtained with 8 MOP. The absorption through the gastrointestinal tract occurs at approximately the same rate such that the timing of the UVA delivery with 5 MOP is within 1 to 1.5 hours after ingestion. Psoralens are ingested very readily from the gastrointestinal tract, and after absorption in the proximal small bowel, direct transport to the liver by the hepatic venus circulation occurs. The psoralens demonstrate a saturable first pass effect in the liver, which causes a rapid rise in blood levels once the capacity for liver metablism of the molecule has been saturated. As a result, the delivery of psoralens must be consistent with regards to the dose, the food ingested with psoralen, and the timing before the delivery of UV light. Alterations in one of these three variables may result in more of a phototoxic reaction because of variability in the blood levels of the psoralen at the time of UV light delivery. Further advancement in treatments using different psoralen molecules should strive to decrease the possibility of long-term side effects. The most important long-term side effect demonstrated with the use of PUVA therapy has been the development of cutaneous malignancies, which occurred after cumulative highdose therapy extended over time. For example, patients having had more than 200 PUVA treatments are at increased risk for developing squamous cell carcinomas. This is especially an important consideration with regard to the areas of male genitalia, which is more prone to having squamous cell carcinoma in relation to PUVA therapy.10 This effect from PUVA seems to be due to a cumulative dose. There is an induction period for the development of squamous cell carcinomas, which appears to be 10-15 years. Evidence reported from the North American cohort of PUVA patients followed over the past 25 years dem-
THE PARADIGM OF PHOTOTHERAPY
401
onstrates an increased frequency of development of melanoma in certain groups.11 It is important that patients having a Type I Fitzpatrick or Type II Fitzpatrick response to ultraviolet light not receive excessive exposures to photochemotherapy. In addition to patients with Type I or Type II skin being at increased risk, patients who have received greater than 200 PUVA treatment are also likely to have an increased chance of developing melanoma. Finally, patients who have received a high number of treatments and experienced a 15- to 20-year latency period should be followed because of a possible increased incidence of melanoma. A component of the theoretic basis for such incidence of squamous cell carcinoma in the high-dose group of PUVA patients are the photobiologic effects of PUVA on DNA. Psoralen molecules can enter the nucleus of cells and intercalate between DNA base pairs. With absorption of a photon of light, a covalent bond is formed with adjacent pyrimidine bases, producing a cyclobutane ring. If a second photon of light is absorbed by the psoralen molecule when it already has had formation of a cyclobutane ring, a DNA cross-link is formed across the strands of DNA base pairs. Theoretically, this is the prime basis for repetitive errors in DNA and plays a role in formation of squamous cell carcinoma. The influence of the direct DNA damage in the pathogenesis of malignancy may be either a direct effect on the keratinocytes or indirect through abnormalities in the altered immunologic surveillance of the skin. One of the directions for continued refinement of photochemotherapy in the future, as well as one of the new paradigms associated with photochemotherapy itself, is development of other psoralen molecules that do not form bifunctional adducts, which provide a basis for the DNA cross-linking. One such class of psoralens is the methylangelicins.12 This type of psoralen only forms monofunctional adducts, and although long-term studies are needed, there is clearly a theoretical basis that monofunctional adducts would be less likely to promote cutaneous malignancies as compared to bifunctional adducts.
