Chapter 237 Phototherapy

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

PH!!HE"AP# A! A $%A&CE
Phototherape'tic de(ices ha(e (ar)ing properties *ith respect to depth of
+, penetration into the skin, e-ects on cells and molec'les, potenc), side
e-ects and diseases in *hich the) are most e-ecti(e.
.n 'se toda) are narro*/and and /road/and +,B, +,A as part of psoralen
photochemotherap) 0P+,A1, +,A2 and targeted phototherap) 0e3cimer
lasers and nonlaser monochromatic e3cimer light so'rces1.
&arro*/and +,B is c'rrentl) preferred to treat psoriasis, other
in4ammator) skin diseases, and (itiligo.
Psoralen5+,A photochemotherap) 0P+,A1 com/ines oral or topical
psoralen compo'nds *ith +,A light so'rces. .ts main 'ses are treatment
of c'taneo's !5cell l)mphoma, (itiligo, and psoriasis that is resistant to
narro*/and +,B.
+,A2 phototherap) is partic'larl) e-ecti(e for sclerotic skin diseases s'ch
as locali6ed scleroderma, ac'te 4ares of atopic dermatitis and 'rticaria
pigmentosa.
!argeted phototherap) allo*ing relati(el) high +, doses to /e deli(ered to
diseased skin *hile sparing normal skin.
7iseases amena/le to phototherap) incl'de psoriasis, atopic dermatitis,
c'taneo's !5cell l)mphoma, (itiligo, locali6ed and s)stemic scleroderma,
pr'rit's, photodermatoses, lichen plan's, pit)riasis lichenoides, 'rticaria
pigmentosa and gran'loma ann'lare.
Phototherap) is the 'se of 'ltra(iolet radiation or (isi/le light for therape'tic
p'rposes. .ts /ene8cial e-ects in (itiligo *ere 8rst recogni6ed tho'sands of )ears
ago in .ndia and Eg)pt, and its acti(it) is no* *ell esta/lished for a (ariet) of
other dermatologic conditions. !he end'ring appeal of phototherap) is /ased on
its relati(e safet) co'pled *ith an ongoing interest in its molec'lar and /iological
e-ects. !he man'fact're of light so'rces that emit selecti(e *a(elengths of
radiant energ), identi8cation of photosensiti6ers *ith 'ni9'e photochemical
properties, and the de(elopment of no(el methods for the deli(er) of light to
c'taneo's and nonc'taneo's s'rfaces ha(e all contri/'ted to its e3panded 'se
for dermatologic and nondermatologic conditions. Aside from lasers, high o'tp't
incoherent light so'rces, and (isi/le light so'rces emplo)ed for photod)namic
therap), the main phototherapic de(ices that are in 'se toda) are /road/and
+,B 0BB5+,B1, narro*/and +,B 0&B5+,B1, +,A2, and +,A for psoralen
photochemotherap) 0P+,A1. .deall), de(ices 'sed for therape'tic 'ltra(iolet
radiation 0+,"1 sho'ld do so in a safe, e:cient and cost5e-ecti(e manner.
+nderstanding the /asic principles of these de(ices is important for
dermatologists and other pro(iders 'tili6ing phototherap) for the management of
dermatologic diseases.2;2
<ECHA&.=<= > PH!!HE"AP#
!he di-erent *a(elengths of 'ltra(iolet radiation 'sed for phototherap) each
ha(e distinct photochemical and photo/iologic properties, *hich incl'de
di-erences in depth of penetration and the range of molec'les in the skin *ith
*hich the) interact. As a conse9'ence, each form of phototherap) has 'ni9'e
properties *ith respect to potenc), side e-ects, and diseases in *hich the) are
e-ecti(e.
<ost +,B radiation 02?@;32@ nm1 is a/sor/ed /) the epidermis and s'per8cial
dermis.3 !his form of radiant energ) prod'ces man) di-erent t)pes of 7&A
damageAB ho*e(er, p)rimidine dimers and C,A p)rimidine5p)rimidone
photoprod'cts are tho'ght to /e partic'larl) important for /oth its e:cac) and
its to3icit). +,B also ca'ses photochemical changes in trans5'rocanic acid,
con(erting it to the cis5form of the molec'le. +rocanic acid is a /reakdo*n
prod'ct of histidine and is present in large amo'nts in the strat'm corne'm.
riginall) considered to /e a nat'ral photoprotectant, there is no* a s'/stantial
e(idence that cis5'rocanic acid is a mediator of the +,B5ind'ced
imm'nos'ppression.D A third direct target of +,B radiation is the amino acid
tr)ptophan. +,B con(erts tr)ptophan into C5form)lindoloE3,25/Fcar/a6ole 0>.CG1,
*hich /inds to the intracell'lar ar)lh)drocar/on h)dro3)lase 0Ah1 receptor,
initiating a series of e(ents that c'lminates in acti(ation of signal transd'ction
path*a)s. ne s'ch path*a) res'lts in e3pression of c)cloo3)genase52, an
en6)me re 9'ired for s)nthesis of prostaglandin E2.CF >inall), there is e(idence
that +,B e3pos're leads to the generation of reacti(e o3)gen intermediates,
*hich has do*nstream e-ects s'ch as 7&A damage in the form of H5o3o5
deo3)g'anosine, lipid pero3idation, acti(ation of signal transd'ction path*a)s
and stim'lation of c)tokine prod'ction.7
.n contrast to +,B radiation, *hich has a relati(el) s'per8cial depth of
penetration, +,A radiation 032@;A@@ nm1 can reach the mid5 or lo*er dermis.3 .t
is therefore more e-ecti(e than +,B for skin diseases in *hich the c'taneo's
patholog) lies deeper than the s'per8cial dermis. %ike +,B, +,A radiation can
prod'ce p)rimidine dimers in 7&A, /'t, on a per photon /asis, it is m'ch less
e-ecti(e at doing so.H .n most sit'ations, the maIor /iological e-ects of +,A
radiation are d'e to the generation of reacti(e o3)gen intermediates.? >ollo*ing
+,A e3pos're, reacti(e o3)gen intermediates are formed in mitochondrial
en6)me comple3es d'ring o3idati(e phosphor)lation. Altho'gh the skin contains
antio3idants, reacti(e o3)gen intermediates formed d'ring phototherap) e3ceed
the amo'nt that can /e ne'trali6ed /) endogeno's photoprotecti(e acti(ities.
