CHAPTER 27: PSORIASIS 1053
Phototherapy and Photochemotherapy The dosage of UVB used in the treatment is decided
For centuries, it has been observed that sunlight
is beneficial for psoriasis271; however, about 5.5%
patients may be photosensitive, experiencing a
summer exacerbation of their disease. The active
part of the sunlight is the UVL (ultraviolet light),
which induces apoptosis of activated T cells. The
choice of UVL for psoriasis includes UVB (broad
and narrow band), UVA, and UVA1 with psoralens
(topical or oral). Generally UVB was considered
safer but less effective than PUVA. A useful strat-
egy to reduce the cumulative exposure to UVL is
to determine the exact minimal erythema dose
(MED) and minimal phototoxic dose (MPD) and to
avoid exposure to subtherapeutic doses of UVL.
UVB Phototherapy
As early as 1920, Goeckerman of Mayo Clinic
established the fact that combination of UVB and
coal tar is beneficial for psoriasis; however, later
reports indicated that UVB alone is also quite
effective, especially in discoid, guttate, and sebor-
rheic psoriasis.
Clearing of lesions is seen with wavelengths 296,
300, 304 and 313 nm, but the most effective range
of wavelength is 311–313 nm; referring to middle
and long wave UVB (300–313 nm).272 Narrowband
UVB (311 ± 2 nm) has been found to be superior
to conventional broadband UVB (300–320 nm),
with longer remissions, lower incidence of burning,
and perhaps less carcinogenicity. The ­mechanism
of action seems to be the depletion of T cells, par-
ticularly those in the epidermis, by apoptosis, and
a shift from a Th1 to a Th2 immune response in
lesions.
The efficacy of UVB is almost equivalent to PUVA
and it is emerging as a popular therapy for pso-
riasis. Compared to UVA, it produces remission
in less number of patients (73% with UVB versus
87.5% with PUVA); however, in patients with less
than 50% of skin affected, it was found to be as
effective as PUVA or even better.
Narrowband UVB is significantly more effective than
broadband UVB therapy. The normal epidermis
allows 2.4% of incident UVB to enter the ­ dermis
whereas the normal stratum corneum allows 44%
to pass through.273 The psoriatic c ­orneal layer
is thicker and has multiple air–tissue interfaces
thereby reflecting UVB many times over. To over-
come this effect, psoriatic plaques should be rubbed
with petrolatum before UVB phototherapy.274 This
was probably why prolonged contact with topicals
was advocated before light exposures in the origi-
nal Goeckerman and Ingram regimens.
Chapter_27.indd 1053
either based on measuring MED or Fitzpatrick skin
type. The initial dose should be about 80% of the
MED, with a 20% i­ncrement at each exposure if
no erythema is seen. Lower initiating doses and
lesser increments lead to poor results due to photo
tolerance, whereas higher doses or increments
can cause phototoxicity. Experience is needed to
achieve a balance between the two extremes.
A thrice weekly schedule of increasing suberythe-
mogenic doses of UVB given for 20–30 sittings,
can potentially clear 90% of ­ psoriasis lesions in
80% of patients.275 Thereafter, the ­ frequency
of exposures can be gradually reduced down to
once a week over the next 2–3 months. When
adequate suberythemogenic doses are used, the
rates of clearance approach those with PUVA and
remissions are longer.276 However, maintenance
dosages are frequently once or twice weekly com-
pared to once or twice fortnightly for PUVA.277
Advantages of UVB phototherapy over PUVA are
that the psoralen side effects are avoided and the
duration of exposure is substantially reduced. It
is claimed that the long-wave UVB used in selec-
tive UVB phototherapy units is less carcinogenic
than PUVA.
Because the shorter UVB wavelengths are not
effective in psoriasis and bring with them the
risk of acute and chronic phototoxicity, ­ modern
phototherapy systems do not have emissions in
­
this range except for the narrow band between
311 nm and 313 nm. This minimizes the
­potential for causing skin cancer.274 Over the last
10–15 years, numerous phototherapy equipments
have been developed for clinic or home treatment
of psoriasis. Used as second line therapy for the
treatment of psoriasis in the developed world,
these ­phototherapy systems are expensive and
therefore not easily available in India.