Narrow-band UVB The introduction of narrow-band UVB was made possible through the development of the proper fluorescent tubes that can deliver UVB therapy in a conventional manner. The initial studies demonstrating the efficacy of narrow-band UVB therapy for treatment of psoriasis were done by colleagues in Europe.13,14 Additional studies have been done over the past decade, which demonstrate the comparative efficacy of broad-band UVB and narrow-band UVB therapies as well as NBUVB and PUVA. North American studies demon-
402 ZANOLLI
strating the superiority of narrow-band UVB over conventional UVB have also been completed.4 When compared with PUVA therapy, narrow-band UVB treatments are not quite as effective in clearing psoriasis, although the improvement scores are very similar. The most marked difference between narrowband UVB and PUVA therapy lies in the duration of remission once good to excellent clearing is obtained, which occurs in more than 70% of individuals.15 Studies investigating the possible mechanism of actions of narrow-band UVB have demonstrated apoptosis of T cells in the epidermis and superficial dermis without apparent keratinocyte alteration.5 The availability of narrow-band UVB is finally increasing in North America. Our European colleagues have had the availability of narrow-band UVB fluorescent tubes for the past 10 years, and in Europe, it has become the treatment of choice within the UVB spectrum (personal communication). Because of its effectiveness in treating psoriasis, narrow-band UVB therapy is now gaining much more acceptance and is more frequently used in North America. The standardized protocols and methodologies used in the Unted States and Europe appear to be similar. However, the initial dose of narrow-band UVB continues to be variable from one center relative to another. The most accurate starting dose of narrow-band UVB is between 50% and 75% of the measured minimal erythema dose (MED). An important feature of treatment is the accurate detemination of the MED due to the marked variation in response to this narrow wavelength. To evaluate this accurately and determine the initial treatment dose, effort should be taken to obtain the MED. Protocols are available with the starting point estimated by skin type, but the range of the dose within each skin type varies. Without the MED, the initial treatments may greatly underestimate the more effective doses needed to advance treatments in the early stages of therapy. Significantly, advancement of therapy can easily occur by increasing the dose by 10% to 20% of the MED each treatment, with a treatment frequency of three times a week.6,16 As with broad-band UVB therapy, narrow-band UVB therapy is not limited to use of psoriasis itself. Numerous applications of this modality of therapy have been used in atopic dermatitis, vitiligo, cutaneous T cell lymphoma, lichen planus, pruritus, and as a preventative treatment for photodermatoses.
Variations in UVB, Including Excimer Laser and Delivery of Localized UVB Successful application of narrow-band UVB in treating psoriasis has renewed interest in UVB treatment for inflammatory dermatosis. Newer variations in delivery of UVB may be helpful for treatment of psoriasis and
Clinics in Dermatology
Y
2003;21:398 – 406
other phototherapy responsive dermatosis. Current development of delivery systems for localized light is being refined due to the insight into the more pronounced effects of 310 to 315 nm UV light on activated T cells and antigen-presenting cells in the epidermis and superficial dermis. The two main variations in traditional UVB and even in narrow-band UVB are the application of 308 nm laser light in the form of the EXTRAC laser and a localized delivery system for a light source with a broad region of UVB emission. Both of these devices have been approved for use in treating psoriasis and have applications for the diseases traditionally treated with UVB phototherapy such as vitiligo. There are ongoing investigations that will provide further conformation on their efficacy and other aspects of treatment. The use of laser light at 308 nm for treatment of psoriasis has been under investigation for the past 6 years. An early report regarding a limited number of patients indicated that use of high energy laser light at multiples of the minimal erythema doses produces a phototoxic reaction locally.17. This report showed clearing of areas within larger plaques of psoriasis where the laser light was delivered. Although the reaction at the site provoked a marked amount of redness, at times blistering, after the initial healing of this superficial phototoxic reaction, there was persistence of normal skin for many weeks. This result promoted additional investigation into the use of this laser device for localized plaques of psoriasis.18 The methods used very high multiples of the minimal erythema dose and produced clearing of the psoriasis with a very low number of treatments. Because the initial reports were enthusiastically received, a larger size study was done on a very limited area of psoriasis at minimal erythema doses within the 4 to 6 MED range. Patients’ own self assessment of the approach to treatment was very positive.19 In this study, standardization of the protocols and the delivery of the ultraviolet light matured with treatments at twice a week using the lower MEDs for 10 weeks. A good to excellent response in 70% of the subjects was reported in this multicenter trial. The duration of remission and the potential for a lower number of treatments required for a clinical response remain some of the most desirable effects of the use of high intensity laser light for treatment of psoriasis. Further investigations using more tolerable MEDs and larger patient sample sizes to focus on the duration and durability of the remission are currently ongoing. The EXTRAC laser option is available worldwide for treatment of resistant localized plaques of psoriasis. One limitation of the laser device is that its current spot size is only 3.2 cm2 so multiple doses would be required if a large surface area is to be treated at one setting. The application has been primarily used for treatment of a
Clinics in Dermatology
Y
2003;21:398 – 406
limited surface area where resistant plaques of psoriasis persist. The more recent advent of a device having a limited wavelength range than that of the fluorescent UVB tube has occurred through the efforts of the Lumenins company with development of a device called B CLEAR. This device also takes advantage of the action spectrum for treating psoriasis, such that it has a peak admission between 310 and 315 nm, although its range extends below 300 and above 320 nm. The light source for this device is a filamentous element that produces an incoherent source of UV light delivered through fiberoptics to a hand held mechanism for final delivery to the skin surface. However, because the spot size is approximately 16 mm in diameter, the B CLEAR device is used for localized treatment of limited plaques of psoriasis. As with a laser application of specific wavelengths of light in treating psoriasis, the delivery of this light to the skin is done in multiples of the minimal erythema dose, producing more redness and direct effect at the targeted site. Both of these systems have the added benefit of limiting skin exposure to UV light, as compared to whole body irradiance in a booth or by a panel of fluorescent lamps. Larger, longer term reports regarding the use devices such as the EXTRAC laser and the B CLEAR system or modifications for their delivery are currently underway.
