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.1–2

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 (290–320 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 required 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 (320–400 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 effector 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 keratinocytes14–16; 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.12

EFFECTS ON MAST CELLS

Both UVA1 and PUVA have deleterious effects on mast cells, although the mechanisms of action
differ.21–22 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 cell–mediated 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),23–24 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.25 PUVA has also been shown to increase MMPs.26 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.29–32 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.30–32 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) generated 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
(340–400 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 <290 nm (i.e., in the UVC range).
The wavelengths that most efficiently clear psoriasis are approximately 313 nm.41 In contrast,
wavelengths less than 300 nm are the most efficient at causing erythema and nonmelanoma skin
cancer. Based on this knowledge, light sources, termed narrowband UVB (NB-UVB), have been
produced.38 These light sources emit only wavelengths between 308 and 313 nm, and have largely
supplanted BB-UVB UV radiation sources for phototherapy. Although originally used to treat
psoriasis, they have now been used to treat a number of other inflammatory skin diseases as well.
The initial starting dose of both broadband and narrowband UVB is determined in one of two
ways (Tables 237-1 and 237-2). In the first, the minimal erythema dose (MED) is determined by
exposing 6 one cm2 areas of skin on the inner aspect of the forearm or lower back to gradually
increasing amounts of UV radiation from the same device that will be used for phototherapy. Twenty-
four hours later, the UV exposed areas of skin are examined and the smallest UV dose that results in
uniform erythema over the entire area, considered the MED, and phototherapy is initiated at 50% to
70% of that amount. Alternatively, the initial dose of phototherapy is established based empirically
on Fitzpatrick skin phototype42 (see Tables 237-1 and 237-2). Subsequent exposures are given 2–5
times per week and the dose is increased at each treatment, assuming the patient has not developed an
erythema response. If an erythema response has occurred, then, depending on its severity, the dose is
either reduced or the treatment is delayed (see Tables 237-1 and 237-2). The maximum NB-UVB
dose that should be administered is 2,000–5,000 mJ/cm2 depending on the photoreactive skin type. If
patients miss treatments, dosage modifications should be made to avoid burns (see Table 237-5).

TABLE 237-1
Narrowband UVB Phototherapya

TABLE 237-2
Broadband UVB Phototherapya
PUVA
Psoralen-UVA photochemotherapy (known by the acronym PUVA) combines the oral ingestion or
topical application of psoralens with exposure to UVR in the UVA range. Although psoralens and
sunlight had been employed for thousands of years for the treatment of vitiligo, it was not until 1947
that PUVA in its modern form was described, initially for the treatment of vitiligo, and subsequently
for the treatment of psoriasis.43
Three forms of psoralen are used in photochemotherapy regimens: 8-methoxypsoralen (8-MOP),
5-methoxypsoralen (5-MOP), and 4,5′,8-trimethylpsoralen (TMP). In the United States, only 8-
methoxypsoralen is available. There are two oral formulations of 8-MOP, a micronized form which
is typically given at a dose of 0.6 mg/kg 120 minutes prior to UVA exposure or a dissolved form
which is given at a dose of 0.4–0.6 mg/kg 90 minutes before UVA exposure. The dissolved
preparation is absorbed faster and yields higher and more reproducible serum levels and is therefore
more commonly employed as a part of PUVA phototherapy regimens.
The most common sources of radiation for PUVA therapy are UVA fluorescent lamps, which have
a maximum emission at 352 nm, near the absorption maximum for psoralens. For oral PUVA therapy,
UVA radiation is usually initiated at a dose that corresponds to the 50%–70% of the minimum
phototoxic dose (MPD) or according to the Fitzpatrick skin phototype (Table 237-3). The MPD is
determined by having the patient take the dose of the oral psoralen to be used for the
photochemotherapy treatment and exposing 6 one-cm2 areas of skin to gradually increasing doses of
UVA. The MPD is evaluated 72 hours after UVA exposure and is the lowest amount of UVA that
produces a uniform erythema over the entire area. In the United States, it is more common to initiate
therapy based on the Fitzpatrick skin phototype (see Table 237-3). Treatments are usually given 2–4
times per week, avoiding consecutive days. The amount of UVA that is to be given is increased with
each treatment. UVA dose modifications are made if an erythema response develops or treatments
are missed (see Table 237-3).

TABLE 237-3
Oral PUVA Photochemotherapya

Delivery of psoralens in bathwater is popular in some areas of the world because it provides a
uniform drug distribution over the skin surface, is associated with very low psoralen plasma levels,
and rapid elimination of free psoralens from the skin. This form of psoralen delivery circumvents
gastrointestinal side effects and possible phototoxic hazards to the eyes associated with the oral
form. Skin psoralen levels are highly reproducible, and photosensitivity lasts no more than two
hours. Bath-PUVA consists of 15–20 minutes of whole-body immersion in solutions of 1-mg 8-MOP
per liter of body temperature bathwater (Table 237-4). 5-MOP and trimethylpsoralen are also
employed for bath PUVA. Irradiation is performed immediately after bathing, as photosensitivity
decreases rapidly. Bath PUVA is started at 30% of the MPD. Treatments are typically given twice
weekly. Guidelines for bath, local immersion, and other topical PUVA forms have been published by
the British Photodermatology Group.44 A cost-effectiveness analysis of data collected across four
centers in Scotland revealed that courses of both bath PUVA and other topical PUVA were
consistently more expensive than oral PUVA.44 This is related predominantly to the increased nursing
time required, although the cost of topical preparations also tends to be greater than oral
preparations.

TABLE 237-4
Bath PUVA Photochemotherapya
I. Psoralen Dose
8-MOP dissolved in bath water for a final concentration of 1.0 mg/L
Bath water is at body temperature (98.6°F) Duration of bath is 15-20 minutes
II. UVA Exposure
A. MPD Determination
Expose 1-cm2 areas on the lower back or inner aspect of the forearm; read 72 h after UVA
exposure
Fitzpatrick skin phototype I or II: 0.5, 1.0, 2.0, 3.0, 4.0 and 5.0 J/cm2 UVA
Fitzpatrick skin phototype III or IV: 1.0, 2.0, 4.0, 6.0, 8.0 or 10.0 J/cm2 UVA
B. UVA exposure immediately after bathing
C. Initial exposure: 30% of MPD
D. Subsequent exposures: 2 times per week Increase UVA dose by 20% each week
aModified from Refs. 1, 330, and 331.

More recently, cream PUVA has been developed, which can be used to treat local and more
widespread disease. Thirty minutes following the application of a psoralen-containing cream,
patients are exposed to UVA irradiation.

AVOIDANCE AND MANAGEMENTS OF BURNS

Sunburn-like reactions are the most common short-term adverse effect of phototherapy. UVB burns
usually peak at 12–24 hours, and PUVA burns at 24–48 or even 72 hours, with more severe burns
peaking later than mild ones. Severe burns over a large portion of the skin surface produce systemic
toxicity with fever and malaise in addition to pain. Severe PUVA burns, which extend well into the
dermis, can lead to epidermal sloughing and are an indication for admission to a burn-care hospital
facility. To avoid exacerbating a still developing PUVA burn, it is recommended that PUVA
treatments not be given on consecutive days. Table 237-5 specifies the UVB or UVA dose
adjustments in the event of a burn reaction during phototherapy. A burn reported by the patient at the
next visit, even if no longer visible, should be managed in the same manner as a still-visible reaction.
Burns over limited body areas, such as just the face or breasts, can be managed by local application
of an appropriate sunscreen before or part way through subsequent treatments, especially if the area
is not affected by the disease being treated. However, care must be taken to consistently protect the
same area(s) in order to avoid a sudden full treatment to previously shielded skin.

TABLE 237-5
Modification of Phototherapy Dose for Erythema or Missed Sessionsa
 Repeated UV-irradiated skin develops tolerance to subsequent exposures, allowing and indeed
mandating progressively larger doses for optimal therapeutic effect. However, this tolerance is
rapidly lost when exposures cease, requiring downward adjustments of dose after as little as 1 week
(Table 237-5) to avoid burns.

UVA1.
Because of its longer wavelength, UVA1 phototherapy (340–400 nm) is able to penetrate more
deeply into the skin than UVB or shorter range UVA called UVA2 (i.e., 320–340 nm). The first report
describing a device capable of emitting UVA1 occurred in 1981.45 It was not until 1992 when the
therapeutic benefit of UVA1 was demonstrated for atopic dermatitis that greater interest in the
therapeutic properties of UVA1 occurred.46–47 Initially, one obstacle to the widespread use of the
initial UVA1 devices was the intense heat that they generated. Newer UVA1 phototherapy units
incorporating a specialized filtering and cooling system that removes nearly all wavelengths above
530 nm have largely eliminated this problem. Though not widely available in the United States, these
light sources are useful for the management of a variety of dermatological conditions for which other
forms of phototherapy are not helpful.48–49
UVA1 is administered 3–5 times per week. There have been several studies, which have
attempted to establish the optimal amount of UVA1 to administer at each treatment session.50–54
Three dosing regimens have been used: (1) low dose (10–30 J/cm2), (2) medium dose (40–70
J/cm2), and (3) high dose (130 J/cm2).50–54 Although several comparison studies have been
performed, at this point, there is no consensus as to which dose is best. In general, patients are
started at 20–30 J/cm2 and increased to the full dose within 3–5 treatments.55 The risk of burns is far
less than with UVB or PUVA therapy.
TARGETED PHOTOTHERAPY
Unlike the previously described phototherapy devices that expose both lesional and uninvolved skin
to UVR, targeted phototherapy delivers therapeutic doses of UVR only to lesional skin. Targeted
phototherapy has also been called focused phototherapy, concentrated phototherapy, and
microphototherapy. Several devices are available to deliver targeted phototherapy including both
monochromatic (one wavelength) and polychromatic systems. There are several advantages to
targeted phototherapy. These devices spare normal skin, thereby allowing higher fluences to be
delivered to diseased skin while decreasing the risk of acute and chronic side effects to normal skin.
Targeted therapy can be used on treatment-resistant lesions and on difficult anatomic locations (such
as the scalp, chin, and nails). The handheld nature of a targeted phototherapy device may be easier
for young children than receiving treatments in a phototherapy booth, which can be large and
intimidating. The limitations of targeted phototherapy are device expense and the fact that it may not
be practical for patients with more than 10% to 20% of body surface area involved to receive
treatments in this manner. The preventive action of phototherapy on uninvolved but at-risk skin is also
lost. Targeted phototherapy devices include excimer lasers and nonlaser devices known as
monochromatic excimer light (MEL) devices.37 Both types of devices have been used to deliver
targeted therapy to treat specific lesions of diseases such as psoriasis and vitiligo.36–37 While both
types deliver monochromatic UVB irradiation (most commonly at 308 nm), they differ in several
respects. Lasers typically deliver UVR to a smaller area but are capable of emitting higher amounts
of radiation over a shorter period of time. In contrast, MEL devices deliver monochromatic
irradiation to a larger area but with a lower power density. There are also several devices that emit
polychromatic UVA or UVB (BB- or NB-UVB) to targeted areas. These devices typically utilize
fiberoptic systems coupled with UVB generating sources. These devices have spot sizes from 1–3
cm. In addition, they have multiple delivery programs and automatic calibration, which makes
treatment with predetermined dosages possible. These devices are smaller, less expensive, and have
less maintenance problems than lasers.56–57 Treatment protocols with targeted phototherapy vary
depending on the type of device that is employed.

