Download Chapter 135 Abnormal Responses to Ultraviolet Radiation

Chapter 135 Abnormal Responses to Ultraviolet Radiation: Idiopathic, Probably
Immunologic, and Photoexacerbated
Fitzpatrick’s Dermatology in General Medicine
Chapter 135
John Hawk Paul Norris Herbert Hönigsmann
Abnormal Responses to Ultraviolet Radiation: Idiopathic, Probably Immunologic, and
Photoexacerbated
POLYMORPHIC (POLYMORPHOUS) LIGHT ERUPTION
Epidemiology
Etiology and Pathogenesis
Clinical Features
Histology
Diagnosis
Treatment
ACTINIC PRURIGO
Pathogenesis
Clinical Features
Histology
Diagnosis
Treatment
HEREDITARY POLYMORPHIC LIGHT ERUPTION OF NATIVE AMERICANS
HYDROA VACCINIFORME
Pathogenesis
Incidence
Clinical Features
Histology
Diagnosis
Treatment
SOLAR URTICARIA
Pathogenesis
Clinical Features
Differential Diagnosis
Histology
Diagnosis
Treatment
CHRONIC ACTINIC DERMATITIS
Historical Aspects
Etiology and Pathology
Clinical Features
Histology
Diagnosis
Treatment
PHOTOEXACERBATED DERMATOSES
Acne
Darier's Disease
Disseminated Superficial Actinic Porokeratosis
Herpes Simplex
Lichen Planus Actinicus
Eczema
Lupus Erythematosus
Pellagra
Pemphigus
Bullous Pemphigoid
Psoriasis
APPROACH TO THE PATIENT WITH PHOTOSENSITIVITY
Clinical Features
Laboratory Studies
Phototesting
Photopatch Testing
REFERENCES
Abnormal responses to ultraviolet radiation (UVR) exposure can be broadly categorized into
four groups ( Table 135-1): acquired idiopathic, probably immunologic photodermatoses;
DNA repair-defective photodermatoses; photosensitization by exogenous drugs or chemicals;
and dermatoses exacerbated by UVR. The first group, the idiopathic, probably immunologic
photodermatoses, and the last, the photoexacerbated dermatoses, as well as the approach to
assessing a photosensitive patient, are all discussed in this chapter; the other groups are
covered in Chap. 136, Chap. 149, and Chap. 155.
TABLE 135-1 Abnormal Reactions of Ultraviolet Irradiation
POLYMORPHIC (POLYMORPHOUS) LIGHT ERUPTION
Polymorphic (or polymorphous) light eruption (PMLE) is a common acquired disorder
characterized clinically by the abnormal occurrence, within hours to a day or so of UVR
exposure, of itchy, nonscarring, erythematous papules, vesicles, or plaques of some or, less
commonly, all light-exposed skin. The lesions are generally symmetric, and they resolve
completely over days to a week or two. Histologically, there is a dense, dermal,
predominantly perivascular, lymphocytic cellular infiltrate.
Epidemiology
PMLE is the most common photodermatosis: approximately 20 percent of Scandinavians 1
and 10 to 15 percent of those living in the northern United States 2 and the United Kingdom 3
appear to suffer from the condition. Conversely, only 5 percent of Australians 3 and virtually
no equatorial Singaporeans 4 have the disease. The prevalence of the condition thus increases
steadily with increasing distance from the equator.
The disorder 1 , 2 , 5 usually has onset in the first three decades of life and affects females
two to three times more often than males. It may occur in all skin types and racial groups but
appears more commonly to affect relatively fair-skinned individuals. A positive family history
is present in about a sixth of the patients. 1
Etiology and Pathogenesis
A delayed-type hypersensitivity response to a sunlight-induced, cutaneous neoantigen, first
proposed in 1942 by Stephen Epstein because of the hours usually taken for the eruption to
develop, and the lesional histologic appearances, has proved almost certainly to be the cause
of PMLE, although the now fairly substantial evidence for this remains circumstantial. The
underlying reason for the occurrence of the disorder in any given patient appears likely to be
genetic, perhaps 70 percent of all subjects having a tendency to the condition, but its actual
expression depends on the degree of gene penetrance. 6 Furthermore, the inherited defect may
be a diminished capacity in patients for normal UV-induced cutaneous immunosuppression.
