Chapter 237 Phototherapy

Jennifer A. Cafardi, Brian P. Pollack, & Craig A. Elmets

PHOTOTHERAPY AT A GLANCE

Phototherapeutic devices have varying properties with respect to depth of UV penetration into the skin, effects on cells and molecules, potency, side effects and diseases in which they are most effective.

In use today are narrowband and broadband UVB, UVA as part of psoralen photochemotherapy (PUVA), UVA1 and targeted phototherapy (excimer lasers and nonlaser monochromatic excimer light sources).

Narrowband UVB is currently preferred to treat psoriasis, other inflammatory skin diseases, and vitiligo.

Psoralen-UVA photochemotherapy (PUVA) combines oral or topical psoralen compounds with UVA light sources. Its main uses are treatment of cutaneous T-cell lymphoma, vitiligo, and psoriasis that is resistant to narrowband UVB.

UVA1 phototherapy is particularly effective for sclerotic skin diseases such as localized scleroderma, acute flares of atopic dermatitis and urticaria pigmentosa.

Targeted phototherapy allowing relatively high UV doses to be delivered to diseased skin while sparing normal skin.

Diseases amenable to phototherapy include psoriasis, atopic dermatitis, cutaneous T-cell lymphoma, vitiligo, localized and systemic scleroderma, pruritus, photodermatoses, lichen planus, pityriasis lichenoides, urticaria pigmentosa and granuloma annulare.Phototherapy is the use of ultraviolet radiation or visible light for therapeutic purposes. Its beneficial effects in vitiligo were first recognized thousands of years ago in India and Egypt, and its activity is now well established for a variety of other dermatologic conditions. The enduring appeal of phototherapy is based on its relative safety coupled with an ongoing interest in its molecular and biological effects. The manufacture of light sources that emit selective wavelengths of radiant energy, identification of photosensitizers with unique photochemical properties, and the development of novel methods for the delivery of light to cutaneous and noncutaneous surfaces have all contributed to its expanded use for dermatologic and nondermatologic conditions. Aside from lasers, high output incoherent light sources, and visible light sources employed for photodynamic therapy, the main phototherapic devices that are in use today are broadband UVB (BB-UVB), narrowband UVB (NB-UVB), UVA1, and UVA for psoralen photochemotherapy (PUVA). Ideally, devices used for therapeutic ultraviolet radiation (UVR) should do so in a safe, efficient and cost-effective manner. Understanding the basic principles of these devices is important for dermatologists and other providers utilizing phototherapy for the management of dermatologic diseases.12

MECHANISMS OF PHOTOTHERAPY

The different wavelengths of ultraviolet radiation used for phototherapy each have distinct photochemical and photobiologic properties, which include differences in depth of penetration and the range of molecules in the skin with which they interact. As a consequence, each form of phototherapy has unique properties with respect to potency, side effects, and diseases in which they are effective.

Most UVB radiation (290320 nm) is absorbed by the epidermis and superficial dermis.3 This form of radiant energy produces many different types of DNA damage4; however, pyrimidine dimers and 6,4 pyrimidine-pyrimidone photoproducts are thought to be particularly important for both its efficacy and its toxicity. UVB also causes photochemical changes in trans-urocanic acid, converting it to the cis-form of the molecule. Urocanic acid is a breakdown product of histidine and is present in large amounts in the stratum corneum. Originally considered to be a natural photoprotectant, there is now a substantial evidence that cis-urocanic acid is a mediator of the UVB-induced immunosuppression.5 A third direct target of UVB radiation is the amino acid tryptophan. UVB converts tryptophan into 6-formylindolo[3,2-b]carbazole (FICZ), which binds to the intracellular arylhydrocarbon hydroxylase (Ah) receptor, initiating a series of events that culminates in activation of signal transduction pathways. One such pathway results in expression of cyclooxygenase-2, an enzyme re quired for synthesis of prostaglandin E2.6] Finally, there is evidence that UVB exposure leads to the generation of reactive oxygen intermediates, which has downstream effects such as DNA damage in the form of 8-oxo-deoxyguanosine, lipid peroxidation, activation of signal transduction pathways and stimulation of cytokine production.7