SAFETY OF PHOTOTHERAPY
Safety principles are common to most phototherapy devices. Equipment should be checked on a
regular basis by the clinical staff or the manufacturer’s engineer, since bulb output may change over
time, and internal dosimetry components may fail. While phototherapy is usually delivered without
incident, the risk of overtreatment is real, although the exact incidence of adverse events attributable
to phototherapy is unknown and varies depending on the device. Importantly, with the exception of
PUVA therapy for which formal long-term follow-up studies established an increased risk of
lentigines, squamous cell carcinoma and melanoma, other forms of phototherapy appear to be
remarkably safe.36,58 Newer therapies such as narrowband UVB and UVA1 appear to be relatively
safe especially compared to nonphototherapeutic options for the same diseases, but await longer
follow-up.

UVB
Repeated exposure of the skin to UV irradiation does result in cumulative actinic damage regardless
of the source. With respect to nonmelanoma skin cancer, most studies have shown that there is little
risk beyond that associated with habitual sun exposure with either BB-UVB or NB-UVB
phototherapy.59–60 Greater than 300 treatments BB-UVB is associated with a modest but significant
increase in SCC and BCC.61 However, the carcinogenic risk of a single PUVA treatment is about
seven times greater than a single UVB treatment.62 As a result of its safety profile and efficacy, NB-
UVB has emerged as a leading therapy for a number of skin diseases. Several studies have also
shown that long-term exposure to BB-UVB combined with topical tar preparations is not associated
with an increased risk of SCC.63

PUVA

ACUTE SIDE EFFECTS.

The side effects of PUVA include drug intolerance reactions as well as the combined action of
psoralens plus UVA radiation. Oral 8-MOP may cause nausea (10% of patients) and vomiting, and
this occasionally necessitates discontinuation of treatment. These side effects are more common with
liquid preparations rather than with crystalline preparations, probably because of higher psoralen
serum levels. The nausea may be minimized or avoided by instructing the patient to take 8-MOP with
milk, food, or ginger (e.g., ginger cookies, ginger ale, ginger supplements)64 or to divide the dose into
two portions, taken approximately one-half hour apart. Other reported effects include nervousness,
insomnia, and depression. With 5-MOP, nausea is rare, even with doses up to 1.8 mg/kg body weight.
Following exposure to UVA, approximately 10% of patients undergoing PUVA therapy will
experience pruritus. In most cases, this can be alleviated by bland emollients. Some patients with
severe pruritus may require systemic treatment. A stinging pain may rarely occur, and the mechanism
for this is unknown. The symptoms are usually unresponsive to antihistamines, and, in most instances,
subside when the treatment is discontinued.
Mild and often transient focal erythema after PUVA therapy occurs frequently. Any area showing
erythema with tenderness or blistering should be shielded during subsequent UVA exposures until the
erythema has resolved. As noted above, erythema appearing within 24 hours may signal a potentially
severe phototoxic reaction, and may worsen progressively over the next 24 hours, since peak
erythema with PUVA characteristically occurs at least 48 hours after the treatment. In that situation,
patients should be protected from further UVA exposures and sunlight, and should be monitored
closely until the erythema has resolved.
Very rare side effects of PUVA include polymorphous light eruption-like rashes, acne-like
eruptions, subungual hemorrhages caused by phototoxic reactions of the nail beds, onycholysis of the
nails, and occasionally hypertrichosis of the face. These disappear when treatment is discontinued.
Analysis of laboratory data in several large studies revealed no significant abnormal findings in
patients receiving PUVA over prolonged periods of time.65–67

Chronic Actinic Damage.

Chronic exposure to PUVA may result in skin changes that resemble photoaging, and which is
aggravated by chronic natural sun exposure. PUVA lentigines are small brown macules with irregular
borders and uneven pigmentation68 and are histologically characterized by proliferation of large
melanocytes.69 In contrast to solar lentigines, melanocytes in PUVA lentigines often display an
increased size of melanosomes, clustering and binucleation with nuclear hyperchromatism, and
cellular pleomorphism. T1799A B-type Raf (BRAF) mutations have been found to be present in
PUVA lentigines,70 but the full significance of this is not yet understood, as both cutaneous malignant
melanoma and benign melanocytic nevi often have BRAF mutations.71–74 The presence of these
lesions is directly related to the number of PUVA treatments and total UVA dose that has been
administered. The absence of PUVA lentigines serves as a useful indicator of a lower risk of PUVA
malignancy.75

Carcinogenesis.
Cutaneous malignancies are the major concern of long-term and repeated PUVA treatments. The risk
of nonmelanoma skin cancer and possibly malignant melanoma increases in a dose-dependent
manner. In laboratory animals, 8-MOP and 5-MOP have unequivocally induced skin cancer at levels
of drug and UVA irradiation comparable to those used in PUVA therapy.76 Cancer development is
thought to stem from both DNA damage and down-regulation of the immune system. The PUVA
Follow-up Study, which evaluated 1,380 patients who began PUVA treatment for psoriasis in 1975
and 1976 has documented major health events in these individuals in a prospective manner. Overall,
patients who were treated with at least 337 PUVA treatments exhibited a 100-fold increased risk of
SCC compared to that expected from population incidence rates.77 Moreover, almost 4% of patients
with SCC developed metastases, most commonly originating in the genital area. There is uncertainty
about PUVA being the sole factor as many of the patients in the long-term follow-up studies also had
significant exposure to sunlight and to treatments with carcinogenic potential, including arsenic, UVB,
and methotrexate. The risk of developing SCC with PUVA may be further potentiated by the use of
cyclosporine and, for this reason, cyclosporine is contraindicated in individuals who have been
treated with PUVA.78 Oral retinoids used concurrently with PUVA, on the other hand, reduce the risk
of SCC.79
Individuals treated with PUVA are at increased risk of cutaneous malignancies of the genitalia,
and this has led to standard protection of the genitalia during phototherapy.80 The risk is dose-
dependent, with a 90-fold increased risk of genital tumors among patients exposed to high doses of
PUVA compared with that expected in the general population. Men treated with high-dose exposures
to both PUVA and topical tar/UVB have the greatest risk of genital tumors.80–81 There is currently no
standardized regimen for genital shielding. There are pouches for genital shielding that are
commercially available, but the cost and availability may be prohibitive. Factors influencing the
effectiveness of UV irradiation protection include fiber composition, porosity (intrinsic to which is
number of layers, weave type, and thread count), mass, and color.82–83 Commonly used protective
agents include surgical masks, paper towels, blue surgical towels, and underwear. The efficacy of
these materials has been studied, and surgical masks were found to provide insufficient protection
against UV irradiation most likely due to increased porosity (looser weave) and decreased mass.84
The relationship between PUVA and melanoma has also been examined in detail. The PUVA
Follow-Up Study has provided evidence that individuals with at least 250 treatments and at least 15
years from the first PUVA treatment were at increased risk of developing melanoma.85 Patients who
developed a phototoxic reaction more easily were at higher risk for melanoma than those with darker
skin.86 As a result of those studies, a personal or family history of melanoma or a history of greater
than 200 PUVA treatments is considered to be a relative contraindication to further PUVA therapy.86
In patients employing PUVA therapy in combination with methotrexate for at least 36 months, the
incidence of lymphoma was more than 7 times higher than that of cohort members earlier in the study
who had not taken methotrexate.87

Ophthalmologic Effects.
UVA is absorbed in the lens and in the presence of UVA, psoralens can bind protein, DNA, and
RNA. Because the lens never sheds its cells, protein-bound 8-methoxypsoralen accumulates in the
lens, increasing the risk of irreversible opacification.88 There have been reports of various ocular
problems in patients on PUVA including cataracts, 89–90 conjunctival hyperemia,91 and decreased
lacrimation.91
A 25-year prospective study92 sought to evaluate the effect of PUVA on the eyes. Participants
were instructed to use UVA-blocking eyewear when outside or looking outside through window
glass during daylight for a minimum of 12 hours, although current labeling calls for 24 hour
protection. This study found no relationship between increasing numbers of PUVA sessions and
visual impairment or cataracts, and demonstrates that increasing exposure to PUVA does not increase
cataract risk among middle-aged and older persons using eye protection as practiced by this cohort.92
Other smaller studies have also found no increase in cataract formation or visual impairment.93–96

UVA1
UVA1 phototherapy is generally well tolerated.52–53 Reported side effects include intense tanning,
erythema, pruritus, urticaria, tenderness, a burning sensation, polymorphous light eruption, eczema
herpeticum and bacterial superinfection.48–49,54 However, because UVA1 phototherapy has only been
available since the 1990s, the long-term effects are still under investigation.

SPECIAL CONSIDERATIONS

HIV.
The safety of phototherapy and photochemotherapy in HIV-positive patients has been debated.
Ultraviolet radiation may activate HIV by the induction of NF-κB,97–99 and UVB therapy increases
HIV-1 gene expression in the skin.100–102 However, BB-UVB phototherapy does not appear to affect
plasma HIV levels nor does it have an effect on CD4 counts.101,103–104 In general, phototherapy is
thought to be safe for HIV patients.105 A consensus statement published by the American Academy of
Dermatology in 2010 concluded that for moderate-to-severe psoriasis in HIV-positive patients,
phototherapy and antiretrovirals are the recommended first-line therapeutic agents.106

CHILDREN.
NB-UVB is now preferred to PUVA in children for most skin conditions, because of concern about
PUVA side effects including phototoxicity, carcinogenicity, photoaging, and the potential
development of cataracts.
MISCELLANEOUS.
Patients who have had arsenic exposure are at increased risk for cutaneous malignancies and should
avoid phototherapy. Transplant patients have a much higher risk of skin cancer compared to the
general population and, in that patient population there is a relative contraindication to phototherapy.
Photosensitizing medications should theoretically be avoided during phototherapy treatment, although
in practice many patients uneventfully receive phototherapy while taking tetracycline,
hydrochlorothiazide, or other photosensitizing drugs. There are anecdotal reports of an association
between chronic use of voriconazole and the development of aggressive cutaneous malignancies
including melanoma.107–110

DISEASES AMENABLE TO PHOTOTHERAPY

(Table 237-5)
Responses of the diseases listed in eTable 237-6 are discussed in detail online. See also Chapter
238.