INDUCTION OF PMLE Difficulty in the reliable laboratory induction of clinical lesions has
long frustrated investigations into the pathogenesis of PMLE. This frequent lack of response,
often to adequate doses of artificially produced UVR, by patients who react readily to just
suberythemogenic doses of natural sunlight, appears to relate to a number of variables. These
include in particular the size of the UV irradiation site and its location and the irradiation of
small, normally unaffected areas perhaps not eliciting sufficient immunologic stimulus to
activate the response. It also may relate to the UV irradiation spectrum, irradiation dose,
irradiation dose rate, and degree of cutaneous immunologic tolerance, which may be
increased by any recent prior exposure. 7 The complex interrelationships between factors such
as these have contributed significantly to the conflicting nature of reports concerning the most
effective wavelengths for PMLE induction. In most series, UVA (315 to 400 nm) has been
more reliably effective than UVB (280 to 315 nm). 7 , 8 Thus, in one of these studies, 8
following exposures of buttock skin to UVA or UVB daily for 4 to 8 days, the action
spectrum was in the UVA range in 56 percent, UVB in 17 percent, and both in 27 percent.
However, Miyamoto 9 later confirmed earlier reports that induction with UVB can also be
successful in a high proportion (57 percent) of selected patients. This apparent diversity in
action spectrum for the induction of PMLE may very possibly be the result of different UVevoked inducing antigens, as also appears likely in solar urticaria, 10 and perhaps also of
different cutaneous levels for these antigens. Contradictory results regarding the action
spectrum for PMLE induction could also conceivably be accounted for by the presence of
inhibitory wavelengths in some patients. Pryzbilla et al. 11 reported patients in whom the
condition could not be induced by broad-spectrum UVA; however, lesions developed at sites
deprived of the shorter UVA wavelengths by filters, suggesting an inhibiting effect by this
waveband. This phenomenon has not been confirmed by other investigators, however, and
remains speculative, but theoretically could be due to interference with photoallergen
induction or with subsequent reactions, as are also suggested to occur on occasion in solar
urticaria. 12 Although chromophores for PMLE have not been identified, one study suggested
that a form of heat shock protein may be responsible. 13 In addition, the induction of lesions
by a UVA sunbed in the nontanning sacral pressure area 14 further suggests that the UVchromophore interaction in some patients may be oxygen-independent. Variation in the
proportions of UVA and UVB present in terrestrial sunlight may also explain certain clinical
characteristics of PMLE. Thus, the greater proportion of UVA to UVB in temperate climates
and during the spring and fall months might be expected to contribute to a higher incidence of
PMLE in temperate rather than tropical regions, 3 with greater susceptibility to the condition
in spring and occasionally fall, rather than summer, in most patients. Moreover, the higher
proportion of UVB to UVA in summer sunlight probably inhibits PMLE development
through a predominantly UVB-induced cutaneous immunosuppressive mechanism.
Paradoxically, the use of sunscreens, which often predominantly remove UVB but are also
generally advised for PMLE patients and are required for normal sun protection, might also
have the same UVA- and PMLE-enhancing effect.
IMMUNOLOGIC ASPECTS Early immunohistochemical characterization of the
inflammatory infiltrate in naturally occurring PMLE lesions of uncertain and varying age
gave inconsistent results. However, a later study 15 of timed biopsies from such lesions
induced by low-dose, solar-simulated radiation demonstrated the consistent appearance of a T
cell-dominated perivascular infiltrate within 5 h, peaking by 72 h. CD4+ T cells were most
numerous in the early lesions, whereas after 72 h CD8+ T cells were predominant, perhaps
helping to limit the previous immunologically mediated tissue damage. Increased numbers of
dermal and epidermal Langerhans cells and dermal macrophages were also present. These
findings are similar to those in allergic contact dermatitis and the tuberculin reaction, both
known delayed-type hypersensitivity reactions, thus supporting a similar mechanism for
PMLE. Intercellular adhesion molecule-1 (ICAM-1), which assists lymphocyte tissue
trafficking, is absent from resting keratinocytes but strongly induced on them by interferon-?.