Indications for use in psoriasis include stable
or guttate psoriasis with more than 20% body
area affected for which narrow-band UVB can
be used if it fails to respond to adequate trial of
topical therapies. Patients who have a history of
improvement with sunlight and those with lighter
skin colors (except skin type I) respond better
to phototherapy. Thick lesions over the elbows,
knees, palms, soles, and lower legs respond
poorly probably because of a thick stratum cor-
neum whereas scalp and other sanctuary sites
are naturally shielded and hence are resistant to
phototherapy.
Combination therapy further increases the effi-
cacy of UVB phototherapy. UVB can be prescribed
either alone or in combination with other topical
06/02/15 2:06 PM
 1054 IADVL TEXTBOOK OF DERMATOLOGY
or systemic therapeutic agents to produce better
results. It can be combined with prior application
of coal tar, with cumulative UVB dosage needed to
achieve clearing being much lower with this combi-
nation. However, the resultant benefit is reported
to be additive and minimal rather than synergis-
tic.278 Doubts have been raised as to whether addi-
tional use of tar is worthwhile especially because it
may increase the risk of carcinogenicity. The addi-
tion of systemic drugs, such as acitretin, may also
increase the efficacy of UVB therapy.
UVB phototherapy is contraindicated in patients
with photosensitivity and whose preexisting dis-
ease may be aggravated with UV radiation.
Moreover, UVB should be avoided in patients on
phototoxic or photosensitizing medications. Other
relative contraindications for UVB therapy include
unstable, erythrodermic or pustular psoriasis,
past history of skin cancer, and persons with skin
type I. Individuals with black skin have very high
MEDs and hence respond poorly.
Excimer Laser
Supraerythemogenic fluences of UVB result in
quicker clearing of psoriasis, but cannot be used
because the surrounding normal skin cannot
­tolerate them. The 308-nm excimer laser emits
a monochromatic and coherent beam in the
UVB spectrum and delivers high fluencies selec-
tively to a lesion while sparing the ­surrounding
healthy skin. It thus shares the same indications
as conventional phototherapy.279 Initially, high
fluences (MED, 8–16) were used, with e ­ xcellent
clinical results, to treat psoriasis vulgaris. The
significance of side effects and the potential
­
long-term carcinogenic risk associated with such
fluences have resulted in medium doses (about
3 MED) being recommended.279 An average of
6 treatments delivered twice weekly results in
at least 75% improvement in most patients.
The major indication is stable and recalcitrant
limited psoriasis, such as that on the elbows
and knees.
Photochemotherapy (320–400 nm)
This is a combination therapy with naturally
occurring furocoumarins (known as psoralens)
­ effective as 8-MOP and requires only half of its
and long-wave UVA radiation, also known as
PUVA t­herapy. Psoralens are naturally occurring
­compounds and their derivatives, which are acti-
vated by UV light. The action spectrum of psoralens
lies within the UVA range. The conventionally
used psoralen for PUVA therapy was 8-methoxy
psoralen (8-MOP). Others include 4,5,8 trimethyl
psoralen, 5-methoxypsoralen (5-MOP), and so
on. The therapy was approved by FDA in the year
Chapter_27.indd 1054
1982, mainly for cases of extensive plaque psoria-
sis and in patients intolerant to MTX. It involves
oral or topical application of psoralens followed by
UVA exposure.280,281
The mechanism of action of PUVA therapy in
psoriasis has not been fully elucidated, but it
­
is known that it interferes with DNA synthe-
sis, decreases cellular proliferation, and induces
apoptosis of cutaneous lymphocytes, leading to
a localized immunosuppression. Psoralens act
by intercalating with DNA to form bifunctional
photo-adducts, leading to an irreversible inhibition
of DNA synthesis and mitosis. This combination
produces two types of reactions. The first is an
anoxic reaction that affects cellular DNA with the
formation of photo-adducts, inhibiting the prolif-
eration of epidermal cells and inducing apoptosis.