TABLE 237-6
Diseases Amenable to Phototherapy

KEY REFERENCES
Full reference list available at www.DIGM8.com
 DVD contains references and additional content

1. Menter A et al: Guidelines of care for the management of psoriasis and psoriatic arthritis:
Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and
photochemotherapy. J Am Acad Dermatol 62(1):114-135, 2010
12. Krutmann J, Morita A, Elmets CA: Mechanisms of Photo(chemo)therapy. In: Dermatological
Phototherapy and Photodiagnostic Methods, edited by J Krutmann, H Hönigsmann, and CA
Elmets. Berlin, Springer-Verlag, 2009, pp. 63–77
40. Schneider LA, Hinrichs R, Scharffetter-Kochanek K: Phototherapy and photochemotherapy. Clin
Dermatol 26(5):464-476, 2008
60. Hearn RM et al: Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet
B phototherapy. Br J Dermatol 159(4):931-935, 2008
124. Asawanonda P, Nateetongrungsak Y: Methotrexate plus narrowband UVB phototherapy versus
narrowband UVB phototherapy alone in the treatment of plaque-type psoriasis: A randomized,
placebo-controlled study. J Am Acad Dermatol 54(6):1013-1018, 2006
Chapter 238
Photochemotherapy and Photodynamic Therapy
Herbert Hönigsmann, Rolf-Markus Szeimies, & Robert Knobler

PHOTOCHEMOTHERAPY AND PHOTODYNAMIC THERAPY

AT A GLANCE
Photochemotherapy [psoralen and ultraviolet A light (PUVA)] has been successfully used for
more than 30 years. Its effectiveness has profoundly influenced dermatologic therapy in
general, providing treatment for a number of diverse disorders besides psoriasis and vitiligo.
PUVA can be combined with topical treatments and with some systemic agents (retinoids,
methotrexate, and, perhaps, biologics) to enhance efficacy and to reduce the number of
exposures.
The most important adverse effects of oral PUVA consist of an increased risk of squamous cell
carcinoma and a possible risk of melanoma. No such increased risk was found so far with
bath-PUVA.
Extracorporeal photochemotherapy (ECP) was introduced in the 1980s for the palliative
treatment of erythrodermic cutaneous T-cell lymphoma.
ECP appears to have a major impact in the treatment of graft-versus-host disease after
allogeneic bone marrow transplantation where it allows progressive reduction or even
discontinuation of the concomitant immunosuppressive therapy without an increase in graft-
versus-host disease activity. Several other indications are under investigation.
No serious side effects have been reported with ECP.
Photodynamic therapy (PDT) for skin tumors started with the introduction of topical
photosensitization by a porphyrin precursor (5-aminolevulinic acid) that would avoid
generalized light sensitivity over many weeks.
Current experience with PDT of epithelial cancers and precancerous conditions suggests that
actinic keratoses, Bowen disease, superficial and nodular basal cell carcinomas, and early
squamous cell carcinomas can be treated curatively.
The only significant side effect of topical PDT is a stinging pain during and shortly after
irradiation. PDT has neither mutagenic nor carcinogenic potential.

PHOTOCHEMOTHERAPY
Photochemotherapy with psoralens combines the use of oral or topical psoralens (P) and ultraviolet
A radiation (UVA), termed PUVA. Psoralens are phototoxic compounds that enter cells and then
absorb photons to produce photochemical reactions that alter the function of cellular constituents.1
This interaction results in a beneficial therapeutic effect after repeated controlled phototoxic
reactions. Psoralens can be administered orally or applied topically to the skin in the form of
solutions, creams, or baths. This therapy is currently used in the treatment of several common and
uncommon skin diseases.

HISTORICAL BACKGROUND
In the 1970s, it was shown that orally administered 8-methoxypsoralen (8-MOP) and subsequent
irradiation with artificial UVA was a highly effective treatment for psoriasis.2,3 Psoralen baths
(soaking in a dilute psoralen solution) and subsequent UVA exposure (bath-PUVA), which originated
in Scandinavia,4 is also being used in many European institutions. The effectiveness of all variants of
PUVA has been widely confirmed and has profoundly influenced dermatologic therapy, in general,
providing treatment for numerous disorders in addition to psoriasis (Table 238-1). A major advance
in phototherapy was the development of fluorescent bulbs that emitted narrowband UVB radiation at
311–313 nm in the mid-1980s. This narrow spectrum is slightly inferior in clearing psoriasis or
mycosis fungoides. However, due to the fact that it is easier to perform and possibly safer than
PUVA, it is now more frequently used in many phototherapy centers. Narrowband UVB phototherapy
is also beneficial for a variety of other dermatoses that were previously treated with PUVA.
Nevertheless PUVA has still remained the mainstay for recalcitrant diseases.

TABLE 238-1
Phototherapy-Responsive Diseases
PRINCIPLES OF PHOTOCHEMOTHERAPY
The rationale for PUVA therapy is to induce remissions of skin diseases by repeated, controlled
phototoxic reactions. These reactions occur only when psoralens are photoactivated by UVA. Due to
the penetration characteristics of UVA, absorption of photons is confined to the skin. However, there
is also some evidence that PUVA may exert systemic effects through circulating lymphocytes affected
while transiting through the skin. Clinically, PUVA-induced phototoxic reactions are characterized by
a delayed sunburn-like erythema and inflammation.

PSORALENS.
Three psoralens are used in PUVA therapy. Methoxsalen or 8-methoxysporalen (8-MOP), obtained
from the seeds of a plant called Ammi majus, is most widely used and the only psoralen available in
the United States. Bergapten or 5-methoxypsoralen (5-MOP) and trioxsalen or 4,5′,8-
trimethylpsoralen (TMP) are available in Europe and elsewhere.

Psoralen Photochemistry.5–7
Psoralens intercalate between apposing DNA base pairs in the double helix in the absence of UV
radiation. Absorption of photons in the UVA range results in the formation of a 3,4- or 4,5-
cyclobutane addition product (adduct) with pyrimidine bases of native DNA. In the first step of this
photochemical reaction, a monofunctional adduct with thymine or cytosine is formed. Some
psoralens, including 8-MOP, TMP, and 5-MOP, can absorb a second photon, and this reaction leads
to the formation of a bifunctional adduct with a 5,6 double bond of the pyrimidine base of the
opposite strand, thus producing an interstrand cross-link of the double helix (Fig. 238-1). This
intercalation of psoralens with epidermal DNA suppresses both DNA synthesis and cell division,
and it was originally assumed that this was the therapeutic mechanism in psoriasis. However, cross-
linking does not appear to be a prerequisite for the therapeutic effect,7 and successful PUVA
treatment of other skin diseases is unlikely to be directly caused by this molecular reaction; psoralens
also react with RNA, proteins, and other cellular components, and indirectly modify proteins and
lipids via singlet oxygen-mediated reactions or by generating free radicals.7 Perhaps these
mechanisms contribute to the effects of PUVA in diseases that are not hyperproliferative in nature.

Figure 238-1 Psoralen photochemistry. Psoralens intercalate between apposing DNA base pairs
forming a “dark complex.” Absorption of ultraviolet A (UVA) photons leads to a 3,4- or 4,5-
cyclobutane monoadduct with pyrimidine bases of native DNA. The absorption of a second photon
results in a bifunctional adduct producing an interstrand cross-link of the double helix.

The formation of mono- and bifunctional photoadducts in DNA results in the immediate inhibition
of DNA synthesis. The interstrand cross-links are believed to be largely responsible for eliciting
skin photosensitization reactions of linear psoralens such as 8-MOP. Excessive production of these
cyclobutane adducts causes cell death. Mutation and skin carcinogenesis also result from
photoconjugation of psoralens to DNA because the cells surviving this DNA damage tend to repair it
through an error-prone repair process.7
In type II reactions (see Chapter 90), reactive oxygen species (1O2, O2, or OH) induce the
oxidation of cellular lipoprotein membrane lipids and destruction of membrane-bound cytochrome
P450. The membrane-damaging events activate the arachidonic acid metabolism pathway, which
results in an increase of secondary oxidation products that contribute to the increased synthesis of
eicosanoids. Furthermore, the reactive oxygen species can directly damage DNA by generating DNA
strand breaks.7

Mechanisms of Photochemotherapy.
Hypotheses about the mechanism of action in psoriasis are based on the known photoconjugation of
psoralens to DNA with subsequent suppression of mitosis, DNA synthesis, and cell proliferation,
expected to revert increased cell proliferation rates in psoriasis to normal. However, PUVA also
alters the expression of cytokines and cytokine receptors, downregulates certain lymphocyte and
antigen-presenting cell functions, influences adhesion molecule expression, and diminishes
Langerhans cell numbers within the epidermis. In addition, PUVA affects immune effector cells such
as lymphocytes or polymorphonuclear leukocytes. Because there is evidence that psoriasis is caused
primarily by the action of blood-derived immunocytes, it is reasonable to speculate that PUVA
therapy may act by affecting immune function through a direct phototoxic effect on lymphocytes in
skin infiltrates. This is consistent with the observation that several other disorders that are not
hyperproliferative in nature but immunomediated also respond well to PUVA. PUVA can revert
pathologically altered patterns of keratinocyte differentiation and reduce the number of proliferating
epidermal cells. Infiltrating lymphocytes are strongly suppressed by PUVA, with variable effects on
different T-cell subsets. Lymphocytes are far more likely to undergo apoptosis than keratinocytes8 in
response to PUVA, which may explain the high efficacy in cutaneous T-cell lymphoma (CTCL), as
well as in inflammatory skin diseases including psoriasis that is now recognized to be in part T-cell
mediated as well as hyperproliferative. Although much is known about pathways and mechanisms of
psoralen photosensitization, the interactions and relative contributions to the clearing of a specific
disease are not well understood.
Psoralens also stimulate melanogenesis. This involves the photoconjugation of psoralens to DNA
in melanocytes, mitosis, and subsequent proliferation of melanocytes, an increased formation and
melanization of melanosomes, an increased transfer of melanosomes to keratinocytes, and activation
and increased synthesis of tyrosine mediated in part by stimulation of cAMP activity.