Such expression has previously been demonstrated in the tuberculin reaction 16 and allergic
contact dermatitis, 17 but not irritant contact dermatitis or following irradiation with two
minimal erythema doses (MEDs) of UVB on normal skin. 16 ICAM-1 may therefore be a
marker for immunologically specific responses, and its presence on keratinocytes overlying
the perivascular infiltrate in PMLE 18 is probably secondary to interferon-? release by
immunologically activated lymphocytes in the underlying dermis, further supporting an
immunologic basis for PMLE. Finally, in a study of PMLE patients, high-dose UVB and
UVA irradiation increased the stimulatory capability of epidermal cells in unidirectional
culture with autologous peripheral blood mononuclear cells, 19 again consistent with immune
sensitization against autologous UV-modified antigens. Beyond this, unpublished results by
one of us (JH) indicate that patients with PMLE cutaneously immunosuppress significantly
less easily than do normal subjects following solar simulated irradiation, such that they are
more easily sensitized to dinitrochlorobenzene (DNCB) after UVR exposure than are normal
subjects. This is very likely the genetically determined factor mentioned previously, 6 which
leads to the putative immune recognition of photoinduced cutaneous antigen in PMLE but not
normal subjects, although the antigen is presumably expressed in all individuals.
VARIATIONS IN ARACHIDONIC ACID METABOLISM In 13 of 23 patients with PMLE,
the topical application of indomethacin for 2 h after irradiation inhibited UVB but not UVA
erythema, as in normal subjects, whereas in the remaining 10 patients, it caused an abnormal
augmentation of both UVB and UVA responses. 20 The 10 patients in the latter group had
clinically more severe disease and more persistent lesions, and in general, they demonstrated
abnormal erythemal responses to monochromatic UVA and sometimes to UVB irradiation.
Such findings probably result from variations in disease severity rather than pathogenesis.
However, polyunsaturated fatty acids compete with arachidonic acid as a substrate for
prostaglandin A 2 resulting in the formation of less active prostanoids, and dietary
supplementation with fish oil rich in omega-3 polyunsaturated fatty acids is reported to reduce
both basal and UVB-generated prostaglandin levels in skin and to increase PMLE UVAinduced provocation thresholds, 21 leading to trials of their use in treatment.
Clinical Features
The eruption of PMLE 5 ( Fig. 135-1) typically begins each spring, on sunny vacations, or
after recreational sunbed use, often moderating with continuing exposure. Rarely, it occurs in
winter after exposure to UVR reflected from snow; it may also occur only through window
glass. Individual susceptibility varies considerably, the period of sun exposure needed to
trigger the eruption usually being from 30 min to several hours, occasionally more or less, but
often up to several days on vacations. Following exposure, new lesions appear after a latent
interval of hours to days, but not less than about 30 min, although itching may develop
sooner. In the absence of further exposure, all the lesions gradually subside completely
without scarring over 1 to 7 days, occasionally 2 weeks, or, very rarely, longer in severe
cases. In a given patient, the eruption tends always to affect the same skin sites, although its
distribution may gradually spread or recede overall. Lesions also generally occur
symmetrically and affect only some exposed sites, often those normally covered in winter
such as the upper chest and arms. Associated systemic symptoms are rare, but chills,
headache, fever, nausea, and a variety of other sensations are possible. Over 7 years, 64 of
114 patients (57 percent) reported steadily diminishing sun sensitivity, including 12 (11
percent) who totally cleared. 22 There is a higher chance than normal of prior PMLE in
patients with lupus, but very few patients with PMLE ever develop that condition. 23
FIGURE 135-1 Polymorphous light eruption. Lesions are on habitually exposed sites, which
is unusual because they most often occur on areas normally covered in winter.