The second one is an oxygen-dependent reaction
that gives rise to free radicals and reactive ­oxygen
that may damage membranes by lipid peroxida-
tion and induce activation of mediators of the
eicosanoid system.282 Photochemotherapy inhib-
its angiogenesis and induces apoptosis of human
microvascular endothelial cells in vitro. It down-
regulates the expression of angiogenic factors in
keratinocytes and impairs DNA synthesis and cell
proliferation.283–287 Other potential mechanisms
include immunological alterations, increased skin
pigmentation, effect on the biosynthesis, and
metabolism of prostaglandins in the skin,288 and
the induction of drug metabolizing mixed fraction
oxidases.289
Indications for PUVA therapy are primarily
patients with moderate to severe psoriasis, aged
more than 50 years. Children less than 18 years
of age; pregnant females; severe renal, hepatic,
or CVS diseases; premature cataract formation;
multiple melanocytic nevi; or other photosen-
sitive disorders are contraindications to PUVA.
Screening of whole body for evidence of cuta-
neous malignancies, eye protection, and shield-
ing of genitalia are very important during PUVA
therapy.
The efficacy of PUVA therapy in psoriasis is now
well established.290–294 Trimethylpsoralen is as
dose to produce the same therapeutic response.295
When administered at twice the standard dose
of 8-MOP, 5-MOP produces fewer phototoxic and
drug intolerance reactions.
Administration of PUVA is based on several
regimens. The most commonly employed is the
­
administration of 8-MOP or 5-MOP, 0.6 mg/kg body
weight, on alternate days followed 2 hours later
06/02/15 2:06 PM

by exposure to UV rays.296 The initial UVA dose is
based on the skin type and subsequent increments
of 0.5–1.5 J/cm2 are made at every ­ subsequent
sitting. Exposure is according to United States or
European protocols (on alternate days or twice in
a week, respectively).
Various causes of treatment failure include a
decreased serum concentration of 8-MOP due
to other drugs.297 The drug undergoes hepatic
metabolism and enzyme inducers like phenytoin,
can produce such complications.
Over the recent years, PUVA has undergone a few
advances. These have resulted in optimization of
dosage and reduction in the time required to clear
psoriasis, hopefully reducing the carcinogenic-
ity.232 Soft gelatin capsules of liquid m
­ ethoxsalen
are used, which are more rapidly absorbed,
­producing a higher plasma concentration than the
currently available crystalline preparation, with
which, unpredictable bioavailability is the major
­drawback.298 Correspondingly, the clinical e ­ fficacy
is also improved in a greater proportion of patients,
presumably due to the superior pharmacokinetic
behavior of liquid 8-MOP.299
Other modifications of PUVA include topical
­administration of psoralens. This comprises bath,
soaks, and paints. Topical PUVA is especially
useful in localized recalcitrant psoriasis such as
­ mous cell carcinoma has been noted especially in
palmoplantar and nail psoriasis. The advantage is
that the intervening areas of skin are spared from
phototoxic damage. 8-MOP, 0.15% in an oil base
and as 1% hydrophilic ointment, is ­effective.300,301
Topical 8-MOP lotions (0.1%–1%) are effective
especially for palmoplantar psoriasis. Combination
of ­topical methoxsalen and anthralin has also been
used. The other advantage is that it is devoid
of side effects such as nausea, headache, and
dizziness.
PUVA bath using either trimethylpsoralen or
methoxsalen may improve psoriasis.302–306 Bath
PUVA is almost as effective as oral PUVA, with
added advantage of requiring less doses of
UVA and also the gastrointestinal tract (GIT)
disturbances are less. Cutaneous side effects
­ An increase in the number of lentigenes may
are however more common. Trimethylpsoralen,
50 mg in 100 mL ethanol, is added to a 150 L
bath. The patient may be allowed to bathe for
15 minutes and then exposed to UVA. Absorption
of psoralen from the bath is low. Photosensitivity
achieved immediately after a psoralen bath is
15 times greater than that after oral psoralen.
