DERMATOLOGIC THERAPY 0733-8635/98 $8.00 + .

OO

THE BENEFITS AND RISKS OF

LONG-TERM PUVA
PHOTOCHEMOTHERAPY
Khosrow Momtaz T., MD, and Thomas B. Fitzpatrick, MD

Psoralen (methoxsalen, 8-methoxypsoralen psoriasis, especially in light-sensitive individ-

or 8-MOP) and UVA/PUVA therapy is widely
accepted and approved by the U.S. Food and
Drug Administration as one of the standard
treatment modalities for severe forms of pso-
riasis. PUVA photochemotherapy is the use
of oral psoralens, methoxsalen (8-methoxy-
psoralen), or bergapten (5-methoxypsoralen)
followed by exposure to UVA (320400 nm)
or narrow-band UVB (311 nm). Repeated ex-
posures are given two, three, or four times
uals (skin phototypes I and 11). In the more
than two decades since PUVA was introduced
for the treatment of psoriasis vulgaris,56there
has been substantial progress in modifying
and optimizing the therapy.
Evidence to date suggests that the inci-
dence of short-term risks, primarily the signs
and symptoms of inflammation,', 74 and long-
term hazards such as skin cancer,18,=, 38, 44, 47,
59, 60. 68, 72 actinic degeneration,15, 28, 30, 62, 73 and

weekly until clearing in psoriasis is obtained immunologicM,36, 48, 49, 51 and ophthalmologic8,
in 12 to 22 exposures. This is followed by 'Or 12, 32, 39, 41, 55, 71 effects of UV radiation, are

maintenance with a gradual reduction: once
weekly for 1 month, once biweekly for 1
month, and then once per month for 2
months. Treatments are then stopped, and
there are varying periods of remission from 6
months to years; treatments are resumed with
recurrences of the psoriasis.
The most commonly reported side effects
of PUVA therapy are nausea and pruritus,
which occur in approximately 15% of pa-
t i e n t ~Rarely,
. ~ ~ the use of oral methoxsalen in
PUVA therapy is limited by drug intolerance,
manifested as severe nausea78;bergapten is
better tolerated with less or no nausea. In
some individuals, PUVA therapy is more dif-
ficult because of skin phototoxicity reactions
in the form of severe erythema, edema, and
even blistering; therefore, cautious UVA do-
simetry and delivery are required to clear
related to the total number of treatments and
the degree of inflammation induced by each
treatment. Skin cancer and actinic degenera-
tion are known to result from the accumu-
lated effects of sun exposure, but the exact
relationship to the number of exposures, the
degree of sunburn, or the total cumulative
dose is not known.
RISK OF LONG-TERM PUVA
PHOTOCHEMOTHERAPY
Actinic Degeneration
The side effects of chronic PUVA therapy
are premature cutaneous aging, PUVA kerato-
ses,14 14T17.74.80 and PUVA lentigines.2.3,6 7 . 9
Histologically, the long-term changes with

From the Department of Dermatology, Harvard Medical School, Boston, Massachusetts