PMLE has many morphologic variants, while any combination of these is also possible. Thus,
papular, papulovesicular ( Fig. 135-2), plaque ( Fig. 135-3), vesiculobullous, eczematous,
insect bite-like, and erythema multiforme-like variants have been described, relating mostly to
the clinical severity of the disorder and its site. Rarely, only pruritus may occur. 24 Such
subdivisions do not apparently relate to differences in disease pathogenesis. The papular form,
of either large or small separate or confluent lesions (generally tending to be in clusters), is
the most common, followed by the papulovesicular and plaque variants; the others are rare.
The eczematous form probably does not exist, representing instead chronic actinic dermatitis
(see below), although PMLE may on occasion become secondarily lichenified or eczematized
during resolution. Differing morphologies may also occur at different skin sites in the same
patient; thus, diffuse facial erythema and swelling, for example, may accompany typical
papular lesions at other sites. Complete sparing of small or large areas of exposed skin is an
important characteristic distinguishing the disorder from other photodermatoses. Juvenile
spring eruption, 25 which affects mainly boys, apparently represents an extreme example of
this phenomenon. This condition is a self-limited eruption of pruritic grouped papules and
vesicles confined to the light-exposed helices of the ears and characterized by a dense
perivascular lymphocytic infiltration, although typical PMLE may sometimes coexist in the
same patient. A final morphologic variant, a small papular form generally sparing the face and
occurring after several days' exposure, has been designated as benign summer light eruption
in continental Europe.
FIGURE 135-2 Polymorphous light eruption. Rash composed of papulovesicular lesions on
an arm.
FIGURE 135-3 Polymorphous light eruption. Variably sized plaques on cheek, simulating
lupus erythematosus. However, they disappear in a few days.
Histology
The histologic features 26 of PMLE are characteristic but not pathognomonic and vary with
the different clinical presentations. There is a moderate to intense, tight, perivascular infiltrate
in the upper dermis and mid-dermis in all clinical types, the infiltrate consisting
predominantly of T cells. Neutrophils are also present, while eosinophils are infrequent. Other
common features are upper dermal and perivascular edema and endothelial cell swelling, and
while epidermal changes may be absent or variable in severity, spongiosis, occasional
dyskeratosis, exocytosis, and basal cell vacuolization are common.
Diagnosis
Diagnosis is made largely on clinical grounds, particularly based on the time course for lesion
evolution and the morphology of the eruption, particularly because the responses to routine
phototesting are often normal except in very photosensitive patients. Subacute cutaneous
lupus erythematosus, not generally itchy as in PMLE, must be excluded by measurement of
the circulating antinuclear, anti-SSA and anti-SSB antibody titers. Persistent plaque-type
PMLE must also be differentiated from Jessner's lymphocytic infiltrate of the skin, while the
photoexacerbation of dermatoses, such as atopic and seborrheic eczema, may occur in
susceptible subjects with the same time course as for PMLE, but with differing and
characteristic morphologies. Erythropoietic protoporphyria must also be distinguished from
the pruritic variant of PMLE without eruption, as must any exaggerated sunburn of patients
with xeroderma pigmentosum or very fair skin. Finally, solar urticaria may be readily
differentiated on history, its lesions being wheals and typically appearing within just 5 to 10
min and resolving within only 1 to 2 h.
Treatment
The mild disease of many patients is satisfactorily controlled by the moderation of sun
exposure at times of high UVR intensity and the regular application of broad-spectrum
sunscreens with high protection factors, particularly against UVA. However, as stated earlier,
sunscreens protecting against mostly UVB may be ineffective, perhaps delaying the onset of
protective cutaneous immunosuppression while permitting longer UVA exposure before
sunburning. More severely affected subjects suffering frequent attacks of their disease
throughout the summer, may instead require courses of prophylactic low-dose
photo(chemo)therapy (see Chap. 266). Thus, in a controlled trial in which UVR exposure was
monitored by means of polysulfone film lapel badges, PUVA was more effective than UVB,
satisfactorily controlling symptoms in 91 percent, as compared with 62 percent, of cases. 27
Furthermore, in another study 8 of 122 patients treated with PUVA, total protection was
achieved in 64 percent and partial protection in 26 percent; only 10 percent did not respond.