Pharmacokinetics.
The important steps between the ingestion of a psoralen and its arrival at the site of action include
absorption, first-pass effect, blood transportation, and tissue distribution. The absorption rate of a
psoralen from the gut depends mainly on the physical characteristics of the preparation and the fat
content of the concomitant food intake. Liquid preparations of 8-MOP and 5-MOP give higher and
earlier peak serum levels than do crystalline formulations. In addition, peak serum levels are
achieved by liquid preparations after a relatively reproducible time interval in all subjects, whereas
wide time variability occurs with crystalline formulations. Before reaching the skin via the
circulation, psoralens are metabolized during passage through the liver. Plasma levels of 8-MOP
administered orally at different doses show a strong nonlinearity, indicating a saturable first-pass
effect. The unpredictable pharmacokinetic behavior is probably due to inter- and intraindividual
variations of intestinal absorption, first-pass effect, blood distribution in the body, metabolism, and
elimination of the drug.
Within the same individual, serum levels of 8-MOP correspond fairly well with skin reactivity,
the peak of skin phototoxicity coinciding with peak serum levels. However, phototoxic responses to
PUVA show large interindividual variations. Hence, measurement of serum psoralens is a research
tool and not used to monitor clinical therapy.
The pharmacokinetics of 8-MOP after topical treatment depend on the method of application. 8-
MOP topically applied as a 0.15% emulsion or solution leads to plasma levels comparable to those
found with oral treatment if large areas of the body are treated. In contrast, plasma levels after bath-
PUVA treatment of almost the total body surface are very low. Bathwater-delivered psoralens are
readily absorbed in the skin but are promptly eliminated without cutaneous accumulation.8

Ultraviolet A Radiation.
UVA sources commonly used for PUVA therapy are fluorescent lamps or high-pressure metalhalide
lamps. The typical fluorescent PUVA lamp has an emission peak at 352 nm and emits approximately
0.5% in the UVB range. UVA doses are given in Joules per centimeter2, usually measured with a
photometer with a maximum sensitivity at 350–360 nm. Although the action spectrum of antipsoriatic
activity and phototoxic erythema peaks at 335 nm, longer wavelengths have proved equally effective
for clearing psoriasis if delivered in an adequate dose to obtain an equal erythemogenic response.9

Photosensitivity Effects of Photochemotherapy.

PUVA treatment produces an inflammatory response that manifests as delayed phototoxic erythema,
proportional to the dose of both drug and UVA as well as to the individual’s sensitivity to phototoxic
reactions. 8-MOP dose changes within individuals, over a narrow but clinically relevant range,
appears to significantly alter the threshold for PUVA erythema, but not the rate of increase in
erythema intensity with increasing UVA dose.10 Importantly, the time course of PUVA erythema
differs from sunburn or UVB erythema that appears after 4–6 hours and peaks 12–24 hours after
exposure. PUVA erythema does not appear before 24–36 hours and peaks at 72–96 hours, or even
later. Hence, daily PUVA treatments can result in unexpected severe delayed cumulative
phototoxicity. PUVA erythema has a shallower dose-response curve than UVB erythema (by a factor
of approximately 2) and this difference is maintained even at the point of maximum erythema.11
Severe PUVA reactions may lead to blistering and to superficial skin necrosis. Overdoses of UVA
are frequently followed by swelling, intense pruritus, and, sometimes, by a stinging sensation in the
affected skin area, possibly as a consequence of damage of superficial nerve endings. Erythema is at
present the only available parameter that allows an assessment of the magnitude of the PUVA
reaction; thus, it represents an important criterion for dose adjustments.9
Pigmentation is the second important effect of PUVA. It may develop without clinically evident
erythema, especially when oral 5-MOP or TMP is used; this is particularly important in the treatment
of vitiligo and for the preventive therapy of certain photodermatoses. In unaffected skin, PUVA
pigmentation is maximal approximately 7 days after a PUVA exposure and may last from several
weeks to months. As with sun-induced pigmentation, the individual’s ability to tan is genetically
determined, but the dose-response curve is much steeper. A few PUVA exposures result in a much
deeper tan than that produced by multiple exposures to solar radiation.

TREATMENT PROTOCOLS

Topical Treatment.
Application of 8-MOP in creams, ointments, or lotions followed by UVA irradiation is effective in
clearing psoriasis but has several disadvantages. The nonuniform distribution on the skin surface
induces unpredictable phototoxic erythema reactions and irregular patches of cosmetically
unacceptable hyperpigmentation. Furthermore, if numerous lesions are present, the application is
laborious and time consuming, and the treatment does not prevent the development of new active
lesions in previously unaffected, untreated areas. Therefore, topical PUVA with psoralen creams,
ointments, or lotions is now used only for limited plaque psoriasis and for palmoplantar disease.

Bath Photochemotherapy.
The use of bathwater delivery of psoralens provides for a uniform drug distribution over the skin
surface, very low psoralen plasma levels, and rapid elimination of free psoralens from the skin.
Bathwater delivery of 8-MOP circumvents gastrointestinal side effects and possible phototoxic
hazards to the eyes because there is no systemic photosensitization. Skin psoralen levels are highly
reproducible, and photosensitivity lasts no more than 2 hours. The higher incidence of unwanted burn
reactions can be prevented by a lower starting dose [50% of the minimal phototoxic dose (MPD)]
and a more cautious dosimetry in the initial treatment phase. A major drawback in many treatment
facilities is the requirement for a bathtub. Originally, bath-PUVA was performed with TMP, but 8-
MOP and 5-MOP are now being used as well. Bath-PUVA consists of 15–20 minutes of whole-body
immersion in solutions of 0.5- to 5.0-mg 8-MOP per liter of bathwater. Irradiation needs to be
performed immediately, as photosensitivity decreases rather rapidly. TMP is more phototoxic after
topical application and is used at lower concentrations than 8-MOP. Minimal phototoxicity dose
(MPD) determination for bath-PUVA must take into account that the phototoxic threshold declines
during the early treatment phase,8 in contrast to oral PUVA. Guidelines for bath, local immersion, and
other topical PUVA forms have been published by the British Photodermatology Group and are
based, where possible, on the results of controlled studies, or otherwise on consensus.12

Oral Treatment.
In oral PUVA, 8-MOP is administered orally (0.6–0.8 mg/kg body weight) 1–3 hours before
exposure, depending on the absorption characteristics of the particular drug brand. Liquid drug
preparations are absorbed faster and yield higher and more reproducible serum levels than
microcrystalline forms. For 5-MOP, the usual dosage is 1.2- to 1.8-mg/kg body weight.
The initial UVA doses are determined by either the patient’s skin type13–15 or by MPD testing.9
The MPD is defined as the minimal dose of UVA that produces a barely perceptible, but well-
defined, erythema when template areas of the skin are exposed to increasing doses of UVA. Erythema
readings are performed 72 hours after testing, at which time the psoralen phototoxicity reaction
usually reaches its peak. The MPD test should be performed on previously nonexposed skin (e.g.,
buttocks). Although the MPD test is more time-consuming than phototyping, it allows for more
accurate and higher UVA doses during initial treatment. Table 238-2 shows recommendations for
dosimetry in bath and oral PUVA.

TABLE 238-2
Recommended Treatment Schedule for Photochemotherapya

Repeated exposures are required to clear PUVA-responsive diseases, with gradual dose
increments as pigmentation develops. Lower doses quite frequently result in failure of treatment
except in those diseases in which induction of pigmentation is the desired objective. In most
dermatoses amenable to PUVA, the frequency of treatments is reduced after satisfactory clearing of
disease, and the last UVA dose is used as a maintenance dose, if maintenance treatment is planned.
The duration of this maintenance phase and the frequency of treatments depend on the particular
disease being treated and its propensity to relapse.

INDICATIONS FOR PHOTOCHEMOTHERAPY

PHOTOCHEMOTHERAPY FOR PSORIASIS.

Basically all types of psoriasis respond to PUVA (Figs. 238-2 and 238-3), although the management
of erythrodermic or generalized pustular psoriasis is more difficult.8 The effectiveness of oral PUVA
in inducing and maintaining remission of psoriasis has been widely documented and confirmed by
large-scale clinical trials (see Figs. 238-2 and 238-3).
Figure 238-2 Twenty-three-year-old patient with generalized psoriasis (seborrheic type). A. Before
photochemotherapy treatment. B. After treatment. (From Wolff K et al: Photochemotherapie bei
Psoriasis. Klinische Erfahrungen bei 152 Patienten. Dtsch Med Wochenschr 100:2471, 1975 with
permission.)

Figure 238-3 Twenty-three-year-old patient with generalized psoriasis (plaque-type). A. Before

photochemotherapy treatment. B. After treatment. (From Wolff K, Hönigsmann H: Clinical aspects of
photochemotherapy. Pharmacol Ther 12:381, 1981 with permission.)

Administration.
Three studies have compared bathwater delivery of 8-MOP with oral administration.8 In two reports,
initial doses were determined by skin typing, and treatments were given two to three times weekly.
Dose increments were instituted with every treatment in one study, whereas smaller increments were
given every third treatment in the other. In the third report, patients were treated according to the
standard European regimen for oral PUVA, which is still in use (treatments four times weekly with an
intermission on Wednesdays until clearing). This showed the lowest incidence of treatment failures
and overdose phenomena, despite the potential burn risk of back-to-back PUVA treatments.
Compared with oral 8-MOP, bath-PUVA showed equal clearing rates with fewer exposures.8 The
greater therapeutic efficacy could be because of a higher penetration of psoralens through the
abnormal stratum corneum overlying psoriatic plaques, as compared with healthy perilesional skin
where phototoxicity is monitored during the therapy. The incidences of erythema and pruritus were
similar or lower compared with oral therapy. Systemic intolerance, such as nausea and vomiting,
were not observed.
Oral 5-MOP–PUVA represents an alternative to oral 8-MOP–PUVA. Psoriatic lesions are
cleared with a comparable number of treatments, but at the expense of significantly higher cumulative
UVA doses. This difference may be due to the lower phototoxicity potential of 5-MOP and of its
higher tanning activity. However, 5-MOP–PUVA therapy is not associated with nausea and vomiting
and has a lower incidence of pruritus and severe phototoxic erythema.8
On complete clearing, patients are often assigned to maintenance therapy, during which the
frequency of treatments is gradually reduced. The purpose of maintenance therapy is to achieve
longer remission. Maintenance therapy in the original European regimen consisted of 1 month of
twice-weekly treatments, with the last UVA dose used for clearing, followed by another month of
once-weekly exposures. According to other recommendations,16 maintenance treatment should be
considered only on rapid relapses, because patients with a stable remission may be overtreated, and
long-term risks of PUVA are related to the total cumulative phototoxic doses. In one recent left-right
comparison study with psoriatics, PUVA maintenance treatment over 2 months did not increase the
length of remission.17 Thus, maintenance treatment should be given only in selected cases.
Erythrodermic and generalized pustular psoriasis (von Zumbusch type) respond to PUVA (Fig.
238-4), but the time required to induce remission is considerably longer, more treatments are needed,
and higher failure rates are reported, compared with plaque or guttate varieties. Pustular eruptions of
palms and soles are quite recalcitrant to treatment, regardless of whether they are true localized
pustular psoriasis, nonpsoriatic palmoplantar pustulosis or pustular psoriasis, or pustular eczema.
Oral PUVA alone can produce a slow but definite remission in many cases, but a considerable
number of patients require adjunctive therapy for clearing. As mentioned above, the combination
with topically applied 8-MOP can be beneficial, but bath-PUVA appears to be also quite effective in
such cases.
Figure 238-4 Eighteen-year-old patient with pustular psoriasis (von Zumbusch type). A. Before
photochemotherapy treatment. B. After treatment. (From Hönigsmann H et al: Photochemotherapy for
pustular psoriasis (von Zumbusch). Br J Dermatol 97:119, 1977, with permission.)