DERMATOLOGIC CLINICS

VOLUME 16 * NUMBER 2 APRIL 1998 227

228 MOMTAZ & FITZPATRICK
PUVA therapy involve all of the skin such as
epidermal maturation disorder, activation of
melanocytes, and degeneration of dermal col-
lagen and elastic tissues.3,11.13.19,20.25,26,37,61,74,80
Skin Cancer
Neoplastic changes, specifically nonmela-
noma skin cancers, are side effects of long-
term PUVA therapy and are dependent on the
total number of treatments, previous lifetime
ultraviolet exposure from sunlight or from
UVB phototherapy, methotrexate, immuno-
suppression, the patient’s skin phototype, and
previous carcinogenic treatment (e.g., topical
nitrogen mustard, x-ray therapy for skin dis-
orders, and cyclosporine).
In 1984, a United States 16 Center Coopera-
tive Study68reported there was an increased
risk of nonmelanoma skin cancer in patients
treated with PUVA.68The report was based
on prospective data collected for 10 years on
over 1000 patients and demonstrated a two-
fold increase in the risk for squamous cell
carcinoma in psoriatic patients receiving more
than 260 treatments, compared to patients re-
ceiving less than 160 treatments. Also re-
ported was a modest dose-dependent in-
crease in the risk for the development of basal
cell carcinoma for patients who received an
excess of 200 treatments, compared to those
who had received fewer than 160 treatments
within the same time period.79Although ini-
tially the European PUVA study did not re-
veal an increased risk of squamous cell carci-
nomas unless the patients belonged to certain
risk groups, a positive correlation has now
been observed.27* 43 However, a recent follow-
up study of 496 patients revealed that using
European PUVA treatment protocols PUVA
appears to be only a weak carcinogen by itself
with a linear increase in tumor risk for squa-
mous cell cancer, but not for basal cell carci-
n~ma.~~
We introduced the concept of oral PUVA
photo~hemotherapy~~ and have, from the be-
ginning, been careful to look for PUVA-in-
duced skin cancer. Our group first reported
the development of skin cancer in a large
follow-up study of over 1000 patients begin-
ning in 1977.68This cohort of patients had
been treated in 16 different centers in the
United States, and the patients enrolled had
severe disabling psoriasis, the majority of
which had been previously treated with
methotrexate or topical and oral corticoste-
roids. Also, the protocols used in the U.S.
PUVA trial were treatments given two or
three times weekly, which was in contrast to
the clinical trial in Europe of over 3000 pa-
tient~ in~which
~ a more ”aggressive” protocol
of treatments was given four times weekly. In
fact, in the European trials the total number
of treatments to clear was almost half that of
the U.S. trial.
There is a discrepancy in the incidence of
PUVA-induced skin cancer in the U S . follow-
up study compared to the Vienna follow-up
in which few carcinomas developed.
Was this low incidence related to the differ-
ence in the patient populations of the United
States and Vienna or the protocol used (four
treatments per week) and the careful
adjustment of UVA doses? Regarding UVA
doses, in the University of Vienna Photother-
apy Unit each patient is seen by a physician
at the time of each treatment, and the dose of
UVA is adjusted accordingly. PUVA can in-
duce squamous cell carcinoma in patients
who have had previous mutagenic or immu-
nosuppressive treatments, but for those pa-
tients without high risk factors (history of
immunosuppressive drugs such as metho-
trexate, systemic and topical corticosteroids,
or x-ray treatment), there is a serious gap in
the numbers of PUVA-induced carcinomas in
the United States versus Europe, especially in
the closely followed Vienna patient popula-
tion. Vienna has the largest population of pa-
tients in the world who have been treated
with PUVA for over two decades; each pa-
tient is evaluated by total skin examination at
each treatment session by a dermatologist,
and this evaluation was not done in the U.S.
trial. Because of this careful follow-up, the
Vienna PUVA experience is the most accurate
evaluation of the toxicity of oral PUVA photo-
chemotherapy.
Increased risk of developing malignant
melanoma in psoriatic patients who received
PUVA has been rep~rted.~, 16, 22, 33 In a prospec-
tive study among 1380 patients with psoriasis
who were treated with PUVA since 1975, a
total of 11 malignant melanomas in nine pa-
tients was reported. It was concluded that
about 15 years after the first treatment with
PUVA, the risk of malignant melanoma in-
creases, especially among patients who re-
ceived 250 treatments or more.7oThe major
concern about this report is that the U.S. trial
had a serious omission in the original design
of the clinical trial; it was not possible to have
a control group of patients and, therefore, the
 THE BENEFITS AND RISKS OF LONG-TERM PUVA PHOTOCHEMOTHERAPY
data had to be compared to historical con-
trols. The reason for the lack of a control
group is because the drug %MOP was al-
ready commercially available. It cannot be de-
termined whether one or more confounding