+,A5ind'ced o3idants are capa/le of harming 7&A, lipids, str'ct'ral and
nonstr'ct'ral proteins and organelles s'ch as mitochondria. !he generation of
o3idants follo*ing +, e3pos're has /een implicated in photoaging of the skin
and skin cancer.
.n psoralen photochemotherap), psoralen photosensiti6ers are acti(ated /) +,A
radiation, and the depth of penetration of P+,A is the mid5dermis. !he maIor
photochemical e-ect of psoralen photochemotherap) is damage to 7&A. !he
changes in 7&A di-er from those of +,B and +,A *itho't psoralens.2@ Psoralens
'sed for photochemotherap) ha(e t*o do'/le /onds that can a/sor/ +,A
radiation. Jhen administered to an indi(id'al, these compo'nds intercalate *ith
7&A. >ollo*ing +,A e3pos're, the) form a single add'ct *ith 7&A and then
/ecome a /if'nctional add'ct, cross5linking the 7&A strands in the do'/le heli3
*hen a second photon is a/sor/ed. !here is also some e(idence that
photochemotherap) a'gments the prod'ction of reacti(e o3)gen intermediates
s'ch as singlet o3)gen. !his e-ect has /een implicated in ind'ction of the
c)cloo3)genase en6)me and acti(ation of arachidonic acid path*a)s.22
E>>EC!= & !HE .<<+&E =#=!E<
0=ee also Chapter ?@1
!he photoimm'nological e-ects of phototherap) are tho'ght to pro(ide an
e3planation, at least in part, for its e:cac) in c'taneo's diseases in *hich !5cell
h)peracti(it) predominates 0e.g., psoriasis, atopic dermatitis, lichen plan's1.
+nder normal circ'mstances, /oth ef -ector and reg'lator) !5cells are
generated, *ith the o(erall intensit) of the imm'ne response dependent on the
relati(e proportion of e-ector and reg'lator) !5cells pop'lations that are present.
+,B e3pos're inhi/its acti(ation of e-ector !5cells, *hereas it lea(es formation
reg'lator) !5cells 'naltered.22 As a res'lt, the e9'ili/ri'm of e-ector and
reg'lator) !5cells is /iased to*ard a diminished cell5mediated imm'ne response.
!his pert'r/ation in the /alance of e-ector and reg'lator) !5cells re4ects
disr'ption of the acti(ities of dendritic cells *ithin the skin, the maIor f'nction of
*hich is to present antigen to !5l)mphoc)tes. !his is d'e to direct e-ects of +,B
on dendritic cells and indirectl) thro'gh the prod'ction of .%52@ and
prostaglandin E2, /oth of *hich ha(e /een sho*n to diminish the capacit) of
dendritic cells to present antigen to e-ector !5cells and to s'ppress !5cell
responses.23 .ncreased le(els of .%52@ ha(e /een fo'nd after +,B, +,A2, and
P+,A e3pos're. P$E2 prod'ction occ'rs thro'gh +,B e-ects on keratinoc)tes2A;
2CB +,B is an ind'cti(e stim'l's for c)cloo3)genase52, *hich is important for
P$E2 prod'ction. ther imm'nos'ppressi(e sol'/le mediators that ha(e /een
reported to /e increased follo*ing +,B e3pos're incl'ding agonists of the
platelet5acti(ating factor receptor,27 <=H, and calcitonin gene5related
peptide.2H
P+,A has e-ects that are similar to +,B *ith respect to antigen presenting cells
*ithin the skin, the /alance /et*een e-ector and reg'lator) !5cells, and the
prod'ction of sol'/le imm'nos'ppressi(e mediators.22 !here is limited
information on the e-ect of +,A2 on antigen presenting cells and on e-ector and
reg'lator) !5cells.
.n addition to its actions on c'taneo's antigen presenting cells, phototherap)
ca'ses cell death /) apoptosis in !5cells present in c'taneo's l)mphoid
in8ltrates. !his has /een demonstrated for +,A2 phototherap) in the
l)mphoc)tic in8ltrate in atopic dermatitis,2? and for narro*/and +,B in
psoriasis.2@
Another imm'nological e-ect of phototherap) is on e3pression of .CA<52 0C7DA1
and other adhesion molec'les. .CA<52 is not normall) present on epidermal
keratinoc)tes, /'t can /e ind'ced in a (ariet) of in4ammator) skin conditions. .t
facilitates !5cell /inding to keratinoc)tes, thro'gh its interaction *ith %>A52 that is
present on !5cells. +,B, +,A2, and P+,A ha(e all /een sho*n to interfere *ith
keratinoc)te e3pression of .CA<52, and this e-ect of phototherap) ma) therefore
contri/'te to its e:cac) in diseases, *hich ha(e increased keratinoc)te .CA<52
e3pression.
E>>EC!= & <A=! CE%%=
Both +,A2 and P+,A ha(e deleterio's e-ects on mast cells, altho'gh the
mechanisms of action di-er.22;22 P+,A is not c)toto3ic for mast cells, and
/eca'se of this the red'ction in mast cell concentrations in the dermis of P+,A5
treated skin is relati(el) small. Ho*e(er, it does sta/ili6e mast cell mem/ranes
and in so doing limits the release of histamine and other mediators *hen these
cells are stim'lated to degran'late.22 .n contrast, chronic therap) *ith +,A2
res'lts in apoptosis of mast cells *ith a marked red'ction in their concentrations
in the dermis, *hich can last for se(eral months.2@ Both P+,A and +,A2 ha(e
/een emplo)ed to treat selecti(e mast cell;mediated diseases.
E>>EC!= & C%%A$E&
ne of the do*nstream e-ects of +,A5ind'ced generation of reacti(e o3)gen
intermediates is acti(ation of matri3 metalloproteinase52 0<<P521, the maIor
/iologic acti(it) of *hich is degradation of collagen. +,A radiation also increases
the prod'ction of .%52 and .%5C, *hich are stim'li for <<Ps. P+,A has also /een
sho*n to increase <<Ps. !hese e-ects of +,A2 and P+,A on <<P52 and collagen
degradation pro(ide the rationale for its 'se in sclerotic skin diseases.