PUVA alone can produce definite remissions in many patients with psoriasis, but a considerable
number require additional therapies for clearing. Such combination therapy improves efficacy and
may reduce side effects.

Combination Treatments

Topical Combinations.
Topical adjuvant therapies with glucocorticoids, anthralin, and tar preparations, and, more recently,
with calcipotriol and tazarotene, have yielded good results. However, adjunctive topical therapy is
unacceptable to some patients.

Methotrexate.
A combination of PUVA and methotrexate can reduce the duration of treatment, number of exposures,
and total UVA dose and is also effective in clearing patients unresponsive to PUVA or UVB alone.18
This combination appears to be safe if used during the clearing phase only. However, if used for
long-term treatment, PUVA and methotrexate may act synergistically in the development of skin
cancers.19

Cyclosporine.
Cyclosporine plus PUVA dramatically enhances skin carcinogenesis. This is in keeping with the
observation of a greatly increased risk of cutaneous squamous cell carcinomas in patients with solid
organ transplants maintained on this immunosuppressant. Thus, this combination should be definitely
discouraged.8,20–22
Retinoids.
The therapeutic efficacy of PUVA therapy is dramatically increased by daily oral retinoid (etretinate,
acitretin, isotretinoin; 1 mg/kg) administration beginning 5–10 days before the initiation of PUVA,
and continued throughout the clearing phase. This so called RePUVA characteristically reduces the
number of exposures by one-third and the total cumulative UVA dose by more than one-half.
RePUVA also often clears “poor responders” who are not brought into complete remission by PUVA
alone.23
The mechanism of the synergistic action of retinoids and PUVA is unknown, but may be a result of
the accelerated desquamation that optimizes the optical properties of the skin and reduction of the
inflammatory infiltrate. As an additional theoretic benefit, etretinate and other retinoids may protect
against long-term carcinogenic effects of PUVA. In one study, patients with psoriasis treated with
PUVA in combination with systemic retinoids showed a reduced risk of squamous cell carcinoma but
not a significantly altered incidence of basal cell carcinoma (BCC).24 Although retinoid toxicity is
generally not a concern because the administration is limited to the clearing phase, the potential
teratogenicity of retinoids represents a serious concern for women of childbearing age. In these
patients, the use of isotretinoin is advisable because contraception is necessary for only 1 month after
discontinuation of therapy, in contrast to etretinate and acitretin, which require 2 years of
contraception because of their slower elimination.8

Biologics.
The mechanism of action of biologic agents suggests that there may be additive effects in treating
psoriasis with PUVA, but this remains to be further defined in clinical trials.25,26 Presently, there are
no long-term studies evaluating the safety and efficacy of the combination of any biologics with
PUVA.

PUVA FOR CUTANEOUS T-CELL LYMPHOMA (CTCL, MYCOSIS

FUNGOIDES).
Since the first promising results with PUVA in CTCL in 1976,27 numerous investigators from the
United States and Europe have confirmed the efficacy of PUVA for CTCL.28 Treatment schedules and
dosimetry are essentially the same as for psoriasis. The treatment consists of a clearing phase (Fig.
238-5), a maintenance phase consisting of two exposures per week for 1 month and one exposure per
week for another month, and a follow-up phase without therapy. Remission should be confirmed by
histologic examination of previously involved skin sites. After therapy is discontinued, the patient is
monitored monthly and later bimonthly. If a relapse occurs, the patient is again subjected to a full
PUVA course. Some investigators advocate permanent maintenance treatment consisting of treatments
once monthly or every other month. However, the course of CTCL varies considerably from patient
to patient, and clinical experience suggests that patients benefit most from individualized treatment
schedules.8
Figure 238-5 Forty-six-year-old patient with cutaneous T-cell lymphoma (mycosis fungoides) stage
IB. A. Before photochemotherapy treatment. B. After treatment (clearing phase).

Relapses often respond as well as the initial lesions when PUVA is resumed. Clinical remissions
appear to be directly related to phototoxic destruction of the malignant lymphocytes that infiltrate the
skin. Thus, complete clearing may be induced when the cells are confined to the epidermis and
superficial dermis, the depth of effective UVA penetration into the skin.
Present knowledge indicates that PUVA is an excellent treatment option that may induce long-
lasting disease-free intervals in CTCL if used in the early stages of the disease.28 In later stages,
PUVA may reduce the tumor cell burden and thus may act synergistically with other treatment. It
improves quality of life and may prolong survival when used in combination with more aggressive
treatment modalities. Prolonged remissions were observed with combinations of PUVA with
retinoids, bexarotene,29,30 or interferon-α 2a.31–33
Patients with tumor-stage CTCL exhibit a high rate of early recurrences and, therefore, require
indefinite maintenance treatment. PUVA causes complete tumor resolution only when used in
combination with local x-ray treatment and/or systemic chemotherapy. Most follow-up studies have
demonstrated that the great majority of patients with early disease can be kept in remission with or
without maintenance therapy for several years, but tumor-stage patients (IIB) usually experience
multiple recurrences despite aggressive combination therapies and eventually die within a few
years.28 Currently, no therapeutic regimen is known to alter the disease course of CTCL. Psoralen
UV-A is an effective treatment for MF, inducing long-term remissions and perhaps in some cases
disease “cure.” Thirty percent to 50% of patients remain disease free for 10 years, but late relapses
occur.34
Successful treatment of erythrodermic CTCL (Sézary syndrome) has been reported with
extracorporeal PUVA (photopheresis) [see Section “Extracorporeal Photochemotherapy
(Photopheresis)”]. Possible long-term hazards related to frequent PUVA treatments are better
justified for patients with CTCL, compared with patients with benign conditions.

PHOTOTHERAPY FOR ATOPIC DERMATITIS.

Many patients with atopic eczema can benefit from PUVA therapy.35 The treatment guidelines are the
same as for psoriasis. However, the condition is more difficult to treat, and quite often a higher
number of treatments are required to clear the eczema. There is a high and early recurrence rate,
requiring frequent maintenance exposures. However, in a recent study, PUVA provided a better
short- and long-term response than medium-dose UVA1 in patients with severe atopic eczema.36 A
combination of PUVA with topical glucocorticoids appears to be superior to PUVA alone in
maintaining remissions. Because the average patient is young, long-term maintenance therapy is
problematic; and combination of PUVA with topical immune modulators (tacrolimus, pimecrolimus),
although effective, cannot be recommended until more data are available. The mechanism of action of
PUVA in atopic eczema is unclear; current concepts support an alteration of lymphocytes in the
dermal infiltrate.

PHOTOTHERAPY FOR LICHEN PLANUS.

In generalized lichen planus, PUVA can provide an effective alternative to systemic glucocorticoid
treatment, although it appears to be more resistant to PUVA than psoriasis when treated according to
a similar schedule. More exposures and higher cumulative UVA doses are required for clearing, and
not all patients respond satisfactorily. An exacerbation during PUVA treatment has been reported in a
few patients. In patients who clear, relapses respond equally well when PUVA is resumed. Bath-
PUVA can also clear lichen planus, and combined PUVA-etretinate regimen may be considered.37

PHOTOCHEMOTHERAPY FOR CUTANEOUS MASTOCYTOSIS.

In cutaneous mastocytosis (urticaria pigmentosa), PUVA leads to a temporary involution of skin
lesions38 probably due to chronic degranulation of the mast cells. The treatment results in loss of
Darier sign, relief of itching, and flattening and even complete disappearance of cutaneous papules
and macules. Surprisingly, even systemic symptoms such as histamine-induced migraine and flushing
improve gradually as treatment is continued.38 In most patients, the manifestations of the disease recur
several months after discontinuation of PUVA, but the recurrences respond as well as the original
lesions.
Because treatment of cutaneous mastocytosis has been unrewarding with other modalities, the use
of PUVA, although not curative, seems to be warranted in patients when the disease is causing severe
distress.

PHOTOTHERAPY FOR MISCELLANEOUS DERMATOSES.

Both acute and chronic pityriasis lichenoides37 respond to PUVA, and favorable results have been
reported for lymphomatoid papulosis.39 However, the experience with these conditions is limited to a
few anecdotal cases. In pityriasis rubra pilaris, the results are quite inconsistent. Some cases seem to
respond well, others may flare, and some require combination treatment with retinoid or methotrexate
therapy. Generalized granuloma annulare has been reported to clear completely, but long-term
maintenance treatment was required to maintain remissions.40 Regrowth of hair was noted in alopecia
areata with either topical or systemic PUVA exposures localized to the alopecia areas. Follow-up
studies of larger patient groups concluded that PUVA is generally not an effective treatment for
alopecia areata.41 The experience of the present authors has also not been encouraging. Localized
scleroderma and pansclerotic morphea have been successfully treated with bath-PUVA and oral
PUVA.42,43

PHOTOCHEMOTHERAPY FOR CHRONIC GRAFT-VERSUS-HOST

DISEASE.
Acute and chronic cutaneous graft-versus-host disease (GVHD) has become indications of increasing
importance. Because of the clinical and histologic similarities of idiopathic lichen planus and
lichenoid GVHD, PUVA treatment was evaluated for the latter.44 PUVA cleared or improved this
lichen planus-like eruption in patients who had not responded to conventional immunosuppressive
therapy alone. PUVA can also improve acute GVHD,45 although results of PUVA treatment for
scleroderma-like variants of cutaneous GVHD are controversial. According to our own experience,
the more circumscribed, localized forms appear to respond to PUVA with softening of the fibrotic,
sclerotic connective tissue, but more widespread, disseminated lesions hardly respond.
Improvement of mucosal erosions followed by healing, observed during treatment of chronic
lichenoid GVHD with PUVA, suggests that PUVA may exert both local and systemic effects, but this
is not proven. There is no improvement of GVHD of other organs, such as the liver. The therapeutic
regimen used for the treatment of chronic GVHD is basically the same as for psoriasis. UVA doses
should not be increased too aggressively, to avoid erythema and possible (re)activation of GVHD. In
general, increase of the UVA dosage by 0.5 J/cm2 at maximum after every second to fourth exposure
is recommended. Patients are exposed to UVA radiation three to four times weekly. After clearing of
skin lesions, the frequency of exposures is reduced.
Because there appears to be an overall increased risk of secondary malignancies for all bone
marrow/peripheral stem cell recipients, patients should be examined on a regular basis for the
development of cutaneous malignancies, independent of whether they have been treated with PUVA.

PHOTOCHEMOTHERAPY FOR VITILIGO.