variables, including exposure to sunlight, a
history of sunburn (particularly before adult-
hood), previous phototherapy with ultravio-
let B, coal-tar therapy, systemic methotrexate
therapy, and other unknown endogenous or
exogenous factors, may partly or completely
account for the association found.61, Also
very important in this report of melanoma in
patients that we have received are the com-
ments of Wolff of Vienna. He wrote an edito-
rial in the same issue77of the New England
Journal, as follows:
”Stern et al. do not mention whether their pa-
tients who have melanoma after prolonged ther-
apy were at greater risk for melanoma in the first
place-specifically whether they had atypical or
Clark‘s nevocellular nevi or a family history of
melanoma. One of the nine patients had three pri-
mary melanomas; if we assume that he had famil-
ial melanoma or the dysplastic nevus syndrome
and exclude him from the cohort, the statistics of
the study look less frightening.”
The best perspective on the present status
of PUVA in view of the report of patients
with melanoma is given in the reporP of
the National Psoriasis Foundation (NPF), a
nonprofit voluntary health group devoted to
evaluation and dissemination of information
on psoriasis. In an objective summary, the
NPF (see NPF ”PUVA Viable Therapy Despite
Suspected Risk 4-18-97) regarded the ”risk
for melanoma as small,” and that
“There are a few alternative treatments for se-
vere psoriasis, such as cyclosporine and methotrex-
ate, but they too, unfortunately, carry risks. The
NPF has only limited data on the long-term toxic-
ity of these therapies since none of them have been
as carefully studied as PUVA.”
NONCUTANEOUS MALIGNANCIES
There was no indication of increased risk
of noncutaneous cancer in the U.S. multicen-
ter trial.“’
OPHTHALMOLOGIC EFFECTS
Psoralens photobind to the lens proteins
after UVA exposure and probably are bound
229
for a long time because there is no turnover
of the cells in the 66 Some animal stud-
ies have shown the induction of anterior cor-
tical opacities? whereas others have reported
negative results.55Clinical studies, both retro-
spective and prospective, in patients receiving
PUVA have not shown an increase in the
incidence of cataracts compared to the gen-
eral population.2,24, 71
Because &MOP can be detected in the hu-
man lens 12 hours after oral ingestion, it is
recommended that UVA-filtering eyeglasses
be worn for 12 hours after ingesting %MOP.
Although ophthalmologic data on PUVA-
treated patients have been accrued since the
inception of the treatment in 1974, careful
documentation continues because some of
these ocular changes may require a longer
time to develop.
IMMUNOLOGIC CHANGES
PUVA therapy has been found to have a
suppressive effect on T cells, both suppressor
and helper cells, and it may have a preferen-
tial killing effect on the various subpopula-
tions of these cells.5o,51 These dose-dependent
changes in lymphocyte function may be the
result of impaired interleukin-2 p r o d ~ c t i o n . ~ ~
Furthermore, it can also suppress the number
and function of polymorphonuclear cells,
monocytes and macrophages, and Langer-
hans’ cells.17, Clinically, PUVA can suppress
contact hypersensitivity to common antigens
in experimental animals and humans by af-
fecting both the induction (afferent) and sen-
sitization (efferent) phases of the delayed hy-
persensitivity response, probably due to its
effect on T lymphocytes and Langerhans’
cells.31,36 These inhibitory changes produced
by PUVA, which are reversible, have not been
directly reflected up to now in any immuno-
logic skin signs (e.g., herpes simplex or other
virus disorders, molluscum or human papil-
loma virus infections). The effect on antigen-
presenting cells and suppressor T cells could
theoretically accelerate the development of
tumors by acting as a cocarcinogen or may
affect immunologic function in healthy
subjects and, more importantly, in immuno-
suppressed patients. One study@ compared
the immunologic function among 10 patients
with psoriasis who had received more than
200 PUVA treatments over 2 to 6 years with
untreated psoriasis patients. All patients in
the treated group had at least one manifesta-
230 MOMTAZ & FITZPATRICK
tion of suboptimal immune response, based
on mitogen stimulation, suggesting systemic
immunosuppression. The effect on these cells,
on the other hand, may account for some of
the therapeutic benefits of PUVA in diseases
such as cutaneous T-cell lymphoma and li-
chen p l a n u ~ . ~ ~
BENEFITS OF LONG-TERM PUVA
PHOTOCHEMOTHERAPY
PUVA photochemotherapy has remained a
mainstay in the treatment of psoriasis for
more than two decades (1974-1997). An esti-
mated 55,000 people in the United States an-
nually receive PUVA therapy. Nearly half of
the NPF of the U.S. membership have used,
or are currently using, PUVA. For many,
PUVA is the first effective therapy or is an
alternative to hospitalization. A 1992 National
Institutes of Health (NIH) study estimates
that PUVA will save over $50 million in
health care costs through the year 2000 due