E>>EC!= & !HE EP.7E"<.= 0KE"A!.&C#!E=1
+,B, P+,A, and +,A all ca'se acanthosis of the epidermis and thickening of the
strat'm corne'm.27 !his e-ect accent'ates light scattering and increases its
a/sorption /) the 'pper le(els of the epidermis. As a conse9'ence, phototherap)
treatment doses m'st /e progressi(el) increased so that an e9'i(alent n'm/er
of photons can reach the lo*er le(els of the epidermis and dermis *here
therape'tic targets lie. n the other hand, this attri/'te of phototherap) has
/een e3ploited for the management of chronic photosensiti(it) disorders
/eca'se this LhardensM the skin, permitting indi(id'als aNicted *ith these
disorders to tolerate greater amo'nts of s'n e3pos're.
E>>EC!= & <E%A&C#!E=
E3pos're to 'ltra(iolet radiation is also kno*n to stim'late melanogenesis,2H
*hich is at least in part a conse9'ence of 7&A damage andOor its repair.2?;32
E3perimental st'dies ha(e sho*n that treatment of melanoc)tes *ith 7&A repair
en6)mes increases the melanin content of melanoc)tes,33 and application of
small fragments of th)midine din'cleotides to g'inea pig skin prod'ces a tanning
response.3@;32 !he stim'lator) e-ects on melanogenesis increase the tolerance
of patients *ith some photosensiti(it) disorders to am/ient s'n e3pos're, /'t
also decrease the e:cac) of phototherap) 'nless the doses of 'ltra(iolet
radiation are grad'all) increased.
&arro*/and +,B and P+,A are also emplo)ed to repop'late (itiligino's skin *ith
melanoc)tes. !he mechanism /) *hich phototherap) stim'lates repigmentation
of (itiligino's skin is incompletel) 'nderstood, /'t ma) in(ol(e stim'lation of
hair follicle melanoc)te proliferation and migration.3A C)tokines and other
in4ammator) mediators released from other cells, s'ch as keratinoc)tes, are
tho'ght to stim'late inacti(e melanoc)tes in the o'ter root sheath of hair
follicles to proliferate, mat're, and migrate to repop'late the interfollic'lar
epidermis.3D
PH!!HE"AP# APPA"A!+=E=
.n the ideal sit'ation, the *a(elengths that are most e-ecti(e for the treatment
0i.e., the action spectr'm1 for e(er) dermatologic condition *o'ld /e kno*n and
there *o'ld /e a de(ice capa/le of deli(ering those *a(elengths speci8call) to
lesional skin. >or some skin diseases s'ch as psoriasis, great strides ha(e /een
made to*ard this ideal and targeted therap) 'sing de(ices s'ch as e3cimer
lasers3C and nonlaser de(ices kno*n as monochromatic e3cimer light 0<E%1
de(ices37 that can deli(er *a(elengths of +," at or close to those that are most
e-ecti(e at clearing psoriatic pla9'es ha(e /een e(al'ated and are /eing 'sed
clinicall). +nfort'natel), for most dermatologic conditions this information is
'nkno*n. Ho*e(er, the increased a(aila/ilit) of impro(ed phototherap) de(ices
and no(el treatment approaches are pro(iding ne* options for patients and
clinicians. .n addition, as more st'dies are cond'cted 'tili6ing phototherap)
de(ices, a /etter 'nderstanding of ho* /est to 'se older technologies is /eing
o/tained.
BA=.C P".&C.P%E= > PH!!HE"AP# 7E,.CE= A&7 !#PE= > %A<P=
Phototherap) de(ices generate light /) the con(ersion of electrical energ) into
electromagnetic energ). >ilters and 4'orophores are 'sed to modif) the o'tp't
s'ch that the desired *a(elengths are emitted. !here are se(eral t)pes of lamps
0or /'l/s1 'sed to generate therape'tic +,". !hese incl'de incandescent lamps,
arc lamps, and 4'orescent lamps.
.ncandescent lamps generate +," /) passing an electric c'rrent thro'gh a thin
t'ngsten 8lament, *hich, in t'rn, generates heat and light. Beca'se m'ch of the
electrical energ) is con(erted to heat, these lamps are relati(el) ine:cient light
so'rces and ha(e relati(el) short life spans. B) sealing the t'ngsten 8lament in a
9'art6 en(elope that contains a halogen 0/romine or iodine1, the 8lament can /e
made to emit more energetic photons *itho't red'cing the longe(it) of the /'l/.
!hese lamps are called 9'art6 halogen lamps and can emit *a(elengths *ithin
the +,, (isi/le, and ." ranges. .n clinical dermatolog), these lamps are emplo)ed
primaril) for sit'ations s'ch as phototesting and photod)namic therap) that
re9'ire (isi/le light.
Arc or gas discharge lamps *ere the 8rst e-ecti(e arti8cial so'rces of +,". Arc
lamps take ad(antage of the fact that *hen a high (oltage is passed across t*o
electrodes in the presence of a gas, the electrons of the gas atoms /ecome
e3cited. !he arc of an arc lamp refers to the electric arc generated *hen the gas
is ioni6ed 0ioni6ed gas is also kno*n as plasma1 /) a high electric c'rrent. Jhen
the gas electrons ret'rn to their gro'nd state, light is emitted. !he t)pe of gas
incorporated into the lamp determines the *a(elengths that are emitted 0i.e.,
spectral o'tp't1. !he o'tp't of arc lamps can /e mod'lated /) altering the gas
press're *ithin the /'l/ s'ch that at high press'res, the peak *a(elength o'tp't
/roadens. High5press're arc lamps t)picall) contain merc'r) or 3enon gas
*hereas lo*5press're arc lamps 'tili6e 4'orescent material. .n addition to
altering the gas press're to modif) the spectral o'tp't of arc discharge lamps,
the addition of metal halides /roadens the o'tp't spectr'm s'ch that it /ecomes
nearl) contin'o's across the +, spectr'm. >or e3ample, *hen merc'r) arc
lamps are operated at high press'res, the) ha(e o'tp't emission peaks 0so
called merc'r) lines1 seen at 2?7, 3@2, 323, 33A, and 3CD nm. .n contrast, if a
metal halide is added to the merc'r), the o'tp't /et*een these peaks is
increased and is th's more contin'o's. !he 'se of optical 8lters can then f'rther
re8ne the o'tp't of these lamps s'ch that onl) the desired *a(elengths are
emitted. !he ad(antage of metal halide lamps is the high o'tp't, *hich allo*s
for shorter treatment times. Ho*e(er, the) are more costl) and more di:c'lt to
operate than 4'orescent lamps. ne e3ample of a metal halide lamp c'rrentl) in
clinical 'se is the +,A2 light so'rce.
>l'orescent lamps are the most commonl) 'sed so'rces of therape'tic +, light.