Ultraviolet A-1 (UVA-1) The UVA-1 region (340 to 400 nm) of the UV spectrum is less likely to promote a sunburn reaction. Photons of light contained within this region have less energy and are less likely to be absorbed by DNA than UVB wavelengths. Formation of thymidine dimers and resultant long-term alteration of DNA replication are less likely to occur. Understanding some of the benefits of this longer wave ultraviolet light, as compared to the more high energy UVB, is important. One significant benefit is deeper penetration of UVA light into the dermis, especially the longer wave UVA-1 region, thereby enabling the longer wavelengths to reach further into the skin for its site of action. In contrast, UVB is primarily absorbed in the epidermis with a very small percentage of UVB light penetrating into the upper reticular dermis. Its primary action is therefore on epidermal cells whether keratinacytes or mediators of inflammation such as lymphocytes or antigen-presenting cells.20 UVA-1 as compared to UVB, penetrates deeper into the dermis because of shifting of the main chromophore for this longer wavelength to the absorption spectrum of proteins, rather than DNA.20 Knowledge of this theoretical benefit led to further experimentation into the use of UVA-1 as a therapeutic modality. In particular, the two main categories of in-
THE PARADIGM OF PHOTOTHERAPY
403
vestigation, especially in the early reports, focused on treatment of atopic dermatitis and connective tissue disease.21 Over this past decade since the demonstration of the efficacy of UVA-1 for treatment of atopic dermatitis in particular, there has been more interest in the possible mechanisms of action for this modality, especially since it was previously thought to be fairly innocuous, low-energy light. For example, observation by light microscopy of treated skin with atopic dermatitis shows apoptosis of T cells deeper in the middermis when UVA-1 therapy has been used. These findings help generate a direction concerning the underlying mechanisms for UVA-1 treatment.22 These investigations demonstrated evidence of singlet oxygen-induced human T helper cell apoptosis as a basic mechanism of UVA radiation phototherapy. Understanding the basic mechanisms and applications of known effects in skin is necessary to thoughtfully apply new modalities of treatment. The fact that high doses of UVA-1 have beneficial effects on atopic dermatitis is clear; however, identifying the mechanism of action can make it possible to apply a modality of treatment to other diseases in a more selective manner rather than just relying on just trial and error. Because high-dose UVA-1 therapy requires a specialized delivery system, its use internationally has remained limited. The initial methods for therapeutic delivery required 130 mj/cm2 UVA-1 radiation twice a week. This is produced by the UVASUN 30,000 BIOMED system, manufactured by Mutzhis in Munic, Germany. This device produces a very high irradiance and requires a special air-cooling system to prevent overheating of the subject being treated. Although relatively expensive as compared with routine UVB, narrow-band UVB, or PUVA phototherapy equipment, UVA-1 delivery systems are not necessarily expensive when compared with the cost of the majority of laser devices. More recent manufacture of a localized delivery system for UVA-1 has occurred with the availability of a UVA-1 unit by Daavlin Corporation for use in the United States. The application for UVA-1 therapy and investigations concerning its mechanism of action will continue to provide a basis for this ongoing development of therapeutic ultraviolet light treatments. It will be interesting to see whether other diseases previously resistant to treatment with systemic agents or phototherapy, such as resistant hand dermatitis, scleroderma, or other connective tissue diseases, can and will be treated with the developing new methods of UVA-1 therapy.