to the reduced need for hospitalization.
The NIH sponsored long-term follow-up of
1380 PUVA patients and has shown that
PUVA therapy is effective and relatively
There is a higher skin cancer rate (non-
melanoma type) occurring principally on the
lower legs and among those people reaching
a certain high level of exposure to PUVA.
Interestingly, a parallel European trial of 3000
patients confirmed similar efficacy results but
with fewer skin cancers.27Researchers specu-
late that this is because the Europeans use
fewer cumulative joules (an average of 100 as
opposed to 250 in the United States) per pa-
tient to clear. As stated previously, the Euro-
peans, moreover, use a more aggressive
schedule, starting the patient out on a high
dose of ultraviolet A, which leads to a faster
clearance and fewer cumulative joules.
Since its approval by the Food and Drug
Administration in May 1982, the therapy has
become widely used around the world in the
treatment of severe psoriasis, mycosis fun-
goides, and vitiligo, as well as for many other
diseases (see Table 1). PUVA photochemo-
therapy acts in several diseases similarly to
corticosteroids and can be regarded as a non-
steroidal anti-inflammatory modality. In a
subsequent modification of PUVA, which is
called "photopheresis," psoralens are carried
in the blood, and, following exposure to UVA
in vitro, the psoralen molecules bind to the
Table 1. DISEASES THAT RESPOND TO PUVA
PHOTOCHEMOTHERAPY
Effective RX Variably Effective RX
Vitiligo vulgaris' Dyshidrotic eczema
Palrnoplantar pustulosis* Lymphomatoid papulosis
Vitiligo vulgaris Vitiligo, segmental
Mycosis fungoides* (early, autografts + PUVA
stages 1A, 1B) Pityriasis rubra pilaris
Graft vs. host reaction Hydroa vacciniforme
Pityriasis lichenoides Urticaria pigmentosa
Atopic dermatitis Alopecia areata
Generalized lichen planus Granuloma annulare
Melanocomprornised (generalized)
persons (skin phototype Transient acantholytic
1, 11) dermatosis
Polyrnorphous light Erythropoietic
eruption protoporphyria
Actinic reticuloid
Persistent light reaction
Solar urticaria
'Re-PUVA is best Rx. Etretinate in males and in sterile females;
isotretinoin in females of child-bearing age.
T cells in blood. This binding results in a
modification of the antigenicity of T cells that
function as a "vaccine" and then stimulates
the formation of antibodies. PUVA photo-
pheresis has been successfully used for the
treatment of various clinical disorders, but
particularly T-cell lymphoma erythroderma
(Sezary's s y n d r ~ m e ) ?graft-versus-host
~ dis-
and AIDS.4
PUVA photochemotherapy has been a prin-
cipal force in the revolution of phototherapy
that has occurred in the past two decades,
and the publication had an impact that led to
the development of photomedicine as a new
division of medicine. This is because PUVA
photochemotherapy was the very first combi-
nation of light and drugs that was not harm-
ful but was beneficial for treatment of disease,
and thus, this new pharmacologic principle
was called phot~chemotherapy.~~ Further-
more, the research and development of PUVA
resulted in a new approach to UVB using the
new technology in UVR computerized deliv-
ery systems and the development of new pro-
tocols for the treatment of psoriasis.
Future improvements in PUVA photoche-
motherapy will be accomplished by (1) syn-
thesis of new psoralens; (2) development of
new light sources that more precisely repre-
sent the action spectrum of psoralens; (3)
combining PUVA with other drugs (e.g., reti-
noids), which will decrease the total number
of treatments; and (4) improving the methods
of topical bath PUVA, which is believed to be
more efficient than oral PUVA in the treat-
 THE BENEFITS AND RISKS OF LONG-TERM PUVA PHOTOCHEMOTHERAPY
ment of skin diseases (less total number of
joules and less phototoxicity, and, therefore,
probably less skin cancer induction).
PUVA IN PERSPECTIVE AFTER
FOURDECADESOFUSE
In 1953, we first used certain furocoumarins
(called psoralens), in the form of 8-MOP, iso-
lated from an Egyptian plant source to treat
vitiligo.", 57
This new subspecialty of medicine, which
became known as photomedicine, concentrated
on the development of methods for the
treatment of disease using nonionizing elec-
tromagnetic radiation (UVR and visible
radiation) alone or in combination with en-
dogenous or exogenous photoactive chemi-
cals. Because nonionizing ultraviolet radiant
energy has such low penetration compared to
ionizing radiation, this new technology has
been especially applicable to the treatment of
diseases of the skin, with no organ toxicity
(kidney, liver, GI tract) because the UVR pen-
etrates only a few millimeters in the skin and
psoralen is inactive until it interacts with
UVR.
The developmental pharmacology of these
potent molecules has continued from this
date in 1953 to the present Psoralens
are now used to treat 24 disorders as listed in
Table 1. Mycosis fungoides and PUVA treat-
ment are especially important because careful
studies in Sweden have shown that PUVA
photochemotherapy has reduced the mortal-
ity of this disease.62Furthermore, PUVA has