The use of narrow-band 312 nm UVB phototherapy is now also becoming popular, being
simpler to administer, as safe as or safer than, and apparently of comparable efficacy to
PUVA (see Chap. 265). 28 Prophylactic PUVA or UVB may sometimes trigger the eruption,
particularly in severely affected subjects, necessitating concurrent systemic corticosteroid
therapy on occasion; this approach is usually effective. 29
Patients who only develop their disorder during infrequent vacations also generally respond
well to oral corticosteroids prescribed for them in advance. 29 If their eruption should
develop, the medication is taken at the first sign of pruritus and then each morning till clear,
usually after at most several days. Rare adverse effects of nausea or depression only
occasionally necessitate stopping the drug. The treatment, if suitable and effective, may then
be repeated every few months if required. Patients who are unsuitable for this approach or
remain uncontrolled, however, may need phototherapy.
If none of the above therapies is effective or suitable, other potential therapies may be tried,
but none are of certain efficacy. Such remedies include hydroxychloroquine, 30 which is
occasionally helpful although not as much as tradition has long suggested; thalidomide, 31
which is helpful for some persistent forms; beta-carotene, 32 which is rarely useful;
nicotinamide, which is probably not at all effective; and omega-3 polyunsaturated fatty acids,
which are, perhaps, of moderate assistance in some patients. 21
There then remains a small proportion of patients who are unsuitable for, unable to tolerate, or
not helped by any of the above therapeutic measures. UVR avoidance may then be the only
reasonable option. However, very few patients are so sensitive that they are continuously
affected in spite of all reasonable UVR avoidance measures and, for them, intermittent
immunosuppressive therapy with azathioprine or cyclosporine may be considered appropriate,
their use having led to marked clinical improvement in a few patients. 33 , 34
ACTINIC PRURIGO
Actinic prurigo (AP) is a not infrequent, persistent, pruritic, excoriated, papular or nodular
eruption of the sun-exposed and, to a lesser extent, non-exposed skin. It is worse in summer
and frequently fails to clear completely in winter, while also usually arising in childhood and
sometimes remitting at puberty. The condition appears likely to be a persistent variant of the
sometimes coexistent PMLE but is clinically different. A similar condition is hereditary or
familial PMLE, which predominantly affects North, Central, or South Americans of native or
mixed race; this form of the disease is normally more severe and persists into adulthood.
Pathogenesis
UVR exposure appears to be the inducer of AP in that the disorder is more severe in spring
and summer, and that abnormal skin responses to monochromatic irradiation are present in up
to two-thirds of patients, more commonly with UVA than with UVB. 5 In addition, solarsimulated radiation may occasionally evoke a response resembling that of PMLE, while a
dermal, perivascular mononuclear cell infiltrate, also similar to that of PMLE, may sometimes
be seen in early lesions. This has not yet been investigated immunohistochemically. Finally,
the reported augmentation of UVA erythema 35 by the topical application of indomethacin, as
in some patients with PMLE, again suggests that AP may be immunologically mediated.
AP on balance may thus be a slowly evolving, excoriated form of PMLE, and thus also a
delayed type hypersensitivity reaction. This is supported by the fact that more AP patients
than expected have close relatives with PMLE; 6 that human leukocyte antigen (HLA) DR4,
occurring in some 30 percent of normal subjects, is present in around 80 to 90 percent of
those with AP; and that the DR4 subtype DRB1*0407, occurring in some 6 percent of normal
subjects and not infrequently also in Native Americans, is present in approximately 60 percent
of those with AP. 36 , 37 This feature may be the genetic component responsible for
converting PMLE into AP. In addition, some patients with the genetic characteristics of AP
demonstrate clinical PMLE but have persistent lesions, while some with clinical AP may
change to clinical PMLE and vice versa, 37 further suggesting a relationship between the two
conditions. Inducing chromophores have not been studied, but may be the same as for PMLE.