Specialized Use of Visible Light Phototherapy for Treatment of Inflammatory Acne Nontraditional application of ultraviolet light therapy is entering into the main stream of therapy for diseases
404 ZANOLLI
such as acne vulgaris. It is a common observation that acne tends to improve in the summer. There was speculation as to why this occurs. The observation that the primary bacteria of acne (proprionibacterium acnes) has a fluorescence within the visible light region and may be susceptible to different wavelengths of light was made in the late 1990s. The application of both blue wavelengths of light at 415 nm and red wavelengths of light at 660 nm for the treatment of acne was done in a study of over 100 patients.23 The treatment was done with twice-a-week therapy with a combination of the two light sources and compared with benzoyl peroxide. Visible light therapy was a superior treatment with no significant short term adverse effects. Additional investigation into this line of therapy was done using a higher intensity but only a single region of light around the blue region (415 nm). This investigation reported a 64% reduction in the severity of acne with twice a week therapy for five weeks.24 A devise is available in the United States and approved for treatment of acne vulgaris using blue light with a peak emission at 415 nm. The equipment is manufactured by Lumenis and has been demonstrated as a useful adjunctive therapy for inflammatory acne. This is an example of application of phototherapy with a known specific mechanism based on known characteristics of proprionibacterium acne. Both studies report the presence of staphylococcal bacteria which was not irradicated by the use of this ultraviolet light. This new application of therapeutic light in the visible range penetrates deeper into the dermis to reach its site of action. It has minimal potential for photochemical reactions of collagen or other structural chromophores in the skin.
Photodynamic Therapy The concept of using an exogenous chemical followed by delivery of energy in the form of light is not new to dermatologists. Photochemotherapy with PUVA is the best example in our discipline. Photodynamic therapy can be used with a systemic delivery of an exogenous photosensitizer or by topical application of a molecule to produce accumulation of porphyrins in the skin. Advancement of topical photodynamic therapy has occurred since its demonstrated practical use in 1990 using aminolevulonic acid (ALA) as the photosensitizer.25 Currently, topical PDT has been brought to the level of office based treatment. The only approved indication for use of topical PDT in North America is actinic keratosis. However, reports of efficacy in non melanoma cutaneous malignancies exist,26-28 as well as a review of this application in skin conditions other than malignancies.29 Systemic administration of photosenitizers has been used primarily for treatment of solid tumors such as
Clinics in Dermatology
Y
2003;21:398 – 406
gastrointestinal and bronchopulmonary malignancies.30 Previously, Photofrin II has been used as the primary porphyrin for systemic administration. The major disadvantage of this type of delivery system is the long duration of skin photosensitivity following administration of Photofrin II systemically. This can be as long as 2 to 3 weeks in some cases. Systemically administered 5-ALA is not tolerated well by subjects due to gastrointestinal effects. In addition, an increase in hepatic amino transferases and prolonged photosensitivity occurs. More recent interest in systemically administered porphyrin derivatives relate to use of Verteporfin which has a shorter half life and thus a much shorter duration of photosensitivity.31 The use of 5-ALA has facilitated the development of topical PDT. ALA applied topically is metabolized by epidermal cells into protoporphyrin IX (PpIX), which is a molecule sensitive to a broad range of light starting at the Soret band (around 400 nm), at 415 nm, and through the red region of the visible spectrum. The photochemical reaction between PpIX and absorbed photons produces singlet oxygen along with other reactive oxygen species and free radicals. The direct effects of these oxidative molecules causes localized membrane damage to cellular and mitochondrial membranes. An advantage of topical PDT is the preferential accumulation of PpIX in skin tumors helping to localize its effects.32 Another advantage is the rapid loss of photosensitivity within 24 hours.33 Topical application of 5-ALA up to 0.2 g/cm2 does not lead to measurable