Nausea and headache, which are the common
side effects of oral PUVA therapy, can be mini-
mized by bath PUVA.307
Chapter_27.indd 1055
CHAPTER 27: PSORIASIS 1055
Various topical and systemic drugs have been
used in combination with psoralen for treat-
ment of psoriasis to reduce the adverse effects,
increase the efficacy, and reduce the cost of treat-
ment. A combination of PUVA, MTX, and UVB is
more efficacious than either PUVA or UVB photo-
therapy alone and results in a markedly reduced
total exposure dose of radiation. A combination of
etretinate and PUVA (REPUVA therapy) is popular.
It causes faster clearing of skin lesions with fewer
side effects.308–310 Topical corticosteroids have
also been used in combination with PUVA in pso-
riasis,311,312 but the rare possibility of precipitat-
ing severe GPP following steroid application should
be kept in mind. Other drugs used in combination
with PUVA include topical urea, coal tar, dithranol,
and salicylic acid.313–315
Side effects of PUVA therapy include nausea,
vomiting, headache, vertigo, erythema, pruritus,
blistering, and Koebner phenomenon. The effects
of PUVA therapy on the cardiac rhythm are con-
troversial.316–318 Patients not having previous car-
diac disturbances may fibrillate if the temperature
is high enough.319 Other side effects associated
with PUVA include erythema, sunburn, hyperpig-
mentation, hypertrichosis, actinic keratosis, nail
pigmentation, lichenoid eruption, and so on. In
long-standing cases, development of melanoma
and nonmelanoma skin cancers such as squa-
genital area.
Complications include first and foremost, the
ocular complications. Ocular damage consist-
ing of dense central corneal opacification was
seen at significant levels in mice given 8-MOP
or 5-MOP and exposed to UVA.320 In addition,
­opacities in the posterior part of the lens were
seen and appeared to be related to the drug
treatment independent of light exposure. The
eye injury in psoralen-treated guinea pigs is elic-
ited predominantly by wavelengths between 320
and 400 nm.321 Several studies have not found
any increase in the incidence of cataract in PUVA-
treated patients.322–324
occur during PUVA therapy325 and some of these
“PUVA lentigenes” may show atypical features
histopathologically.326,327 Other cutaneous com-
plications of PUVA therapy include hypertricho-
sis,328–330 development of seborrheic dermatitis on
the face,331 atypical psoriasis on the butterfly area
of the face and dorsa of the hands,332 a photoal-
lergic reaction to 8-MOP,333 and lichenoid eruption
and lichen planus.334–336 Development of multiple
keratoacanthomas,337 bullous pemphigoid338,339
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 1056 IADVL TEXTBOOK OF DERMATOLOGY
and photo-onycholysis340 has also been reported.
Systemic lupus erythematosus may develop dur-
ing PUVA therapy or existing lesions may be exac-
erbated.341,342 Bronchospasm and hepatitis may
also occur during therapy in some patients.343,344
The possible induction of skin cancer appears to
be the most potential hazard of PUVA therapy.345
Previous exposure to carcinogens appears to be
the most important factor for nonmelanoma skin
tumor formation in long-term PUVA patients.346 An
American study showed that there was a 13-fold
increase in squamous cell carcinoma after PUVA
therapy with cumulative doses,347 but no such sus-
ceptibility was seen in some other studies.348–350
Still, to be on the safer side, steps should be
taken to lower the dose of PUVA by changing the
­dosage schedule, reducing the unnecessary main-
tenance dose, and by adding topical psoralen or
oral retinoids to the regimen. PUVA therapy is best
avoided in patients with a history of skin cancer
or those who require a high clearance or mainte-
nance dose.
Home phototherapy in the form of UVA sunbeds
is available; however, it is an inadequate form
of treatment with greater risk of side effects.351
Some psoriasis day care centers provide UVA with
the help of solarium that is a specially built glass
chamber, which preferentially traps the UV rays of
the sun.
Photodynamic Therapy
Photodynamic therapy combines the use of a pho-
tosensitizing drug and light for the treatment of a
disease.352 It basically works with a combination of
light and a light-sensitive agent, for example, por-
phyrin, in an oxygen-rich environment. Porphyrins
absorb energy from photons and transfer it to sur-
rounding oxygen molecules to form toxic oxygen
species, which then damage the cell structure.