Clinical Features
AP is more common in females and usually begins by the age of 10 years; 5 it then tends to
improve and resolve by adolescence, but may on occasion persist into adult life. A positive
family history occurs in some 15 to 50 percent of patients, 5 while atopy occurs in
approximately 10 percent. 30 The AP eruption is often present throughout the year, but is
generally worse in summer; very occasionally it occurs in winter instead, or else in both
spring and fall, tolerance in these instances apparently developing during the summer.
Furthermore, lesional exacerbations tend to occur in sunny weather rather than clearly
following episodes of sun exposure, although PMLE-like outbreaks are possible. Lesions are
typically pruritic, often excoriated, papules or nodules ( Fig. 135-4), associated with
eczematization, lichenification, or crusting, at least on some sites. All exposed areas are
usually involved, the condition being most severe on consistently uncovered sites but fading
gradually toward normally covered skin. The latter is often also mildly affected, particularly
over the sacral area and buttocks. Cheilitis, particularly of the lower lip, is also possible, while
facial lesions may sometimes heal with small, pitted or shallow, linear scars.
FIGURE 135-4 Actinic prurigo. Papules and nodules on legs of 15-year-old female.
Some patients clearly have PMLE or AP or both, but others may have a sufficiently mixed
clinical picture to make precise diagnosis difficult. Thus, while AP almost always begins
before age 10 years, PMLE may also begin in childhood. Furthermore, although individual
AP lesions are generally more persistent than those of PMLE, lasting for weeks to months,
those of PMLE may also be present on occasion for at least days to weeks. In addition, while
AP is usually present all year round, patients with severe PMLE may also rarely be affected
by winter sunshine. Finally, AP may be associated with a tendency to eczematization, but this
might occasionally occur in PMLE, especially during its resolution phase. However, the often
marked excoriation, the occasional mild scarring, and the usual fading of lesions toward and
into covered skin sites in AP are very rare indeed in PMLE and their presence or absence
tends usually to clarify the diagnosis.
Histology
Early papular lesions show changes similar to those of PMLE, namely mild acanthosis,
exocytosis, and spongiosis in the epidermis and moderate lymphohistiocytic, dermal
perivascular infiltration. In persistent, excoriated lesions, however, the epidermal features
include also orthokeratosis, acanthosis, and sometimes hypergranulosis.
Diagnosis
Diagnosis is suspected on clinical grounds in the first instance, but there may be abnormal
photosensitivity to monochromatic irradiation in up to two-thirds of patients, 5 which may
involve the UVB, UVB and UVA, or, rarely, just UVA, wavelengths. In addition, lupus
should be excluded by assessment of the circulating antinuclear factor and anti-SSA and antiSSB antibody titers. Hepatic porphyria may occasionally need to be excluded by appropriate
screening. Biopsy rarely aids diagnosis.
Treatment
The restriction of sun exposure and use of broad-spectrum, high-protection sunscreens may
occasionally help milder cases, but these usually provide inadequate control. However,
intermittent courses of low-dose thalidomide (50 to 200 mg at night) are very effective within
a few weeks in the majority of patients, 38 although immediate, generally mild, side effects
may include drowsiness, headache, constipation, and weight gain (see Chap. 264). To avoid
peripheral neuropathy, the careful monitoring of nerve conduction every few months is also
essential, while pregnancy must also be avoided because of the high risk of teratogenicity. If
thalidomide is unavailable or unsuitable, PUVA therapy may occasionally be helpful. Thus,
Farr and Diffey 39 successfully treated 5 patients twice weekly over 15 weeks, the skin
shielded during treatment continuing to show abnormal UV sensitivity, however, suggesting a
local mechanism of action. Nevertheless, this therapy seems to work more reliably as a
prophylactic measure if the skin lesions are cleared first by thalidomide or by oral steroids.
Chloroquine is not useful.
HEREDITARY POLYMORPHIC LIGHT ERUPTION OF NATIVE AMERICANS
This condition, which may affect North, Central, or South American patients of Native
American or mixed race, appears indistinguishable from white AP except that it persists much
more frequently into adulthood, 40 is clinically more severe, and regularly affects the lips and
conjunctivae of patients. In addition, many patients have a positive family history and
demonstrate the same HLA-DR4 and DRB1*0407 subtype positivity as their white
counterparts. 41 , 42 Onset is in childhood and affected females outnumber males by 2 to 1,
while the clinical features are similar to those of white AP, namely a pruritic, excoriated,
papular, eczematized eruption of the sun-exposed areas of the face and limbs with minimal
scarring. As stated earlier, there is also a marked associated tendency to cheilitis and
conjunctivitis.