!hese lamps take ad(antage of the fact that chemicals called phosphors 0a
speci8c t)pe of chromophore also called a 4'orophore1 a/sor/ and then reemit
light. !he light that is reemitted is of lo*er energ) 0and th's longer *a(elength1
than the inciting light. +sing this principle, the +,C irradiation 0that peaks at 2DA
nm1 gener ated from a lo*5press're merc'r) lamp can /e con(erted to the
longer +,B and +,A *a(elengths of light that are desira/le for phototherap). !he
8nal o'tp't of a 4'orescent lamp is dictated /) the speci8c phosphor of the /'l/.
An important ad(ance in photodermatolog) came *ith the de(elopment of a
modi8ed 4'orescent lamp that emits largel) at 322 nm.3H Broad/and +,B and
+,A light so'rces 'sed for P+,A are other e3amples of 4'orescent lamps.
Beca'se di-erent forms of phototherap) are 'sed to treat di-erent diseases, it is
important and practical to di(ide de(ices /ased 'pon *a(elength. 7e(ices to
deli(er /road/and +,B 0BB5+,B1, 3225nm narro*/and +,B 0&B5+,B1, +,A 0for
'se in psoralen photochemotherap)1, and +,A2 03A@;A@@ nm1 are a(aila/le in
the +nited =tates and in most other co'ntries. .n addition to di-ering /) spectral
o'tp't, phototherap) de(ices range in the s'rface area that the) are designed to
treat 0*hole /od), locali6ed regions, or onl) lesional skin1. 7e(ices 'sed for large
/od) s'rface areas resem/le /ooths 0*hich patients enter for each treatment1.
!hese de(ices come in a (ariet) of st)les from ro'nd c)linders to folding 'nits
that can /e 'nfolded for treatments and then collapsed *hile not in 'se. 7e(ices
ha(e /een de(eloped to treat more limited areas 0s'ch as the palms and soles1
and as s'ch the) are s'/stantiall) smaller in si6e. >inall), targeted therap)
'tili6es de(ices that can deli(er therape'tic 'ltra(iolet radiation onl) to lesional
skin and range in si6e from small handheld 'nits to de(ices *ith a handheld
*and attached to a larger +,"5generating component.
B"A7BA&7 +,B A&7 &A""JBA&7 +,B
riginall) 'sed for psoriasis therap), arti8cial so'rces of /road/and +,B 0BB5
+,B1 ha(e /een 'sed therape'ticall) since the earl) t*entieth cent'r). .n
partic'lar, +,B com/ined *ith the topical application of coal tar 0as de(eloped
initiall) /) Jilliam $oeckerman1 *as a mainsta) of psoriasis treatment for man)
decades.3? <ore recentl), *ith the de(elopment and a(aila/ilit) of narro*/and
+,B, some dermatologists ha(e concl'ded that BB5+,B is o/solete.A@ Ho*e(er,
BB5+,B is still *idel) 'sed in the +nited =tates for a (ariet) of conditions
incl'ding psoriasis, atopic dermatitis, pr'rigo nod'laris, and 'remic pr'rit's.3C .n
addition, some patients *ho are 'na/le to tolerate &B5+,B *ill respond to BB5
+,B.3C
!he most commonl) emplo)ed de(ices that deli(er BB5+,B 'tili6e 4'orescent
lamps. !hese de(ices emit +," o(er a /road spectral range. Appro3imatel), t*o5
thirds of the o'tp't is in the +,B range and the rest is primaril) in the +,A.
Ho*e(er, /eca'se *a(elengths.
*ithin the +,B ha(e nearl) m'ch more energ) than *a(elengths *ithin the +,A,
the +,A emitted contri/'tes little to the therape'tic e:cac), ass'ming the
patient is not taking a photosensiti6ing medication. BB5+,B and &B5+,B ha(e
/een speci8call) designed to limit o'tp't /elo* P2?@ nm 0i.e., in the +,C
range1.
!he *a(elengths that most e:cientl) clear psoriasis are appro3imatel) 323
nm.A2 .n contrast, *a(elengths less than 3@@ nm are the most e:cient at
ca'sing er)thema and nonmelanoma skin cancer. Based on this kno*ledge, light
so'rces, termed narro*/and +,B 0&B5+,B1, ha(e /een prod'ced.3H !hese light
so'rces emit onl) *a(elengths /et*een 3@H and 323 nm, and ha(e largel)
s'pplanted BB5+,B +, radiation so'rces for phototherap). Altho'gh originall)
'sed to treat psoriasis, the) ha(e no* /een 'sed to treat a n'm/er of other
in4ammator) skin diseases as *ell.
!he initial starting dose of /oth /road/and and narro*/and +,B is determined in
one of t*o *a)s 0!a/les 23752 and 237521. .n the 8rst, the minimal er)thema
dose 0<E71 is determined /) e3posing C one cm2 areas of skin on the inner
aspect of the forearm or lo*er /ack to grad'all) increasing amo'nts of +,
radiation from the same de(ice that *ill /e 'sed for phototherap). !*ent)5fo'r
ho'rs later, the +, e3posed areas of skin are e3amined and the smallest +, dose
that res'lts in 'niform er)thema o(er the entire area, considered the <E7, and
phototherap) is initiated at D@Q to 7@Q of that amo'nt. Alternati(el), the initial
dose of phototherap) is esta/lished /ased empiricall) on >it6patrick skin
photot)peA2 0see !a/les 23752 and 237521. ='/se9'ent e3pos'res are gi(en 2;D
times per *eek and the dose is increased at each treatment, ass'ming the
patient has not de(eloped an er)thema response. .f an er)thema response has
occ'rred, then, depending on its se(erit), the dose is either red'ced or the
treatment is dela)ed 0see !a/les 23752 and 237521. !he ma3im'm &B5+,B dose
that sho'ld /e administered is 2,@@@;D,@@@ mJOcm2 depending on the
photoreacti(e skin t)pe. .f patients miss treatments, dosage modi8cations sho'ld
/e made to a(oid /'rns 0see !a/le 2375D1.