In contrast to UVB radiation, which has a relatively superficial depth of penetration, UVA radiation (320400 nm) can reach the mid- or lower dermis.3 It is therefore more effective than UVB for skin diseases in which the cutaneous pathology lies deeper than the superficial dermis. Like UVB, UVA radiation can produce pyrimidine dimers in DNA, but, on a per photon basis, it is much less effective at doing so.8 In most situations, the major biological effects of UVA radiation are due to the generation of reactive oxygen intermediates.9 Following UVA exposure, reactive oxygen intermediates are formed in mitochondrial enzyme complexes during oxidative phosphorylation. Although the skin contains antioxidants, reactive oxygen intermediates formed during phototherapy exceed the amount that can be neutralized by endogenous photoprotective activities. UVA-induced oxidants are capable of harming DNA, lipids, structural and nonstructural proteins and organelles such as mitochondria. The generation of oxidants following UV exposure has been implicated in photoaging of the skin and skin cancer.

In psoralen photochemotherapy, psoralen photosensitizers are activated by UVA radiation, and the depth of penetration of PUVA is the mid-dermis. The major photochemical effect of psoralen photochemotherapy is damage to DNA. The changes in DNA differ from those of UVB and UVA without psoralens.10 Psoralens used for photochemotherapy have two double bonds that can absorb UVA radiation. When administered to an individual, these compounds intercalate with DNA. Following UVA exposure, they form a single adduct with DNA and then become a bifunctional adduct, cross-linking the DNA strands in the double helix when a second photon is absorbed. There is also some evidence that photochemotherapy augments the production of reactive oxygen intermediates such as singlet oxygen. This effect has been implicated in induction of the cyclooxygenase enzyme and activation of arachidonic acid pathways.11

EFFECTS ON THE IMMUNE SYSTEM

(See also Chapter 90)

The photoimmunological effects of phototherapy are thought to provide an explanation, at least in part, for its efficacy in cutaneous diseases in which T-cell hyperactivity predominates (e.g., psoriasis, atopic dermatitis, lichen planus). Under normal circumstances, both ef ffector and regulatory T-cells are generated, with the overall intensity of the immune response dependent on the relative proportion of effector and regulatory T-cells populations that are present. UVB exposure inhibits activation of effector T-cells, whereas it leaves formation regulatory T-cells unaltered.12 As a result, the equilibrium of effector and regulatory T-cells is biased toward a diminished cell-mediated immune response. This perturbation in the balance of effector and regulatory T-cells reflects disruption of the activities of dendritic cells within the skin, the major function of which is to present antigen to T-lymphocytes. This is due to direct effects of UVB on dendritic cells and indirectly through the production of IL-10 and prostaglandin E2, both of which have been shown to diminish the capacity of dendritic cells to present antigen to effector T-cells and to suppress T-cell responses.13 Increased levels of IL-10 have been found after UVB, UVA1, and PUVA exposure. PGE2 production occurs through UVB effects on keratinocytes1416; UVB is an inductive stimulus for cyclooxygenase-2, which is important for PGE2 production. Other immunosuppressive soluble mediators that have been reported to be increased following UVB exposure including agonists of the platelet-activating factor receptor,17 MSH, and calcitonin gene-related peptide.18

PUVA has effects that are similar to UVB with respect to antigen presenting cells within the skin, the balance between effector and regulatory T-cells, and the production of soluble immunosuppressive mediators.12 There is limited information on the effect of UVA1 on antigen presenting cells and on effector and regulatory T-cells.

In addition to its actions on cutaneous antigen presenting cells, phototherapy causes cell death by apoptosis in T-cells present in cutaneous lymphoid infiltrates. This has been demonstrated for UVA1 phototherapy in the lymphocytic infiltrate in atopic dermatitis,19 and for narrowband UVB in psoriasis.20

Another immunological effect of phototherapy is on expression of ICAM-1 (CD54) and other adhesion molecules. ICAM-1 is not normally present on epidermal keratinocytes, but can be induced in a variety of inflammatory skin conditions. It facilitates T-cell binding to keratinocytes, through its interaction with LFA-1 that is present on T-cells. UVB, UVA1, and PUVA have all been shown to interfere with keratinocyte expression of ICAM-1, and this effect of phototherapy may therefore contribute to its efficacy in diseases, which have increased keratinocyte ICAM-1 expression.EFFECTS ON MAST CELLS

Both UVA1 and PUVA have deleterious effects on mast cells, although the mechanisms of action differ.2122 PUVA is not cytotoxic for mast cells, and because of this the reduction in mast cell concentrations in the dermis of PUVA-treated skin is relatively small. However, it does stabilize mast cell membranes and in so doing limits the release of histamine and other mediators when these cells are stimulated to degranulate.22 In contrast, chronic therapy with UVA1 results in apoptosis of mast cells with a marked reduction in their concentrations in the dermis, which can last for several months.20 Both PUVA and UVA1 have been employed to treat selective mast cellmediated diseases.