These are retained in the hyperproliferative cells
of psoriasis and carcinomas, which thus get dam-
aged selectively.
Photosensitizers used are of two types. First
generation photosensitizers include hematopor-
phyrin derivative (HPD)353 or ­profimer Na (pho-
tofrin). They produce prolonged and g ­ eneralized
­photosensitivity of skin (for 6–8 weeks). Second
generation photosensitizers, for example, BPD
(verteporfin) exhibit far less photosensitiza-
tion. They have been evaluated for treatment of
primary ­
­ cutaneous c ­arcinomas, metastatic cuta-
neous carcinomas, and chronic stable plaque
psoriasis. Topical photodynamic therapy with the
application of 5-amino-levulanic acid has also
been evaluated.354 Commonly used light sources
Chapter_27.indd 1056
include LASER and LED arrays. Lasers are mono-
chromatic, intense, and coherent light sources but
require a high level of expertise. LED arrays and
florescent light sources are more convenient to
use but require a longer treatment time.
Treatment protocol requires that the patient should
undergo photosensitivity testing and complete
blood count (CBC) before starting therapy. A typi-
cal PDT session consists of intravenous injection or
topical application of the photosensitizing agent,
both of which require a prespecified period of
time to be cleared from the normal tissues (pso-
riatic tissue accumulates more drug as compared
to the normal tissue) or for permeating topically.
This is followed by application of light, which leads
to generation of toxic oxygen species and subse-
quent tissue damage. The singlet oxygen liberated
during the reaction causes lethal alterations of the
cellular membranes.
Side effects include a sensation of warmth, stinging,
and ache in the psoriatic plaques. Bright sources
of sunlight must be avoided for 2–3 days as this
may cause sunburn. Usage of sunglasses must be
emphasized. For psoriasis, porphyrins such as pho-
tofrin I, photofrin II and benzoporphyrin derivative
are commonly used as ­photosensitizing chemicals,
while laser is the most often used source of light.
Photodynamic therapy has been tried with success
in a few patients with psoriasis.355 Topical ami-
nolevulinic acid, a precursor of porphyrin, has also
been used as the ­photosensitizer in psoriasis.
Hyperthermia and Sea Bathing (Balneotherapy)
Ultrasound-induced heat has been used with suc-
cess in the treatment of psoriasis,356 though how
hyperthermia clears psoriasis is not known. Argon
laser and carbon dioxide laser have also been
tried.357,358
Climatotherapy or Balneotherapy is a treatment
strategy that has been evolved from the stud-
ies carried out at Dead Sea Clinics.359 Daily sun-
bathing, sea bathing, and UV exposure are all
known to improve psoriasis.360,361 Many patients
improve at the Dead Sea facilities 1,380 feet
below sea level. At these places, the patient
is first given a bath in highly concentrated salt
waters (>20% salinity) of the Dead Sea. This
is followed by UVB exposure. The elimination
of ­ biologically active peptide mediators and
enzymes, for example, human l­eukocyte elas-
tase from the inflamed skin of psoriasis patients
may be the possible ­mechanism responsible for
the therapeutic improvement. This therapy is
quite effective and popular in Europe.
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The Dead Sea is a land-locked lake, located in the
Mediterranean area, at the lowest point on Earth.
Plenty of sunshine in the atmosphere and a high
mineral content in the Dead Sea water (even up
to 33%) are quite beneficial for patients with
psoriasis. The high water vapor content, thick
atmosphere, and intact ozone layer, allow the
patients to remain in the sun for a long time as
the “sun burning” UVB rays are filtered out, while
the beneficial UVA is retained, making the cli-
mate quite effective in clearing psoriasis. A layer
of air fills this gap and filters out short waves of
the sun, leaving predominantly long waves above
320 nm.362 The dark mud in the Dead Sea helps
absorption of UVL apart from stimulating blood
circulation around the joints affected by psoria-
sis. A large number of patients believe that this
treatment is cost effective and pleasant. A ther-
mal basin in Argentina is another popular site for
this form of therapy.