Vitiligo was the first disease treated with an ancient form of psoralen PUVA in India and Egypt.
PUVA in its modern form stimulates melanogenesis, melanocyte proliferation, and migration, and can
reconstitute the normal skin color in many vitiligo patients although the actual response rate has
still not been defined. However, it is less used now since narrowband UVB phototherapy has been
shown to be effective and possibly safer alternative for repigmentation of this condition (see later).
To induce maximal repigmentation, patients need long-term therapy with 100–200 exposures
given twice or thrice weekly. Approximately 70% of patients respond after 12–24 months (Fig. 238-
6), defined as the development of perifollicular macules of repigmentation. If there is no response
after 6 months or approximately 50 treatments (as defined as perifollicular macules of
repigmentation), PUVA should be terminated. If treatment is discontinued, this newly acquired
repigmentation may be lost. The permanency of PUVA-induced repigmentation in vitiligo is poorly
documented. Some investigators have reported continuing pigment loss following PUVA, while
others have reported the repigmentation to be long lasting.46

Figure 238-6 Twelve-year-old patient with generalized vitiligo of 4 years’ duration. A and C. During
the initial phases of photochemotherapy treatment. B and D. One month after treatment (8-
methoxypsoralen + artificial ultraviolet A) with thrice-weekly exposures for 10 months.

Patient selection appears to be particularly important in vitiligo treatment. Lips, distal dorsal
hands, tips of fingers and toes, areas of bony prominences, palms, soles, and nipples are very
refractory to treatment, and patients with involvement limited to these areas should be excluded.
Segmental vitiligo tends to show a variable response. Because of the different response in different
body areas, total repigmentation is only rarely achieved, and some 30% of patients do not respond at
all despite many months of therapy. Duration of the disease before PUVA therapy does not affect
response rate.46 It should be mentioned here that in a recent trial of nonsegmental vitiligo,
narrowband-UVB therapy resulted in a better color match than oral PUVA.47
The mechanisms by which PUVA induces repigmentation in vitiligo skin are speculative.
However, PUVA’s known effect on a number of immunologic reactions suggests a suppression of the
autoimmune stimulus for melanocyte destruction.

PHOTOCHEMOTHERAPY AS PREVENTION FOR PHOTODERMATOSES.

Tolerance to sunlight can be induced in several photodermatoses by PUVA therapy.48 In
polymorphous light eruption, the most common photodermatosis, PUVA is the most effective
preventive treatment.49 In approximately 70% of patients with this condition, a 3- to 4-week PUVA
course of two to three treatments per week suffices to suppress the disease on subsequent exposure to
sunlight such as a holiday trip or the arrival of summer. The initial exposure and dose increments
during therapy should be performed according to the guidelines outlined for psoriasis. PUVA has the
advantage of a rapid and intense pigment induction at relatively low UVA doses that usually remain
well below the threshold doses for eliciting the rash. Approximately 10% of patients develop typical
lesions during the initial phase of PUVA, but these usually disappear when treatment is continued.
The authors’ treatment schedule consists of three to four treatments per week for 3–4 weeks in early
spring. PUVA protects only temporarily, but subsequent sun exposures usually maintain protection
and many patients remain protected for 2–3 months even after their pigmentation has faded.
The mechanism by which phototherapy induces tolerance to sunlight is not clear.
Hyperpigmentation and thickening of the stratum corneum may be important factors, but other
mechanisms, such as modulations of cutaneous immune function, may also be involved.49
There is also some experience with PUVA prophylaxis of other photodermatoses. In solar
urticaria, PUVA therapy appears to be the most effective preventive treatment available and is
certainly better than antihistamines. Tolerance to sunlight can be increased 10-fold or more after a
single treatment course.50 The suppressive effect may last throughout the summer if the patients have
regular sunlight exposures, which seems to be necessary to maintain tolerance. Problems may arise
during the first PUVA exposures, because, in some patients, the urticaria threshold dose is very low.
In these cases, careful conditioning by stepwise UVA irradiation of single quadrants of the body
surface a few hours before each PUVA treatment has proved useful. Treatments with PUVA are then
given during the refractory period of presumed mast cell degranulation.
Successful PUVA therapy has also been reported in occasional cases of chronic actinic dermatitis
and hydroa vacciniforme. Limited experience in patients with erythropoietic protoporphyria
indicates that, with a very cautious approach and in combination with β-carotene, PUVA may
increase light tolerance considerably.51,52
Extended treatment is usually not required in polymorphous light eruption but may be necessary in
solar urticaria and chronic actinic dermatitis. There exist no ready-to-use schedules for these latter
conditions, and PUVA is usually just one part of the management.51

PHOTOCHEMOTHERAPY IN HUMAN IMMUNODEFICIENCY VIRUS-

INFECTED PATIENTS.
The use of phototherapy and PUVA in human immunodeficiency virus (HIV)-infected patients with
skin diseases is controversial. Both therapies can induce systemic immune suppression and may
modify the immune status of the patient in a way that would worsen HIV disease.53 Both UV radiation
and psoralen photosensitization activate the HIV promoter, which could boost viral gene
transcription and, eventually, virus production,54 although available data and theoretic considerations
indicate that UVB is more likely to be a hazard than PUVA in an HIV-infected population.55,56
Nevertheless, oral PUVA treatment of psoriasis does not detectably accelerate progression of HIV
disease or increase PUVA side effects, and hence PUVA is not considered contraindicated for HIV-
positive patients with responsive skin diseases.57
SIDE EFFECTS AND TOXICITY OF PHOTOCHEMOTHERAPY
(Table 238-3)

TABLE 238-3
Side Effects and Toxicity of Photochemotherapy

ACUTE SIDE EFFECTS.

The side effects of PUVA include drug intolerance reactions as well as side effects of the combined
action of psoralens plus UVA radiation. Oral 8-MOP (0.6–0.8 mg/kg) has a high incidence of nausea
(30% of patients) and vomiting (10% of patients), and this may occasionally require discontinuation
of the treatment. The mechanism of this adverse effect is unknown. These side effects are more
common with liquid preparations than with crystalline preparations, probably because of higher
psoralen serum levels. With 5-MOP, nausea occurs rarely, even with doses of up to 1.8 mg/kg body
weight.
Undesired acute effects of the combined action of psoralens and UVA include unexpectedly
severe delayed erythema reactions. Severe burns with blistering can occur and may rarely require
hospitalization. When large areas of skin are affected, systemic symptoms of excess phototoxicity,
such as fever and general malaise, may occur. Nonsteroidal anti-inflammatory drugs and topical and
systemic corticosteroids may be required to alleviate the symptoms but have to be given early. Some
patients experience persistent pruritus during PUVA treatment, particularly after slight UVA
overdosage, and, in rare cases, a stinging pain may develop in circumscribed areas. The mechanism
is unknown although a phototoxicity reaction affecting cutaneous nerves is postulated, and the
symptoms are unresponsive to antihistamines. These complaints usually subside on continuation of
treatment. Overdosage phenomena occur mostly in body areas not usually exposed to natural sunlight.
Cautious dosimetry can minimize these side effects. The danger of overdosage is much less with 5-
MOP than with 8-MOP.
Very rare side effects of PUVA include polymorphous light eruption-like rashes, acne-like
eruptions, subungual hemorrhages caused by phototoxic reactions in the nail beds, and occasional
hypertrichosis of the face. These disappear when treatment is discontinued. Single case reports note
exacerbation of systemic lupus erythematosus and bullous pemphigoid during PUVA.

LABORATORY DATA.
Analysis of laboratory data in several large-scale studies showed no significant abnormal findings in
patients receiving PUVA over prolonged periods of time.13,14,58 Serial laboratory examinations
performed over a period of several years have not revealed any substantial evidence for impairment
of hepatic function. Liver biopsies after 1 year of therapy did not reveal hepatotoxicity.59 No
evidence exists suggesting impairment of renal function.13 Several large-scale studies have negated a
suggested relation between PUVA therapy and the occurrence of antinuclear antibodies.60

POTENTIAL LONG-TERM RISKS OF PHOTOCHEMOTHERAPY

Chronic Actinic Damage.

Repeated photodamage to the skin can be expected to result in cumulative injury regardless of
whether it is induced by sunlight, artificial UV radiation, or PUVA. Chronic exposure to PUVA may
produce changes that resemble photoaging and that may compound the injury induced by sunlight.
PUVA lentigines and generalized PUVA lentiginosis result from repeated and prolonged treatment
and are commonly associated with high cumulative doses of UVA and a large number of treatments.14
The lentigines exhibit irregular borders and uneven pigmentation. No increased risk of cutaneous
melanoma has been associated with these lentigines, but the cosmetic effect may be quite disturbing.

Carcinogenesis.
Cutaneous carcinogenicity is the major concern for long-term PUVA treatment associated with high
cumulative UVA doses. PUVA is a photocarcinogen (see Chapter 112). In laboratory animals, 8-
MOP and 5-MOP have been unequivocally shown to induce skin cancer at levels of drug and UVA
irradiation comparable to those used in PUVA therapy.61,62 This risk is related to DNA damage, but
PUVA-induced down-regulation of immune responses may play an additional role. This risk has to be
assessed against the potential therapeutic benefit.
Long-term follow-up PUVA studies are confounded by the fact that patients, particularly those
with severe psoriasis, are likely to have been exposed previously to other carcinogenic treatments,
such as ionizing radiation, UVB therapy, methotrexate, tar, or arsenic, and accurate exposure data are
often lacking.
In PUVA patients, the risk of squamous cell carcinoma, but not of BCC, is significantly increased
in comparison with matched controls and the magnitude of the increase appears to be dose
dependent.19,62 However, there is uncertainty about PUVA being the sole factor—many of the
affected patients had previous exposure to excessive sunlight and to treatments with carcinogenic
potential, including arsenic, UVB, and antimetabolite therapy.63 Particularly, high levels of UVB
exposure appear to increase the risk of nonmelanoma skin cancer in PUVA-treated patients.64 An
increased risk of any skin cancer with oral PUVA has not been shown in the non-Caucasian
population.65 According to one study, the genitalia in men previously treated with tar and UVB
appeared to be particularly susceptible to PUVA carcinogenesis,66 but in a separate population the
risk seemed not to be increased if only PUVA was used.67 In a retrospective study from France
comprising 5,400 patients treated with PUVA between 1978 and 1998, no case of genital skin cancer
was found, despite the fact that the genital area had not been protected.68 This makes it unlikely that
genital shielding is absolutely necessary.
Carcinogenicity of 5-MOP–UVA therapy in PUVA-treated patients is not documented, but 5-MOP
has shown mutagenicity similar to 8-MOP in model systems.
Stern et al reported that of the cohort of 1,380 patients enrolled in the so-called 16 Center PUVA
Follow-up Study, 23 patients have developed 26 invasive or in-situ cutaneous melanomas over a
period of roughly 25 years. Beginning 15 years after first exposure to PUVA, this constituted an
increased risk of melanoma.69,70 This risk was greater in patients exposed to high doses of PUVA and
appeared to increase with the passage of time. Still, the authors conclude that the observed risk of
melanoma does not represent an absolute contraindication to PUVA. Rather, the risks of both
melanoma and squamous cell carcinoma in PUVA should be weighed against the substantial efficacy
of PUVA and the risks of other therapies.70,71 As well, no increased risk of melanoma has been
observed so far in any large-scale study from Europe; and several other US studies did not show an
increased risk of melanoma in patients treated with PUVA72,73 Of note, PUVA’s long-term risks have
been subject to much greater scrutiny than the risks of other therapies advocated for severe psoriasis,
such as methotrexate and, particularly, immunosuppressive therapies such as cyclosporine. These
latter therapies greatly increase cancer risk in populations less likely to have substantial exposures to
other known cutaneous carcinogens such as UVB than are patients with severe psoriasis. Early
detection through careful, long-term follow-up and education of PUVA patients may reduce the long-
term morbidity and mortality associated with this therapy, as can low cumulative dosage regimens.74
Studies of 944 Swedish and Finnish patients75 and 158 Finnish patients76 with psoriasis showing
no association between cutaneous cancer and TMP or 8-MOP bath-PUVA, respectively, are also
reassuring. Mathematic model studies indicate that the observed risk of squamous cell carcinoma is
much higher with PUVA than with UVB,77 but the carcinogenic risk of narrowband UVB in
comparison with PUVA is unknown, and it will be crucial to monitor its long-term effects in
psoriatics.