EFFECTS ON COLLAGEN

One of the downstream effects of UVA-induced generation of reactive oxygen intermediates is activation of matrix metalloproteinase-1 (MMP-1), the major biologic activity of which is degradation of collagen. UVA radiation also increases the production of IL-1 and IL-6, which are stimuli for MMPs. PUVA has also been shown to increase MMPs. These effects of UVA1 and PUVA on MMP-1 and collagen degradation provide the rationale for its use in sclerotic skin diseases.

EFFECTS ON THE EPIDERMIS (KERATINOCYTES)

UVB, PUVA, and UVA all cause acanthosis of the epidermis and thickening of the stratum corneum.27 This effect accentuates light scattering and increases its absorption by the upper levels of the epidermis. As a consequence, phototherapy treatment doses must be progressively increased so that an equivalent number of photons can reach the lower levels of the epidermis and dermis where therapeutic targets lie. On the other hand, this attribute of phototherapy has been exploited for the management of chronic photosensitivity disorders because this hardens the skin, permitting individuals afflicted with these disorders to tolerate greater amounts of sun exposure.

EFFECTS ON MELANOCYTES

Exposure to ultraviolet radiation is also known to stimulate melanogenesis,28 which is at least in part a consequence of DNA damage and/or its repair.2932 Experimental studies have shown that treatment of melanocytes with DNA repair enzymes increases the melanin content of melanocytes,33 and application of small fragments of thymidine dinucleotides to guinea pig skin produces a tanning response.3032 The stimulatory effects on melanogenesis increase the tolerance of patients with some photosensitivity disorders to ambient sun exposure, but also decrease the efficacy of phototherapy unless the doses of ultraviolet radiation are gradually increased.

Narrowband UVB and PUVA are also employed to repopulate vitiliginous skin with melanocytes. The mechanism by which phototherapy stimulates repigmentation of vitiliginous skin is incompletely understood, but may involve stimulation of hair follicle melanocyte proliferation and migration.34 Cytokines and other inflammatory mediators released from other cells, such as keratinocytes, are thought to stimulate inactive melanocytes in the outer root sheath of hair follicles to proliferate, mature, and migrate to repopulate the interfollicular epidermis.35

PHOTOTHERAPY APPARATUSES

In the ideal situation, the wavelengths that are most effective for the treatment (i.e., the action spectrum) for every dermatologic condition would be known and there would be a device capable of delivering those wavelengths specifically to lesional skin. For some skin diseases such as psoriasis, great strides have been made toward this ideal and targeted therapy using devices such as excimer lasers36 and nonlaser devices known as monochromatic excimer light (MEL) devices37 that can deliver wavelengths of UVR at or close to those that are most effective at clearing psoriatic plaques have been evaluated and are being used clinically. Unfortunately, for most dermatologic conditions this information is unknown. However, the increased availability of improved phototherapy devices and novel treatment approaches are providing new options for patients and clinicians. In addition, as more studies are conducted utilizing phototherapy devices, a better understanding of how best to use older technologies is being obtained.

BASIC PRINCIPLES OF PHOTOTHERAPY DEVICES AND TYPES OF LAMPS

Phototherapy devices generate light by the conversion of electrical energy into electromagnetic energy. Filters and fluorophores are used to modify the output such that the desired wavelengths are emitted. There are several types of lamps (or bulbs) used to generate therapeutic UVR. These include incandescent lamps, arc lamps, and fluorescent lamps.

Incandescent lamps generate UVR by passing an electric current through a thin tungsten filament, which, in turn, generates heat and light. Because much of the electrical energy is converted to heat, these lamps are relatively inefficient light sources and have relatively short life spans. By sealing the tungsten filament in a quartz envelope that contains a halogen (bromine or iodine), the filament can be made to emit more energetic photons without reducing the longevity of the bulb. These lamps are called quartz halogen lamps and can emit wavelengths within the UV, visible, and IR ranges. In clinical dermatology, these lamps are employed primarily for situations such as phototesting and photodynamic therapy that require visible light.