HYDROA VACCINIFORME
Hydroa vacciniforme (HV) is a very rare photodermatosis of unknown etiology that
principally starts in childhood. It is characterized by recurrent crops of papulovesicles or
vesicles most commonly on the face and the dorsa of the hands but other sun-exposed areas of
the skin may also be involved. The vesicles resolve with pocklike scarring. The disease was
first described by Bazin in 1862, and it is possible that before the clear definition of
erythropoietic protoporphyria by Magnus and associates (see Chap. 149), some of the cases
that were classified as hydroa may have been protoporphyria.
Pathogenesis
The pathogenesis of hydroa vacciniforme is unknown. No chromophores have been identified
as yet. The UVB MED reaction is normal in the majority of patients but reduced UVA MED
values have been found in some patients. 43 Blood, urine, and stool porphyrins are negative
and all other laboratory parameters, including immunologic tests, are within normal limits.
The course, distribution of lesions and histopathology, with a perivascular lymphocytic
infiltrate, are somewhat reminiscent of polymorphic light eruption. However, the clinical
features are quite different. The action spectrum lies in the UVA region and repetitive
irradiation with broad spectrum UVA has been shown to elicit typical skin lesions that are
clinically and histologically identical to those produced by natural sunlight. 44 , 45 Recent
reports of an association with Epstein-Barr virus infection and lymphoma are interesting, but
some of these cases are atypical, and may not represent the usual form of HV. 46 , 47 , 48 and
49
Incidence
Although HV occurs in early childhood and may resolve spontaneously at puberty, some
patients may suffer from life-long photosensitivity. There is a male predominance for the
severe manifestations, whereas milder forms are more common in females. 43 , 45 Familial
incidence is exceptional. In a recent study, the estimated prevalence of HV was about 0.34
cases per 100,000 with an approximately equal sex ratio. Males had a later onset and longer
duration of disease than did females. 45
Clinical Features
Erythema with a burning or itching sensation, and sometimes with associated swelling, begins
within hours of sufficient sun exposure in light-exposed skin areas, particularly on the face
and the hands. This is followed by the appearance of symmetrically scattered tender papules
within 24 h. These generally later become vesicular, umbilicated, and, on occasion, confluent
and hemorrhagic ( Fig. 135-5). Within a few weeks, crusting followed by detachment of the
lesions leaves permanent, depressed, hypopigmented scars. Vesicles and bullae, as well as the
scars, resemble the lesions of vaccinia. Occasional systemic features include headache,
malaise, and fever. HV usually occurs only during the summer months, and sometimes, but
not always, improves or resolves in adolescence. 43 , 45
FIGURE 135-5 Hydroa vacciniforme. Vesicular, bullous, and crusted lesions on the face that
will result in vacciniform scars.
Histology
Distinctive histologic changes include initial intraepidermal vesicle formation with later focal
epidermal keratinocyte necrosis and spongiosis in association with dermal perivascular
neutrophile and lymphocyte infiltration. Vasculitic features have also been reported. 43
Immunofluorescence findings are nonspecific.
Diagnosis
The differential diagnosis includes several photosensitivity states. However, the typical
history and the clinical features are characteristic. Of particular importance, however, is the
exclusion of erythropoietic protoporphyria which may rarely have similar morphology. An
evaluation of erythrocyte protoporphyrin levels, red cell photohemolysis, and stool analysis
will exclude protoporphyria.
Treatment
The treatment of HV consists of restriction of sun exposure and use of broad-spectrum
sunscreens. Occasionally, antimalarials have been helpful, but their true value remains to be
established. Similar observations have been made with beta-carotene, which in our hands, was
ineffective in three cases. As in polymorphic light eruption, prophylactic phototherapy with
narrowband UVB or PUVA may be helpful, particularly the latter, although it should be
administered with care to avoid exacerbations. 43 , 44 and 45
SOLAR URTICARIA
Solar urticaria (SU) is a rare but severely disabling, rarely even life-threatening,
photosensitive disease in which UVR or visible irradiation leads to whealing of some or all
exposed skin.