!AB%E 23752 &arro*/and +,B Phototherap)
!AB%E 23752 Broad/and +,B Phototherap)
P+,A
Psoralen5+,A photochemotherap) 0kno*n /) the acron)m P+,A1 com/ines the
oral ingestion or topical application of psoralens *ith e3pos're to +," in the +,A
range. Altho'gh psoralens and s'nlight had /een emplo)ed for tho'sands of
)ears for the treatment of (itiligo, it *as not 'ntil 2?A7 that P+,A in its modern
form *as descri/ed, initiall) for the treatment of (itiligo, and s'/se9'entl) for
the treatment of psoriasis.A3
!hree forms of psoralen are 'sed in photochemotherap) regimensR H5
metho3)psoralen 0H5<P1, D5metho3)psoralen 0D5<P1, and A,DS,H5
trimeth)lpsoralen 0!<P1. .n the +nited =tates, onl) H5metho3)psoralen is
a(aila/le. !here are t*o oral form'lations of H5<P, a microni6ed form *hich is
t)picall) gi(en at a dose of @.C mgOkg 22@ min'tes prior to +,A e3pos're or a
dissol(ed form *hich is gi(en at a dose of @.A;@.C mgOkg ?@ min'tes /efore +,A
e3pos're. !he dissol(ed preparation is a/sor/ed faster and )ields higher and
more reprod'ci/le ser'm le(els and is therefore more commonl) emplo)ed as a
part of P+,A phototherap) regimens.
!he most common so'rces of radiation for P+,A therap) are +,A 4'orescent
lamps, *hich ha(e a ma3im'm emission at 3D2 nm, near the a/sorption
ma3im'm for psoralens. >or oral P+,A therap), +,A radiation is 's'all) initiated
at a dose that corresponds to the D@Q;7@Q of the minim'm phototo3ic dose
0<P71 or according to the >it6patrick skin photot)pe 0!a/le 237531. !he <P7 is
determined /) ha(ing the patient take the dose of the oral psoralen to /e 'sed
for the photochemotherap) treatment and e3posing C one5cm2 areas of skin to
grad'all) increasing doses of +,A. !he <P7 is e(al'ated 72 ho'rs after +,A
e3pos're and is the lo*est amo'nt of +,A that prod'ces a 'niform er)thema
o(er the entire area. .n the +nited =tates, it is more common to initiate therap)
/ased on the >it6patrick skin photot)pe 0see !a/le 237531. !reatments are 's'all)
gi(en 2;A times per *eek, a(oiding consec'ti(e da)s. !he amo'nt of +,A that is
to /e gi(en is increased *ith each treatment. +,A dose modi8cations are made if
an er)thema response de(elops or treatments are missed 0see !a/le 237531.
!AB%E 23753 ral P+,A Photochemotherap)
7eli(er) of psoralens in /ath*ater is pop'lar in some areas of the *orld /eca'se
it pro(ides a 'niform dr'g distri/'tion o(er the skin s'rface, is associated *ith
(er) lo* psoralen plasma le(els, and rapid elimination of free psoralens from the
skin. !his form of psoralen deli(er) circ'm(ents gastrointestinal side e-ects and
possi/le phototo3ic ha6ards to the e)es associated *ith the oral form. =kin
psoralen le(els are highl) reprod'ci/le, and photosensiti(it) lasts no more than
t*o ho'rs. Bath5P+,A consists of 2D;2@ min'tes of *hole5/od) immersion in
sol'tions of 25mg H5<P per liter of /od) temperat're /ath*ater 0!a/le 2375A1.
D5<P and trimeth)lpsoralen are also emplo)ed for /ath P+,A. .rradiation is
performed immediatel) after /athing, as photosensiti(it) decreases rapidl). Bath
P+,A is started at 3@Q of the <P7. !reatments are t)picall) gi(en t*ice *eekl).
$'idelines for /ath, local immersion, and other topical P+,A forms ha(e /een
p'/lished /) the British Photodermatolog) $ro'p.AA A cost5e-ecti(eness
anal)sis of data collected across fo'r centers in =cotland re (ealed that co'rses
of /oth /ath P+,A and other topical P+,A *ere consistentl) more e3pensi(e than
oral P+,A.AA !his is related predominantl) to the increased n'rsing time
re9'ired, altho'gh the cost of topical preparations also tends to /e greater than
oral preparations.
!AB%E 2375A Bath P+,A Photochemotherap)a
.. Psoralen 7ose
H5<P dissol(ed in /ath *ater for a 8nal concentration of 2.@ mgO%
Bath *ater is at /od) temperat're 0?H.CT>1 7'ration of /ath is 2D52@
min'tes
... +,A E3pos're
<P7 7etermination
E3pose 25cm2 areas on the lo*er /ack or inner aspect of the forearmB read
72 h after +,A e3pos're
>it6patrick skin photot)pe . or ..R @.D, 2.@, 2.@, 3.@, A.@ and D.@ JOcm2 +,A
>it6patrick skin photot)pe ... or .,R 2.@, 2.@, A.@, C.@, H.@ or 2@.@ JOcm2 +,A
+,A e3pos're immediatel) after /athing
.nitial e3pos'reR 3@Q of <P7
='/se9'ent e3pos'resR 2 times per *eek .ncrease +,A dose /) 2@Q each
*eek
<odi8ed from "efs. 2, 33@, and 332.
<ore recentl), cream P+,A has /een de(eloped, *hich can /e 'sed to treat local
and more *idespread disease. !hirt) min'tes follo*ing the application of a
psoralen5containing cream, patients are e3posed to +,A irradiation.
A,.7A&CE A&7 <A&A$E<E&!= > B+"&=
='n/'rn5like reactions are the most common short5term ad(erse e-ect of
phototherap). +,B /'rns 's'all) peak at 22;2A ho'rs, and P+,A /'rns at 2A;AH
or e(en 72 ho'rs, *ith more se(ere /'rns peaking later than mild ones. =e(ere
/'rns o(er a large portion of the skin s'rface prod'ce s)stemic to3icit) *ith
fe(er and malaise in addition to pain. =e(ere P+,A /'rns, *hich e3tend *ell into
the dermis, can lead to epidermal slo'ghing and are an indication for admission
to a /'rn5care hospital facilit). !o a(oid e3acer/ating a still de(eloping P+,A
/'rn, it is recommended that P+,A treatments not /e gi(en on consec'ti(e da)s.
!a/le 2375D speci8es the +,B or +,A dose adI'stments in the e(ent of a /'rn
reaction d'ring phototherap). A /'rn reported /) the patient at the ne3t (isit,
e(en if no longer (isi/le, sho'ld /e managed in the same manner as a still5(isi/le
reaction. B'rns o(er limited /od) areas, s'ch as I'st the face or /reasts, can /e
managed /) local application of an appropriate s'nscreen /efore or part *a)
thro'gh s'/se9'ent treatments, especiall) if the area is not a-ected /) the
disease /eing treated. Ho*e(er, care m'st /e taken to consistentl) protect the
same area0s1 in order to a(oid a s'dden f'll treatment to pre(io'sl) shielded
skin.