Arc or gas discharge lamps were the first effective artificial sources of UVR. Arc lamps take advantage of the fact that when a high voltage is passed across two electrodes in the presence of a gas, the electrons of the gas atoms become excited. The arc of an arc lamp refers to the electric arc generated when the gas is ionized (ionized gas is also known as plasma) by a high electric current. When the gas electrons return to their ground state, light is emitted. The type of gas incorporated into the lamp determines the wavelengths that are emitted (i.e., spectral output). The output of arc lamps can be modulated by altering the gas pressure within the bulb such that at high pressures, the peak wavelength output broadens. High-pressure arc lamps typically contain mercury or xenon gas whereas low-pressure arc lamps utilize fluorescent material. In addition to altering the gas pressure to modify the spectral output of arc discharge lamps, the addition of metal halides broadens the output spectrum such that it becomes nearly continuous across the UV spectrum. For example, when mercury arc lamps are operated at high pressures, they have output emission peaks (so called mercury lines) seen at 297, 302, 313, 334, and 365 nm. In contrast, if a metal halide is added to the mercury, the output between these peaks is increased and is thus more continuous. The use of optical filters can then further refine the output of these lamps such that only the desired wavelengths are emitted. The advantage of metal halide lamps is the high output, which allows for shorter treatment times. However, they are more costly and more difficult to operate than fluorescent lamps. One example of a metal halide lamp currently in clinical use is the UVA1 light source.

Fluorescent lamps are the most commonly used sources of therapeutic UV light. These lamps take advantage of the fact that chemicals called phosphors (a specific type of chromophore also called a fluorophore) absorb and then reemit light. The light that is reemitted is of lower energy (and thus longer wavelength) than the inciting light. Using this principle, the UVC irradiation (that peaks at 254 nm) gener ated from a low-pressure mercury lamp can be converted to the longer UVB and UVA wavelengths of light that are desirable for phototherapy. The final output of a fluorescent lamp is dictated by the specific phosphor of the bulb. An important advance in photodermatology came with the development of a modified fluorescent lamp that emits largely at 311 nm.38 Broadband UVB and UVA light sources used for PUVA are other examples of fluorescent lamps.

Because different forms of phototherapy are used to treat different diseases, it is important and practical to divide devices based upon wavelength. Devices to deliver broadband UVB (BB-UVB), 311-nm narrowband UVB (NB-UVB), UVA (for use in psoralen photochemotherapy), and UVA1 (340400 nm) are available in the United States and in most other countries. In addition to differing by spectral output, phototherapy devices range in the surface area that they are designed to treat (whole body, localized regions, or only lesional skin). Devices used for large body surface areas resemble booths (which patients enter for each treatment). These devices come in a variety of styles from round cylinders to folding units that can be unfolded for treatments and then collapsed while not in use. Devices have been developed to treat more limited areas (such as the palms and soles) and as such they are substantially smaller in size. Finally, targeted therapy utilizes devices that can deliver therapeutic ultraviolet radiation only to lesional skin and range in size from small handheld units to devices with a handheld wand attached to a larger UVR-generating component.

BROADBAND UVB AND NARROWBAND UVB

Originally used for psoriasis therapy, artificial sources of broadband UVB (BB-UVB) have been used therapeutically since the early twentieth century. In particular, UVB combined with the topical application of coal tar (as developed initially by William Goeckerman) was a mainstay of psoriasis treatment for many decades.39 More recently, with the development and availability of narrowband UVB, some dermatologists have concluded that BB-UVB is obsolete.40 However, BB-UVB is still widely used in the United States for a variety of conditions including psoriasis, atopic dermatitis, prurigo nodularis, and uremic pruritus.36 In addition, some patients who are unable to tolerate NB-UVB will respond to BB-UVB.36

The most commonly employed devices that deliver BB-UVB utilize fluorescent lamps. These devices emit UVR over a broad spectral range. Approximately, two-thirds of the output is in the UVB range and the rest is primarily in the UVA. However, because wavelengths.

within the UVB have nearly much more energy than wavelengths within the UVA, the UVA emitted contributes little to the therapeutic efficacy, assuming the patient is not taking a photosensitizing medication. BB-UVB and NB-UVB have been specifically designed to limit output below