Systemic Therapy
A large arsenal of systemic drugs that are highly
effective in the treatment of psoriasis is avail-
able now, sparing the patient various tedious,
messy, and unpleasant routine topical thera-
pies. However, serious side effects encountered
with these drugs limit their use for moderate to
severe psoriasis. The most commonly used sys-
temic therapeutic agents are MTX, retinoids, and
cyclosporine, with the biologic therapies fast tak-
ing over.
Methotrexate
The drug has been successfully used in the treat-
ment of skin diseases for the past several decades
since 1951.363 MTX was found effective in the
treatment of psoriasis first by Edmonson and Guy
in 1958. The FDA approval for use in psoriasis
was given in 1971. MTX is a synthetic analogue
of folic acid that has been used in dermatologic
therapy.
The primary indications for the use of MTX in
psoriasis include severe forms like erythro-
dermic; pustular psoriasis (acute, particularly
the Von Zumbusch variety); psoriatic arthritis,
not ­controlled with NSAID’s; extensive plaque
type psoriasis, not responding to conventional
therapies; or psoriasis that significantly impairs
­ MTX doses when at risk of acute dehydration
patient’s economic and social well-being.364–368
Pharmacodynamic studies show that the drug
is well absorbed orally with peak blood levels
reaching in 1–1.5 hours. About 95% of the drug
is excreted by the kidneys. There is extensive
enterohepatic cycling of the drug.
Chapter_27.indd 1057
CHAPTER 27: PSORIASIS 1057
The mechanism of action of the drug in psoria-
sis is based on its antimetabolite effect. It acts
as an inhibitor of dihydrofolate reductase enzyme,
thus affecting DNA synthesis. The binding to
dihydrofolate reductase is extracellular, thereby
preventing the conversion of dihydrofolate to tet-
rahydrofolate. It causes cessation of mitosis in the
­hyperproliferative psoriatic epidermis. Initially, it
was thought that this directly inhibited epidermal
cell hyperproliferation369; however, recent stud-
ies have shown that MTX is 10–100 times more
effective in inhibiting the proliferation of lymphoid
cells than cultured keratinocytes, which are pos-
sibly a more important cellular target than epithe-
lial cells.370 Also, the inhibition of folate-dependent
enzymes such as AICART (5-aminoimidazole
carboxamide ribonucleotide transformylase),
involved in purine synthesis, may be playing a
more important role, leading to intracellular accu-
mulation of AICAR and release of adenosine, which
has potent anti-inflammatory effects. This causes
an inhibition of polymorphonuclear function and
retards secretion of TNF-α, IL-6, and IL-8 by his-
tiocytes, thus, may be responsible for the anti-­
inflammatory effects. Other potential mechanisms
include ­modulation of adhesion molecules such as
ICAM-1.
Caution should be exercised when using the drug
in patients with liver disease, significantly impaired
renal function, hematopoietic abnormalities, active
severe infections such as HIV, TB, and so on or
active peptic ulcer disease.364 Patients attempting
to conceive should also avoid this antimetabolite
for obvious reasons. Its use is absolutely contra-
indicated in pregnancy (as it may cause miscar-
riage or birth defects), and should be used with
caution in young children when other modalities,
especially retinoids cannot be used. Relative con-
traindications also include chronic alcoholism,
history of recent or severe hepatitis, mild-to-mod-
erate renal impairment (increases the chances of
toxicity because of retarded elimination of drug
products), past history of malignancies, unreliable
patients, and history of MTX toxicity. In patients
with renal impairment, even low doses may pro-
duce acute myelosuppression, as in the elderly
with concomitant drug administration or illness
such as fever or diarrhea. Consequently, elderly
patients, e
­ specially, should be warned not to take
(e.g., from acute fever, vomiting or diarrhea).371
Diabetes, drug abuse, and obesity are additional
minor risk factors for developing hepatic toxicity.372
Drug interactions with MTX can increase its
toxicity, by decreasing its renal e ­limination
(e.g., ­aminoglycosides, cyclosporine, sulfonamides,
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