Ophthalmologic Effects.
Data from animal studies indicate a risk of premature cataract formation due to PUVA, but clinical
evaluation suggests no increase in lens opacities, even in patients who neglect careful eye protection
during long-term PUVA.78,79

PATIENT SELECTION AND CONTRAINDICATIONS

In view of the potential short-term and long-term hazards of PUVA, the assignment of patients should
be based on consideration of the risks and the benefit for the individual patient. If only a short-term
course of therapy is planned, as, for example, in prevention of photodermatoses, the benefit very
probably outweighs the risk. In the treatment of a malignant condition such as CTCL, long-term risks
may be discounted because other treatment options bear even greater long-term risks. The major
concerns relate to long-term treatment of psoriasis, by far the most common indication for PUVA.
Careful patient selection is mandatory, bearing in mind that long-term risks of alternative therapies
may simply be less well documented rather than less. Guidelines have been published.15
PUVA is not recommended during pregnancy, and women should be advised to use contraceptive
measures while on PUVA. This precaution is only for reasons of absolute safety as there is no
evidence that 8-MOP alone is teratogenic, and UVA does not penetrate through the abdominal and
uterine walls. Further, a retrospective study in 256 deliveries among the cohort of the 16-Center
PUVA Follow-Up Study revealed no birth defects.80 However, it has to be emphasized that RePUVA
bears the risk of retinoid teratogenicity.
Severe impairment of hepatic and renal functions is usually considered a contraindication to
PUVA because metabolism and excretion of psoralens may be inadequate. PUVA is also
contraindicated in patients with known light-aggravated or light-induced diseases such as lupus
erythematosus, porphyria (but, as mentioned earlier, light tolerance can be induced by PUVA in
erythropoietic protoporphyria), and xeroderma pigmentosum. Pemphigus vulgaris and bullous
pemphigoid may be exacerbated by PUVA. Patients with chronic actinic damage and a history of skin
cancers may be at higher risk for the development of new cancers. Previous arsenic intake and
previous treatment with ionizing radiation also seem to increase the risk of nonmelanoma skin
cancers. Immunosuppressed patients should probably not receive PUVA, although this is not yet
clearly defined. As outlined earlier, PUVA can be used in HIV-positive patients. Cataracts and
aphakia are not contraindications if adequate eye protection is employed.

CONCLUSIONS AND PERSPECTIVES

PUVA is a highly effective treatment for several dermatologic diseases. Although there exists
comprehensive clinical experience documenting PUVA’s short-term safety when used according to
standardized methods, potential long-term sequelae are still being studied. Thus, treatment decisions
should take into account whether other equally effective forms of therapy that carry a lower risk are
available. Risk-versus-benefit varies with the disease being treated.
Severe widespread psoriasis is a devastating disease that may impair professional, social, and
private life. After more than three decades of experience with PUVA for the treatment of psoriasis, it
is evident that this therapy offers innumerable patients the chance to resume a normal life. For
disabling psoriasis, the choice of therapies lies not between risk and safety but among modalities
(methotrexate, cyclosporine, UVB, and biologics), none of which is absolutely safe.71

EXTRACORPOREAL PHOTOCHEMOTHERAPY
(PHOTOPHERESIS)
Extracorporeal PUVA (ECP) was introduced in the 1980s for the palliative treatment of
erythrodermic CTCL,81 a disorder characterized by circulating malignant lymphocytes. Its efficacy
was subsequently confirmed by several clinical trials and approved in 1988 by the US Food and
Drug Administration for this indication. At the International Consensus Conference on Staging and
Treatment Recommendations for CTCL in 199482 and at the European Organization for Research and
Treatment of Cancer Consensus Recommendations in 2006,83 ECP was recommended as the first line
of treatment for patients with erythrodermic CTCL.
Attempts to better characterize those CTCL patients likely to respond to ECP revealed a
significant association between response and CD4:CD8 ratio. Patients with a ratio less than 10 are
more likely to respond than patients with a ratio greater than 10. There is also a marginally
significant association between response and lactic acid dehydrogenase (LDH) level, with patients
whose LDH is not elevated at the start of treatment responding better than patients with an elevated
LDH.84
Besides CTCL, ECP also plays an important role in the treatment of chronic GVHD after
allogeneic bone marrow transplantation with excellent response rates. ECP has also been used in
uncontrolled studies in several other autoimmune diseases including systemic sclerosis, acute
allograft rejection among cardiac, lung, and renal transplant recipients85–87 and Crohn disease, with
some success.

TREATMENT METHOD
ECP originally involved the oral administration of 8-MOP followed by phlebotomy at the time of
peak photosensitization passage of blood fractions from one arm vein through a photopheresis
machine and back. A discontinuous flow cell separator harvests peripheral blood mononuclear cells
(PBMCs) in a buffy coat collection and returns the red cell fraction to the patient without further
treatment. The collection of PBMC is then exposed to 2.0 J/cm2 of UVA using a photopheresis device
that ensures exposure of individual PBMC in a thin film to the light source and then reinfused into the
patient. More recently, 8-MOP is administered directly to the heparinized plasma and buffy coat
fraction as it flows through a UVA exposure system, thereby avoiding 8-MOP-induced nausea and
unintended phototoxicity with subsequent incidental sun exposure.88 This treatment is customarily
repeated on 2 successive days at 2- to 4-week intervals.

MECHANISM OF ACTION
The mode of action of ECP remains unknown. The PUVA exposures likely induce apoptosis of
circulating malignant lymphocytes. However, it has also been shown that infusion of autologous
haptenated cells in which apoptosis had been initiated by 8-MOP/UVA induces immunologic
tolerance. This tolerance is likely due primarily to regulatory T cells because transfer can be
achieved in an animal model. Induction of regulatory T cells could also explain why ECP exerts a
beneficial effect in a wide variety of immune-mediated diseases and why generalized
immunosuppression does not occur with ECP.89,90

SIDE EFFECTS
No serious side effects have been reported with ECP. With oral ingestion of 8-MOP, transient nausea
is not uncommon (as in oral PUVA therapy) and, rarely, episodes of hypotension and vasovagal
reflex due to volume shifts during treatments have been noted. However, these events usually do not
interfere with the treatment.

TREATMENT RESULTS

CUTANEOUS T-CELL LYMPHOMA.

Erythrodermic CTCL (Sézary syndrome) was the first disease for which ECP was evaluated. A
response occurs in up to 75% of the patients, with complete remissions in up to 25%. In Sézary
syndrome patients who do not sufficiently respond to ECP alone, ongoing studies are evaluating
possible synergistic effects with other treatments such as interferon-α, methotrexate, bexarotene, and
total-skin electron-beam therapy.91–94

GRAFT-VERSUS-HOST DISEASE AND ALLOGRAFT REJECTION.

ECP appears to have a major impact in the treatment of GVHD after allogeneic bone marrow
transplantation.95,96 In patients with either acute or chronic GVHD, ECP allows reduction or even
discontinuation of immunosuppressive therapy without an increase in GVHD activity. More than 450
patients with chronic (even steroid refractory cases), GVHD treated with ECP have been reported,
with mean response rates of 63% (range 29%–100%). Responses were highest for those patients
with cutaneous or mucous membrane involvement. Positive results have also been published for acute
GVHD.87,97 ECP is especially useful for patients affected by GVHD resistant to conventional
treatment.
As mentioned above, ECP is effective in the treatment of acute allograft rejection among lung,
cardiac, and renal transplant recipients. ECP is effective for patients resistant to conventional
treatments, particularly if started early. Benefit is obtained without the complications typically
encountered with immunosuppressive regimens used to control organ rejection.98,99 Table 238-4
shows indications for photopheresis as currently approved by regulatory agencies.

TABLE 238-4
Indications for Photopheresis (As Seen by Regulatory Agencies in 2006)
PHOTODYNAMIC THERAPY
Photodynamic therapy (PDT) aims to destroy the desired target selectively thereby minimizing
damage to normal tissue. The photodynamic reaction consists of the excitation of photosensitizers
(usually porphyrins) by visible light in the presence of oxygen, resulting in the generation of reactive
oxygen species, particularly singlet oxygen. These reactive oxygen species mediate cellular and
vascular effects, depending on the tissue localization of the photosensitizer, and results in a direct or
indirect cytotoxic effect on the target cells.100 In dermatology, PDT has been used effectively for
precancerous and malignant conditions such as actinic keratosis, BCC, Bowen disease, and
superficial squamous cell carcinoma, as well as for inflammatory and infectious dermatoses such as
localized scleroderma, acne vulgaris, and leishmaniasis. A relatively new approach is the treatment
of ageing skin with PDT (photochemorejuvenation).