!AB%E 2375D <odi8cation of Phototherap) 7ose for Er)thema or <issed =essions
epeated +,5irradiated skin de(elops tolerance to s'/se9'ent e3pos'res, allo*ing
and indeed mandating progressi(el) larger doses for optimal therape'tic e-ect.
Ho*e(er, this tolerance is rapidl) lost *hen e3pos'res cease, re9'iring
do*n*ard adI'stments of dose after as little as 2 *eek 0!a/le 2375D1 to a(oid
/'rns.
+,A2.
Beca'se of its longer *a(elength, +,A2 phototherap) 03A@;A@@ nm1 is a/le to
penetrate more deepl) into the skin than +,B or shorter range +,A called +,A2
0i.e., 32@;3A@ nm1. !he 8rst report descri/ing a de(ice capa/le of emitting +,A2
occ'rred in 2?H2.AD .t *as not 'ntil 2??2 *hen the therape'tic /ene8t of +,A2
*as demonstrated for atopic dermatitis that greater interest in the therape'tic
properties of +,A2 occ'rred.AC;A7 .nitiall), one o/stacle to the *idespread 'se
of the initial +,A2 de(ices *as the intense heat that the) generated. &e*er
+,A2 phototherap) 'nits incorporating a speciali6ed 8ltering and cooling s)stem
that remo(es nearl) all *a(elengths a/o(e D3@ nm ha(e largel) eliminated this
pro/lem. !ho'gh not *idel) a(aila/le in the +nited =tates, these light so'rces
are 'sef'l for the management of a (ariet) of dermatological conditions for
*hich other forms of phototherap) are not helpf'l.AH;A?
+,A2 is administered 3;D times per *eek. !here ha(e /een se(eral st'dies,
*hich ha(e attempted to esta/lish the optimal amo'nt of +,A2 to administer at
each treatment session.D@;DA !hree dosing regimens ha(e /een 'sedR 021 lo*
dose 02@;3@ JOcm21, 021 medi'm dose 0A@;7@ JOcm21, and 031 high dose 023@
JOcm21.D@;DA Altho'gh se(eral comparison st'dies ha(e /een performed, at this
point, there is no consens's as to *hich dose is /est. .n general, patients are
started at 2@;3@ JOcm2 and increased to the f'll dose *ithin 3;D treatments.DD
!he risk of /'rns is far less than *ith +,B or P+,A therap).
!A"$E!E7 PH!!HE"AP#
+nlike the pre(io'sl) descri/ed phototherap) de(ices that e3pose /oth lesional
and 'nin(ol(ed skin to +,", targeted phototherap) deli(ers therape'tic doses of
+," onl) to lesional skin. !argeted phototherap) has also /een called foc'sed
phototherap), concentrated phototherap), and microphototherap). =e(eral
de(ices are a(aila/le to deli(er targeted phototherap) incl'ding /oth
monochromatic 0one *a(elength1 and pol)chromatic s)stems. !here are se(eral
ad(antages to targeted phototherap). !hese de(ices spare normal skin, there/)
allo*ing higher 4'ences to /e deli(ered to diseased skin *hile decreasing the
risk of ac'te and chronic side e-ects to normal skin. !argeted ther ap) can /e
'sed on treatment5resistant lesions and on di:c'lt anatomic locations 0s'ch as
the scalp, chin, and nails1. !he handheld nat're of a targeted phototherap)
de(ice ma) /e easier for )o'ng children than recei(ing treatments in a
phototherap) /ooth, *hich can /e large and intimidating. !he limitations of
targeted phototherap) are de(ice e3pense and the fact that it ma) not /e
practical for patients *ith more than 2@Q to 2@Q of /od) s'rface area in(ol(ed
to recei(e treatments in this manner. !he pre(enti(e action of phototherap) on
'nin(ol(ed /'t at5risk skin is also lost. !argeted phototherap) de(ices incl'de
e3cimer lasers and nonlaser de(ices kno*n as monochromatic e3cimer light
0<E%1 de(ices.37 Both t)pes of de(ices ha(e /een 'sed to deli(er targeted
therap) to treat speci8c lesions of diseases s'ch as psoriasis and (itiligo.3C;37
Jhile /oth t)pes deli(er monochromatic +,B irradiation 0most commonl) at 3@H
nm1, the) di-er in se(eral respects. %asers t)picall) deli(er +," to a smaller area
/'t are capa/le of emitting higher amo'nts of radiation o(er a shorter period of
time. .n contrast, <E% de(ices deli(er monochromatic irradiation to a larger area
/'t *ith a lo*er po*er densit). !here are also se(eral de(ices that emit
pol)chromatic +,A or +,B 0BB5 or &B5+,B1 to targeted areas. !hese de(ices
t)picall) 'tili6e 8/eroptic s)stems co'pled *ith +,B generating so'rces. !hese
de(ices ha(e spot si6es from 2;3 cm. .n addition, the) ha(e m'ltiple deli(er)
programs and a'tomatic cali/ration, *hich makes treatment *ith predetermined
dosages possi/le. !hese de(ices are smaller, less e3pensi(e, and ha(e less
maintenance pro/lems than lasers.DC;D7 !reatment protocols *ith targeted
phototherap) (ar) depending on the t)pe of de(ice that is emplo)ed.
=A>E!# > PH!!HE"AP#
=afet) principles are common to most phototherap) de(ices. E9'ipment sho'ld
/e checked on a reg'lar /asis /) the clinical sta- or the man'fact'rerUs
engineer, since /'l/ o'tp't ma) change o(er time, and internal dosimetr)
components ma) fail. Jhile phototherap) is 's'all) deli(ered *itho't incident,
the risk of o(ertreatment is real, altho'gh the e3act incidence of ad(erse e(ents
attri/'ta/le to phototherap) is 'nkno*n and (aries depending on the de(ice.
.mportantl), *ith the e3ception of P+,A therap) for *hich formal long5term
follo*5'p st'dies esta/lished an increased risk of lentigines, s9'amo's cell
carcinoma and melanoma, other forms of phototherap) appear to /e remarka/l)
safe.3C,DH &e*er therapies s'ch as narro*/and +,B and +,A2 appear to /e
relati(el) safe especiall) compared to nonphototherape'tic options for the same
diseases, /'t a*ait longer follo*5'p.