been used as adjuvant therapy in mycosis
fungoides after completing a course of elec-
tron beam therapy. In 213 patients studied,
the results indicated a beneficial effect of
adjuvant PUVA. The overall 5-year survival
for patients who received PUVA was 100%
and for the nonPUVA group there was a 5-
year overall survival of 82%. The 5-year DFS
for the entire cohort was 53%, and those who
received PUVA had a 5-year DFS of 85% ver-
sus a 5-year DFS for the nonPUVA group of
50%. Toxicity of PUVA therapy was accept-
able, with only two patients requiring a re-
duction in PUVA dosage. It was concluded
that PUVA can maintain remissions in pa-
tients with mycosis fungoides after total skin
electron beam therapy.58
In this span of four decades of the evolu-
tion of PUVA there have been two principal
recurring concerns of the medical community:
231
(1) Psoralens are hepatotoxic. Although there
have been isolated idiosyncratic reactions, 8-
MOP has not been shown to be hepatotoxic
in large numbers of patients (>8000) in the
multicenter studies in the United States and
Europe. (2) Psoralens ure photocarcinogenic.
However, as discussed previously, there is a
discrepancy in the incidence of SCC between
the European and the American experience,
and this is not yet resolved. It would appear
that for the present there should be a careful
selection of patients and close monitoring of
patients after the total number of 250 treat-
ments or cycling of treatments with other op-
tions, such as methotrexate, to reduce or pre-
vent SCC.
TREATMENT OPTIONS FOR
GENERALIZED PSORIASIS
As practicing dermatologists managing pa-
tients with generalized psoriasis, we have
three options for the treatment of psoriasis
with involvement of more than 20% of the
skin. A prudent plan is to rotate among these
three treatment modalities.
UVB Phototherapy
UVB phototherapy is effective in about 50%
of patients, but maintenance is a problem.
This is the way to begin phototherapy. If UVB
fails or if the patient does not have the time
to come for treatment 2 to 3 times weekly,
then PUVA is a better choice.
PUVA Photochemotherapy
PUVA photochemotherapy is very effective
in patients, but the treatments are not always
user friendly. The drug, methoxsalen, causes
malaise and nausea in over 20% of patients.
Bergapten (5-MOP), when available, is better
tolerated because of the relative lack of nau-
sea. Bergapten is not yet approved in the
United States.
Methotrexate
Methotrexate is very effective and useful,
especially in older patients. It requires strict
control in checking WBC and platelets; and
in restricting alcohol. Liver biopsies are neces-
232 MOMTAZ & FITZPATRICK
sary periodically. About 25% of patients will
develop fibrosis, especially if obese or alco-
holic, and then cirrhosis. It must not be used
in child-bearing females.
Other Treatment Options
Other treatments for psoriasis with more
hazards than PUVA or UVB include the fol-
lowing:
Cyclosporine. Renal toxicity is a problem,
even in low doses. It is used only when
other treatments fail. There is also the
problem of delayed onset of lymphoma.
Corticosferoids (systemic). Systemic cortico-
steroids are not that effective and are also
associated with serious long-term prob-
lems, such as osteonecrosis of the femur.
Systemic corticosteroids are contraindi-
cated in psoriasis, yet they are still being
given by some dermatologists.
Corticosteroids (topical). Topical corticoste-
roids are only effective as an adjuvant
treatment and for localized psoriasis;
over the long term, there are problems of
steroid atrophy and tachyphylaxis.
Calcipofriene (topical). Topical calcipotriene
is useful for localized disease and as
adjuvant therapy with photochemother-
apy or UVB.
Retinoids
Oral retinoids are not generally useful for
long-term monotherapy because of lack of
efficacy and are associated with bone changes
and disabling myopathy. However, oral reti-
noids are very beneficial as combination treat-
ment with UVB or PUVA. In fact, retinoids
and PUVA (Re-PUVA) are the method of
choice for generalized psoriasis in many cen-
ters here and abroad. Retinoids are only used
during the clearing phase of PUVA and then
stopped; this limits the total dose of retinoids,
reduces the total number of joules to clear,
and may have a prophylactic effect on the
development of skin cancers.
Topical retinoids (fazarafine gels 0.1% and
.U5%) are new to the U.S. market and look
promising, especially for localized disease or
as an adjunct to UVB or oral PUVA photoche-
motherapy.
Safety Considerations of Long-Term
PUVA Photochemotherapy
Assuming that after more than 250 treat-
ments of PUVA a patient with severe psoria-
sis could develop well-differentiated SCC, the
decision to use PUVA for these patients is for
the concern for their quality of life, with only
a low but not life-threatening risk of SCC,
which can be excised and cured. The quality
of life for 20+ years is a major consideration
for these patients. Psoriasis is a major cause
of devastating disfigurement, especially for
young people.
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