PRINCIPLES OF PHOTODYNAMIC THERAPY

PHOTOSENSITIZERS.
The ideal photosensitizer for PDT in dermatology should meet the following criteria: (1) chemical
purity, (2) high singlet-oxygen quantum yield, (3) significant light absorption at wavelengths that
penetrate the skin sufficiently deeply, (4) high tissue selectivity, and (5) efficacy after topical
application.
Porfimer sodium (Photofrin), a systemically administered mixture of several hematoporphyrin
derivative (HpD) ethers and esters, has a low selectivity for skin tumors and leads to long-lasting
photosensitivity; consequently, it is far from ideal for dermatologic use. In contrast, 5-aminolevulinic
acid (ALA), an intermediate in heme biosynthesis or its methyl ester (MAL) leads to synthesis of
photosensitizing protoporphyrin IX in the target tissue.101 In this case, the concentration of the
photosensitizer depends on the metabolic status of the diseased tissue with photosensitization greatest
in precancerous or malignant tissue. ALA in combination with the blue light and MAL in combination
with red light are approved by the US Food and Drug Administration for the treatment of actinic
keratoses. In Europe, New Zealand, Australia, and South America, MAL has also been registered for
superficial and nodular BCCs, and Bowen disease.
Most photosensitizers generate singlet oxygen with a quantum yield between 5% and 20%. A high
quantum yield means that less sensitizer is required in the target tissue to induce sufficient PDT
effects. The light absorption maxima of the current sensitizers are in the visible range (400–700 nm).
In this range, light penetration in tissue is only up to 3 mm, limiting PDT to superficial tumors unless
interstitial light propagation is used. A high selectivity for sensitizer accumulation in target tissue is
necessary to avoid damage to surrounding normal tissue, and this is particularly important when
larger areas are treated (e.g., actinic keratoses). ALA and MAL show reasonably high selectivity
after topical application, with the ratio of porphyrin induction in skin tumors to the surrounding tissue
higher than 10:1,102 likely due to a combination of enhanced ALA-MAL penetration through an
abnormal stratum corneum and altered metabolism and accumulation within the premalignant or
malignant cells.

LIGHT SOURCES AND DOSIMETRY.

Light penetration into skin increases with longer wavelengths up to 1,100 nm. Although porphyrins
absorb maximally in the Soret band (400–410 nm, blue light), there are minor absorption peaks at
longer visible light wavelengths. To increase depth of penetration while matching the absorption
maxima of porphyrin photosensitizers, wavelengths around 630 nm are often used. Lasers are
effective but they are quite expensive, require regular maintenance, and have a small treatment
aperture. Hence, simpler incoherent light sources represent a valuable alternative. Fluorescent lamps
or light-emitting diodes with appropriate red or blue light emission are commercially available and
designed for treatment of large surface areas. Also, intense pulsed light sources are used for
dermatologic PDT. Dosimetry depends on the photosensitizer and light source used, as well as on the
condition to be treated. For PDT of epithelial cancer, photosensitization must be sufficient to induce
necrosis or apoptosis. With current incoherent light sources (lamps, light-emitting diodes), the
treatment duration, apart from of ALA-MAL incubation time, is approximately 10–15 minutes. For
treating inflammatory dermatoses, significantly lower doses suffice because the goal appears not to
be cell death but rather sublethal damage or modulation of cellular functions.

MECHANISM OF ACTION.
PDT-induced effects are mediated by photo-oxidative reactions. During irradiation, the
photosensitizer absorbs light (energy) and is converted to an excited (triplet) state. The energy can
then be transferred to molecular oxygen (type II photo-oxidative reaction), resulting in the generation
of reactive oxygen species, mainly singlet oxygen. The biologic effects can be divided into primary
cellular and secondary vascular damage. With HpD, early visible damage consists of cell membrane
defects as a consequence of lipid peroxidation with consequent cell lysis. Depending on the
intracellular localization of the photosensitizers, damage to subcellular structures, such as
mitochondria, lysosomes, or endoplasmic reticulum, also occurs, whereas DNA is not a primary
target. These direct effects probably play a key role in topical PDT, whereas vascular effects after
systemic administration of photosensitizers appear to be the decisive event. These effects consist of
vasoconstriction, blood stasis, and thrombosis of tumor vessels leading to tumor ischemia and
subsequent necrosis.103

PHOTODYNAMIC THERAPY IN DERMATOLOGY

Table 238-5 lists current applications for PDT described in the literature. In contrast to other organs,
the skin can be sensitized by either intravenous, topical, or intralesional routes of administration of
the photosensitizer.

TABLE 238-5
Current Indications for Photodynamic Therapy
SYSTEMIC PHOTODYNAMIC THERAPY.
PDT after systemic administration of HpD and porfimer sodium has been used for both skin cancers
and inflammatory dermatoses. Standard therapeutic procedures do not yet exist.

Systemic Photodynamic Therapy for Oncologic Indications.

Systemic PDT with porfimer sodium for Bowen disease is very effective,104 but invasive squamous
cell carcinomas respond less well, with recurrence rates of up to 50% within 6 months. Systemic
PDT for BCCs, first used in 1981,105 has been reported by Oseroff and coworkers106 to give initial
complete responses in 92.2% of 77 patients with sporadic BCC or nevoid BCC syndrome.106 In these
patients, the 5-year recurrence rate was 15%.
Benzoporphyrin-derivative monoacid ring A (verteporfin), registered for the ophthalmologic
indication of age-related macular degeneration, is also under investigation for PDT of BCC and
offers a duration of cutaneous photosensitization of less than 72 hours, significantly shorter than that
of porfimer sodium.107

Systemic Photodynamic Therapy for Nononcologic Indications.

The use of PDT with HpD was reported for the treatment of psoriasis as early as 1937; better results
were reported using red light instead of UVA,108 and systemic PDT with verteporfin was also
investigated in a phase I study of 15 patients in whom clinical severity scores for psoriatic plaques
improved after five weekly treatments.109

TOPICAL PHOTODYNAMIC THERAPY.

Small hydrophilic molecules like ALA or MAL penetrate well into the skin, particularly if the
stratum corneum is abnormal, as is the case in some epidermal tumors.101 In addition, epidermal cells
and the pilosebaceous unit synthesize porphyrins to a much greater extent than fibroblasts, myocytes,
or endothelial cells102; epithelial tumors generally synthesize much higher amounts of protoporphyrin
IX than the surrounding tissue and can therefore be destroyed without equivalent damage to healthy
skin (Fig. 238-7).101,110 Topical ALA-MAL-induced photosensitivity thus preferentially affects the
target area. Systemic porphyrin induction is not observed after topical application.111 The only
significant side effect of topical ALA-MAL PDT is a stinging pain during and shortly after
irradiation, proportional to the intensity of the phototoxicity reaction.

Figure 238-7 Endogenous porphyrin fluorescence after topical application of 20% aminolevulinic
acid formulation to a solid basal cell carcinoma. Twelve hours after aminolevulinic acid application,
there was strong fluorescence of the tumor-bearing areas, and weak-to-no fluorescence of the
surrounding dermis. Also visible is fluorescence in the overlying epidermis. (From Szeimies RM,
Sassy T, Landthaler M: Penetration potency of topical applied & alpha-aminolevulinic acid for
photodynamic therapy of basal cell carcinoma. Photochem Photobiol 59:73, 1994.)
Topical Photodynamic Therapy for Oncologic Indications.112–118
The experience with treatment of epithelial cancers and precancerous conditions with PDT to date
suggests that actinic keratoses,112,113 Bowen disease (Fig. 238-8),114 superficial and nodular
BCCs,115–117 and SCCs (tumor thickness less than 2 mm) are suitable for topical ALA/MAL-PDT.
For this purpose, both photosensitizers are applied topically for variable incubation periods, with or
without occlusion, followed by visible light exposure.

Figure 238-8 Bowen disease. A. Lesion located on the right lower leg. B. Twelve months after
topical aminolevulinic acid-photodynamic therapy [10% aminolevulinic acid ointment, application
for 4 hours, irradiation with argon-pumped dye laser (175 mW/cm2; 180 J/cm2)], clinically and
histologically, there were no signs of tumor residue.

Actinic keratoses have been studied most extensively and respond to PDT as readily as to local
cryotherapy or to broad area 5-fluorouracil (see Chapter 220) or imiquimod therapy (see Chapter
221) administered over weeks to months. Topical application of a 20% ALA solution for 14–18
hours followed by irradiation with blue light (417 nm) for 1,000 seconds (10 J/cm2) clears more than
80% of actinic keratoses after 1–6 months,113 and 90% complete clearance at 1 and 5 months was
observed after one full face treatment using a 1- to 3-hour incubation period.113,114 However,
cutaneous metastases of malignant melanoma, pigmented BCC, and sclerodermiform variants of BCC
respond poorly to ALA-PDT, probably because of insufficient porphyrin synthesis and/or penetration
of light within the lesions.110 Treatment efficacy is enhanced by repeated treatment sessions.117
In superficial and nodular BCCs, two randomized phase-III studies have been reported so far
comparing MAL-PDT with either surgery or cryotherapy. After an observation period of 60 months,
MAL-PDT for superficial BCC showed a similar recurrence rate as cryotherapy (22% versus 20%).
In nodular BCC, MAL-PDT was compared with simple excision; recurrence rates after 60 months
were 14% and 4%, respectively. In both studies, the cosmetic outcome was considered superior for
the PDT-treated groups.115,116 Indeed, these and other reports117 suggest that a major theoretic benefit
of ALA/MAL-PDT is elimination of skin cancers without scarring, as well as prevention of such
lesions in high-risk patients treated periodically with broad area PDT.
 CTCL (mycosis fungoides) also responded in eight single case reports to ALA-MAL PDT after
several treatment sessions. Controlled investigations are currently not available, and, as with PUVA
treatment of single lesions, this treatment would not be expected to prevent the appearance of new
lesions in other areas.118

Topical Photodynamic Therapy for NonOncologic Indications.119–135

Few data are available regarding the treatment of inflammatory and proliferative skin conditions.
These include psoriasis, localized scleroderma, human papilloma virus (HPV)-associated
conditions, leishmaniasis, acne, and rosacea.
ALA/MAL-PDT is also effective for acne and rosacea, although optimal protocols have not been
developed. In two separate studies,128,129 22 patients with mild-to-moderate acne on the back
received 20% ALA cream under occlusion for 3 hours. The areas were then exposed to broadband
(550–700 nm) or laser light (635 nm) using various protocols. The authors observed a significant
reduction in inflammatory acne lesion counts compared with baseline that persisted at least 20 weeks
in some patients.128 One study found a reduction in sebaceous gland size and sebum secretion, as
well as reduced fluorescence attributable to Propionibacterium acne,128 although the other did
not.129
PDT with ALA has also been demonstrated to enhance the treatment of photodamaged skin with a
variety of lasers and light sources. Improvement of global appearance, fine lines, tactile skin
roughness, mottled hyperpigmentation, and telangiectasias has been described.132–135 Mode of action
is based on the degradation of altered collagen and elastotic material and the formation of newly
synthetized collagen directly underneath the epidermis.136,137

PERSPECTIVES
The efficacy of PDT in the treatment of superficial neoplastic skin lesion, particularly actinic
keratoses, Bowen disease, and superficial BCCs, has been sufficiently documented. PDT may also
find a place in the treatment of selected patients with inflammatory dermatoses. Nonetheless, the
limitations of both systemic and topical PDT have to be kept in mind. Crucial issues are the depth of
the penetration of light, as well as of the sensitizer, into the skin, and inability to ensure complete
eradication of malignancy by histologic criteria.

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