+,B
"epeated e3pos're of the skin to +, irradiation does res'lt in c'm'lati(e actinic
damage regardless of the so'rce. Jith respect to nonmelanoma skin cancer,
most st'dies ha(e sho*n that there is little risk /e)ond that associated *ith
ha/it'al s'n e3pos're *ith either BB5+,B or &B5+,B phototherap).D?;C@ $reater
than 3@@ treatments BB5+,B is associated *ith a modest /'t signi8cant increase
in =CC and BCC.C2 Ho*e(er, the carcinogenic risk of a single P+,A treatment is
a/o't se(en times greater than a single +,B treatment.C2 As a res'lt of its
safet) pro8le and e:cac), &B5+,B has emerged as a leading therap) for a
n'm/er of skin diseases. =e(eral st'dies ha(e also sho*n that long5term
e3pos're to BB5+,B com/ined *ith topical tar preparations is not associated *ith
an increased risk of =CC.C3
P+,A
AC+!E =.7E E>>EC!=.
!he side e-ects of P+,A incl'de dr'g intolerance reactions as *ell as the
com/ined action of psoralens pl's +,A radiation. ral H5<P ma) ca'se na'sea
02@Q of patients1 and (omiting, and this occasionall) necessitates
discontin'ation of treatment. !hese side e-ects are more common *ith li9'id
preparations rather than *ith cr)stalline preparations, pro/a/l) /eca'se of
higher psoralen ser'm le(els. !he na'sea ma) /e minimi6ed or a(oided /)
instr'cting the patient to take H5<P *ith milk, food, or ginger 0e.g., ginger
cookies, ginger ale, ginger s'pplements1CA or to di(ide the dose into t*o
portions, taken appro3imatel) one5half ho'r apart. ther reported e-ects incl'de
ner(o'sness, insomnia, and depression. Jith D5<P, na'sea is rare, e(en *ith
doses 'p to 2.H mgOkg /od) *eight.
>ollo*ing e3pos're to +,A, appro3imatel) 2@Q of patients 'ndergoing P+,A
therap) *ill e3perience pr'rit's. .n most cases, this can /e alle(iated /) /land
emollients. =ome patients *ith se(ere pr'rit's ma) re9'ire s)stemic treatment.
A stinging pain ma) rarel) occ'r, and the mechanism for this is 'nkno*n. !he
s)mptoms are 's'all) 'nresponsi(e to antihistamines, and, in most instances,
s'/side *hen the treatment is discontin'ed.
<ild and often transient focal er)thema after P+,A therap) occ'rs fre9'entl).
An) area sho*ing er)thema *ith tenderness or /listering sho'ld /e shielded
d'ring s'/se9'ent +,A e3pos'res 'ntil the er)thema has resol(ed. As noted
a/o(e, er)thema appearing *ithin 2A ho'rs ma) signal a potentiall) se(ere
phototo3ic reaction, and ma) *orsen progressi(el) o(er the ne3t 2A ho'rs, since
peak er) thema *ith P+,A characteristicall) occ'rs at least AH ho'rs after the
treatment. .n that sit'ation, patients sho'ld /e protected from f'rther +,A
e3pos'res and s'nlight, and sho'ld /e monitored closel) 'ntil the er)thema has
resol(ed.
,er) rare side e-ects of P+,A incl'de pol)morpho's light er'ption5like rashes,
acne5like er'ptions, s'/'ng'al hemorrhages ca'sed /) phototo3ic reactions of
the nail /eds, on)chol)sis of the nails, and occasionall) h)pertrichosis of the
face. !hese disappear *hen treatment is discontin'ed. Anal)sis of la/orator)
data in se(eral large st'dies re(ealed no signi8cant a/normal 8ndings in patients
recei(ing P+,A o(er prolonged periods of time.CD;C7
Chronic Actinic 7amage.
Chronic e3pos're to P+,A ma) res'lt in skin changes that resem/le photoaging,
and *hich is aggra(ated /) chronic nat'ral s'n e3pos're. P+,A lentigines are
small /ro*n mac'les *ith irreg'lar /orders and 'ne(en pigmentationCH and are
histologicall) characteri6ed /) proliferation of large melanoc)tes.C? .n contrast
to solar lentigines, melanoc)tes in P+,A lentigines often displa) an increased
si6e of melanosomes, cl'stering and /in'cleation *ith n'clear h)perchromatism,
and cell'lar pleomorphism. !27??A B5t)pe "af 0B"A>1 m'tations ha(e /een
fo'nd to /e present in P+,A lentigines,7@ /'t the f'll signi8cance of this is not
)et 'nderstood, as /oth c'taneo's malignant melanoma and /enign melanoc)tic
ne(i often ha(e B"A> m'tations.72;7A !he presence of these lesions is directl)
related to the n'm/er of P+,A treatments and total +,A dose that has /een
administered. !he a/sence of P+,A lentigines ser(es as a 'sef'l indicator of a
lo*er risk of P+,A malignanc).7D
Carcinogenesis.
C'taneo's malignancies are the maIor concern of long5term and repeated P+,A
treatments. !he risk of nonmelanoma skin cancer and possi/l) malignant
melanoma increases in a dose5dependent manner. .n la/orator) animals, H5<P
and D5<P ha(e 'ne9'i(ocall) ind'ced skin cancer at le(els of dr'g and +,A
irradiation compara/le to those 'sed in P+,A therap).7C Cancer de(elopment is
tho'ght to stem from /oth 7&A damage and do*n5reg'lation of the imm'ne
s)stem. !he P+,A >ollo*5'p =t'd), *hich e(al'ated 2,3H@ patients *ho /egan
P+,A treatment for psoriasis in 2?7D and 2?7C has doc'mented maIor health
e(ents in these indi(id'als in a prospecti(e manner. (erall, patients *ho *ere
treated *ith at least 337 P+,A treatments e3hi/ited a 2@@5fold increased risk of
=CC compared to that e3 pected from pop'lation incidence rates.77 <oreo(er,
almost AQ of patients *ith =CC de(eloped metastases, most commonl)
originating in the genital area. !here is 'ncertaint) a/o't P+,A /eing the sole
factor as man) of the patients in the long5term follo*5'p st'dies also had
signi8cant e3pos're to s'nlight and to treatments *ith carcinogenic potential,
incl'ding arsenic, +,B, and methotre3ate. !he risk of de(eloping =CC *ith P+,A
ma) /e f'rther potentiated /) the 'se of c)closporine and, for this reason,
c)closporine is contraindicated in indi(id'als *ho ha(e /een treated *ith
P+,A.7H ral retinoids 'sed conc'rrentl) *ith P+,A, on the other hand, red'ce
the risk of =CC.7?