blood levels of 5-ALA in serum.34 The accumulation of 5-ALA in diseased skin is thought to be multifactorial. Localized areas of accumulation of the effects of 5-ALA can be identified by fluorescence clearly evident within areas of actinic keratosis and tumors. The factors of altered stratum corneum and porphyrin levels in tumors most likely contribute to the increased uptake.35 Porphyrins absorb light in the visible wavelength range, and multiple devices can be used for delivery of the photons of energy. The basic principles for this aspect of therapy relate to use of a wavelength providing the best penetration of the skin appropriate for the location of disease or tumor to be treated. For example, actinic keratosis occur in the epidermis, while nodular basal cell carcinomas would be both in the epidermis and dermis. A shorter wavelength of light may be more appropriate for actinic keratosis to help limit potential for deeper dermal side effects. In contrast, a longer wavelenght of light would be more desirable for the dermal component of a nodular basal cell carcinoma. Only direct clinical trials are able to answer this question appropriately. The development of the approved methods for treatment of actinic keratosis with topical photodynamic therapy has resulted in the Luvulan® PDT process. The elements of this step-wise treatment are:
Clinics in Dermatology
Y
2003;21:398 – 406
1. Application of a 20% ALA solution to actinic keratosis using a topical applicator (Kerastick™) 2. The patient returns the following day for delivery of the light dose. 3. The specialized light source emits light at a peak emission at 415 nm. The duration of the light treatment is 15 minutes. Aspects of treatment which reinforce the principles of PDT threapy are the selection of the photosensitizer and the wavelength of the light. The selection of the blue light near the Soret band is efficacious for a photochemical reaction with PpIX. The rational use of the shorter wavelength was due to the superficial nature of the actinic keratosis. The most common side effect is a smarting reaction at the time of the treatment which is usually mild and tolerated by the patient. Although, occasionally the treatments must be interrupted to provide analgesia for the patient. The benefit is the one time treatment procedure and multiple lesions being treated simultaneously. Further development and refinement of PDT for multiple applications in dermatology will occur in the years ahead. Variations in the active molecule used to promote increased levels of a photosensitive chromophore in the target site of the skin together with comparison trials vs. conventional therapy will help define increased clinical advantages of PDT.
Conclusions Phototherapy has been used for decades as an effective treatment of skin disorders. Its use continues today and is one of the safest approaches to help modify the cutaneous immune system. Overuse of this modality, especially when an exogenous photosensitiser is used, does have greater risk for side effects. As with other therapies, appropriate use and rotation of therapy when the limit of safe treatment approaches is part of the expertise a dermatologist has when considering the available treatment options. Today, a new paradigm is available when considering the application of the various forms of phototherapy. Significant improvements have been realized by delivery of UVB in the narrow-band range, which is most effective for diminishing the effects of T lymphocytes and antigen-presenting cells. In addition, the direct introduction of a molecule like 5-ALA can be used to target specific tumor cells. These are just a few examples that demonstrate how we can use phototherapy in a more focused, effective manner. The insight of known mechanisms of actions and observable photochemical reactions helps us to better use phototherapy without the added risk of potent immunosuppression of the systemic immune system. The decades ahead will allow more precise use of photodynamic therapy for
THE PARADIGM OF PHOTOTHERAPY
405
cutaneous malignancies and reveal the best combinations of the new biologic therapies with either full body or localized delivery of narrow band UVB to best help our patients.