.ndi(id'als treated *ith P+,A are at increased risk of c'taneo's malignancies of
the genitalia, and this has led to standard protection of the genitalia d'ring
phototherap).H@ !he risk is dose5dependent, *ith a ?@5fold increased risk of
genital t'mors among patients e3posed to high doses of P+,A compared *ith
that e3pected in the general pop'lation. <en treated *ith high5dose e3pos'res
to /oth P+,A and topical tarO+,B ha(e the greatest risk of genital t'mors.H@;H2
!here is c'rrentl) no standardi6ed regimen for genital shielding. !here are
po'ches for genital shielding that are commerciall) a(aila/le, /'t the cost and
a(aila/ilit) ma) /e prohi/iti(e. >actors in4'encing the e-ecti(eness of +,
irradiation protection incl'de 8/er composition, porosit) 0intrinsic to *hich is
n'm/er of la)ers, *ea(e t)pe, and thread co'nt1, mass, and color.H2;H3
Commonl) 'sed protecti(e agents incl'de s'rgical masks, paper to*els, /l'e
s'rgical to*els, and 'nder*ear. !he e:cac) of these materials has /een st'died,
and s'rgical masks *ere fo'nd to pro(ide ins':cient protection against +,
irradiation most likel) d'e to increased porosit) 0looser *ea(e1 and decreased
mass.HA
!he relationship /et*een P+,A and melanoma has also /een e3amined in detail.
!he P+,A >ollo*5+p =t'd) has pro(ided e(idence that indi(id'als *ith at least
2D@ treatments and at least 2D )ears from the 8rst P+,A treatment *ere at
increased risk of de(eloping melanoma.HD Patients *ho de(eloped a phototo3ic
reaction more easil) *ere at higher risk for melanoma than those *ith darker
skin.HC As a res'lt of those st'dies, a personal or famil) histor) of melanoma or
a histor) of greater than 2@@ P+,A treatments is considered to /e a relati(e
contraindication to f'rther P+,A therap).HC
.n patients emplo)ing P+,A therap) in com/ination *ith methotre3ate for at
least 3C months, the incidence of l)mphoma *as more than 7 times higher than
that of cohort mem/ers earlier in the st'd) *ho had not taken methotre3ate.
phthalmologic E-ects.
+,A is a/sor/ed in the lens and in the presence of +,A, psoralens can /ind
protein, 7&A, and "&A. Beca'se the lens ne(er sheds its cells, protein5/o'nd H5
metho3)psoralen acc'm'lates in the lens, increasing the risk of irre(ersi/le
opaci8cation.HH !here ha(e /een reports of (ario's oc'lar pro/lems in patients
on P+,A incl'ding cataracts, H?;?@ conI'ncti(al h)peremia,?2 and decreased
lacrimation.?2
A 2D5)ear prospecti(e st'd)?2 so'ght to e(al'ate the e-ect of P+,A on the e)es.
Participants *ere instr'cted to 'se +,A5/locking e)e*ear *hen o'tside or
looking o'tside thro'gh *indo* glass d'ring da)light for a minim'm of 22 ho'rs,
altho'gh c'rrent la/eling calls for 2A ho'r protection. !his st'd) fo'nd no
relationship /et*een increasing n'm/ers of P+,A sessions and (is'al
impairment or cataracts, and demonstrates that increasing e3pos're to P+,A
does not increase cataract risk among middle5aged and older persons 'sing e)e
protection as practiced /) this cohort.?2 ther smaller st'dies ha(e also fo'nd
no increase in cataract formation or (is'al impairment.?3;?C
+,A2
+,A2 phototherap) is generall) *ell tolerated.D2;D3 "eported side e-ects
incl'de intense tanning, er)thema, pr'rit's, 'rticaria, tenderness, a /'rning
sensation, pol)morpho's light er'ption, ec6ema herpetic'm and /acterial
s'perinfection.AH;A?,DA Ho*e(er, /eca'se +,A2 phototherap) has onl) /een
a(aila/le since the 2??@s, the long5term e-ects are still 'nder in(estigation.
=PEC.A% C&=.7E"A!.&=
H.,.
!he safet) of phototherap) and photochemotherap) in H.,5positi(e patients has
/een de/ated. +ltra(iolet radiation ma) acti(ate H., /) the ind'ction of &>5VB,
and +,B therap) increases H.,52 gene e3pression in the skin. Ho*e(er, BB5+,B
phototherap) does not appear to a-ect plasma H., le(els nor does it ha(e an
e-ect on C7A co'nts.2@2,2@3;2@A .n general, phototherap) is tho'ght to /e
safe. for H., patients.2@D A consens's statement p'/lished /) the American
Academ) of 7ermatolog) in 2@2@ concl'ded that for moderate5to5se(ere
psoriasis in H.,5positi(e patients, phototherap) and antiretro(irals are the
recommended 8rst5line therape'tic agents.2@C
CH.%7"E&.
&B5+,B is no* preferred to P+,A in children for most skin conditions, /eca'se of
concern a/o't P+,A side e-ects incl'ding phototo3icit), carcinogenicit),
photoaging, and the potential de(elopment of cataracts.
<.=CE%%A&E+=.
Patients *ho ha(e had arsenic e3pos're are at increased risk for c'taneo's
malignancies and sho'ld a(oid phototherap). !ransplant patients ha(e a m'ch
higher risk of skin cancer compared to the general pop'lation and, in that patient
pop'lation there is a relati(e contraindication to phototherap). Photosensiti6ing
medications sho'ld theoreticall) /e a(oided d'ring phototherap) treatment,
altho'gh in practice man) patients 'ne(entf'll) recei(e phototherap) *hile
taking tetrac)cline, h)drochlorothia6ide, or other photosensiti6ing dr'gs. !here
are anecdotal reports of an association /et*een chronic 'se of (oricona6ole and
the de(elopment of aggressi(e c'taneo's malignancies incl'ding
melanoma.2@7;22@
7.=EA=E= A<E&AB%E ! PH!!HE"AP#
0!a/le 2375D1
"esponses of the diseases listed in e!a/le 2375C are disc'ssed in detail online.
=ee also Chapter 23H