References 1. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220:524 –7. 2. Fisher T. UV light treatment of psoriasis. Acta Derm Venereol 1976;56:473–9. 3. Parrish JA, Jaenicke KF, Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981;76:359 –62. 4. Walters IB, Burack LH, Coven TR, et al. Suberythemogenic narrow band UVB is markedly more effective than conventional UVB treatment of psoriasis vulgaris. J Am Acad Dermatol 1999;40:893–900. 5. Ozawa M, Ferenczi K, Kikuchi T, et al. 312 nm UV induces apoptosis of T cells. J Exp Med 1999;189:711–8. 6. Hofer A, Fink–Puches R, Kerl H, et al. Comparison of phototherapy with near vs. far erythemogenic doses of narrow-band ultraviolet B in patients with psoriasis. Br J Dermatol 1998;138:96 –100. 7. Duthie MS, Kimber I, Norval M. The effects of ultraviolet radiation on the human immune system. Br J Dermatol 1999;140:995–1009. 8. Parrish JA, Fitzpatrick TB, Tanenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med, 1974;291:1207–11. 9. Tanew A, Ortel B, Rappersberger K, et al. 5-methoxypsoralen for photochemotherapy. J Am Acad Dermatol 1988; 18:333–8. 10. Photochemotherapy Follow Up Study Group, Stern RS, Laird N. The carcinogenic risks of treatments for severe psoriasis. Cancer 1994;73:2759 –64. 11. Stern RS, Nichols KP, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997;336:1041–5. 12. Cristofolini M, Recchia G, Goie S, et al. 6-Methylangelicins: new monofunctional photochemotherapeuitc agents for psoriasis. Br J Dermatol 1990;122:513–24. 13. Green C, Ferguson J, Lakshmipathi T, Johnson BE. 311Nm. UVB phototherapy—an effective treatment for psoriasis. Br J Dermatol 1988;119:691–696. 14. Larko O. Treatment of psoriasis with new UVB lamp. Acta Derm Venereol 1989;69:357–9. 15. Tanew A, Radakovic–Fijan S, Schemper M, et al. Narrow band UVB phototherapy versus photochemotherapy in the treatment of chronic plaque psoriasis. Arch Dermatol 1999;135:519 –24. 16. Dawes RS, Wainwright NJ, Cameron H, Ferguson J. Narrowband ultraviolet B phototherapy for chronic plaque psoriasis: three times or five times weekly treatment? Br J Dermatol 1998;138:833–9. 17. Asawanonda P, Anderson RR, Chang Y, Taylor CR. 308 nm excimer laser for the treatment of psoriasis: a doseresponse study. Arch Dermatol 2000;136:619 –24. 18. Trehan M, Taylor CR. High-dose 308 nm laser for the treatment of psoriasis. J Am Acad Dermatol 2002;46:732–7.
406 ZANOLLI
19. Feldman SR, Mellen BG, Housman TS, et al. Efficacy of the 308 nm excimer laser for treatment of psoriasis: results of a multicenter study. J Am Acad Dermatol 2002;46: 900 –6. 20. Anderson RR, Parish JA. The optics of even skin. J Invest Dermatol 1981;77:13–9. 21. Krutmann J, Cjeck W, Diepgen T, et al. High-dose UVA-1 therapy in the treatment of patients with atopic dermatitis. J Am Acad Dermatol 1992;26:225–30. 22. Morita A, Werfel P, Stege H, et al. J Exp Med. 1997;186: 1763–8. 23. Papgeorgiou P, Katsambas A, Chu A. Phototherapy with blue 415 nm and red 660 nm light in the treatment of acne vulgaris. British J Dermatol 2000;142:973–8. 24. Kawada A, Aragane Y, Kameyama H, et al. Acne phototherapy with a high intensity enhanced narrowband blue light source: an open study and in vitro investigation. J Dermatol 2002;30:129 –35. 25. Kennedy JC, Puttier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol 1990;6:143–8. 26. Morton CA, Mackie RM, Whitehurst C, et al. Photodynamic therapy for basal cell carcinoma: effects of tumor thickness and duration of photosensitizer application on response. Arch Dermatol 1998;134:248 –9.
Clinics in Dermatology
Y
2003;21:398 – 406
27. Morton CA, Whitehurst C, Moseley H, et al. Comparison of photodynamic therapy with cryotherapy in the treatmen of Bowen’s disease. Br J Dermatol 1996;135:766 –71. 28. Fritsch C. Goerz G, Ruzicka T. Photodynamic therapy in dermatology. Arch Dermatol 1998;134:207–14. 29. Ibbotson SH. Topical 5 amino levulonic acid photodynamic therapy for the treatment of skin conditions other than non melanoma skin cancers. Br J Dermatol 2002;146: 178 –88. 30. Pass HI. Photodynamic therapy in oncology: mechanisms and clinical use. J Natl Cancer Inst 1993;85:443–56. 31. Houle JM, Strong HA. Duration of skin photosensitivity and incidence of photosensitivity reactions after administration of verteporfin. Retina 2002;22:691–97. 32. Dougherty TJ. Photosensitizers: therapy and detection of malignant tumors. Photochem Photobiol 1987;45:879 –89. 33. Divaris D, Kennedy JC, Pottier RH. Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5 ALA correlates with localized protoporphyrin IX fluorescence. Am J Pathol 1990;136:891–7. 34. Fritsch C, Verwohlt B, Bolsen K, et al. Influence of topical photosynamic therapy with 5ALA on porphyrin metabolism. Arch Dermatol Res 1996;288:517–21. 35. Peng Q, Berg K, Moon J, et al. 5ALA acid-based photodynamic therapy: principles and experimental research. Photochem Photobiol 1997;65:235–51.