Pathogenesis
SU is due to an immediate type I hypersensitivity response to a cutaneous or circulating
photoallergen generated from a precursor after the absorption of light energy. Both a
circulating photoallergen and reaginic antibodies have been demonstrated.
Two types of SU have been proposed. Type I is an IgE-mediated hypersensitivity to specific
photoallergens generated only in SU patients. Type II is an IgE-mediated hypersensitivity to a
nonspecific photoallergen that is generated in both SU patients and others. 50 Therefore, in
type I SU, passive transfer tests may be positive or negative, while, in type II, passive transfer
tests are always positive. The diversity of the action spectra reported in the literature can be
attributed to differences in photoallergens. Patients with type I appear to have a photoallergen
of molecular mass 25 to 34 kDa and an action spectrum in the visible region, while those with
type II may have a photoallergen of molecular mass 25 to 1000 kDa and a variable action
spectrum. 50
Urticaria develops on exposure to specific, characteristic, and usually broad-spectrum UVB,
UVA, visible light, or a combination of these. 51 Susceptibility to the condition can
occasionally disappear spontaneously, while the range of eliciting wavelengths can also
narrow or broaden over months to years. However, the determination of action spectra has not
led to the identification of chromophores.
Exposure to longwave visible or UVA radiation before, during, or after the urticaria-inducing
irradiation inhibits whealing in some patients, possibly by inactivation of the initial active
photoproduct or the inhibition of subsequent reactions. Conversely, Horio and Fujigaki 52
reported a patient with SU induced by 320 to 420 nm light in whom preirradiation with 450 to
500 nm visible light augmented the whealing. Postirradiation with the same spectrum failed to
increase the response, suggesting that the energy in those wavelengths was absorbed by a
precursor of the photosensitizer, altering it to a state more readily reactive to the urticariaeliciting radiation (for references see Ref. 51 ).
Although mast cell degranulation and histamine release are implicated in SU, antihistamine
therapy is only sometimes effective. This suggests the possible importance of other mediators,
such as neutrophil and eosinophil chemotactic factors that accompany histamine in the venous
blood draining irradiated skin. The initial mast cell degeneration is followed by the
recruitment of circulating neutrophils and eosinophils, along with the tissue distribution of
eosinophil major basic protein, which may, in turn, amplify the whealing response. 51
True SU must not be confused with rare reactions due to photosensization by topical
chemicals (e.g., tar, pitch, or dyes), protoporphyrin in erythropoietic protoporphyria, or some
drugs (e.g., benoxaprofen) as these reactions are clinically different (see Chap. 136); only one
patient with erythropoietic protoporphyria associated with SU has been reported. SU is not
associated with an atopic background.
Clinical Features
SU is slightly more common in females, usually beginning between 10 and 50 years of age
and persisting indefinitely, occasionally slowly worsening or gradually improving. Within 5
to 10 min of sun exposure, patients experience itching, erythema, and patchy or confluent
whealing ( Fig. 135-6), which resolves generally with sun avoidance within 1 to 2 h; very
rarely, however, the onset of symptoms has been reported to be delayed by several hours. 53
SU may affect only normally covered skin, sparing the face and hands, because of a hardening
phenomenon or usually all exposed sites, while sharp demarcation at lines of clothing is often
seen in more severe cases; bruised skin appears particularly susceptible. 54 Attacks may be
accompanied by headache, nausea, bronchospasm, faintness, and syncope, especially if
extensive areas of the skin are affected.
FIGURE 135-6 Solar urticaria. These lesions appeared within 15 min of sun exposure, with
wheals and marked pruritus. They were produced by irradiating the back of this patient
through a template.
Differential Diagnosis
The primary diagnostic criteria are itching, burning, erythema, and whealing, which only
appear after sun exposure and usually disappear within 1 to 2 h. The timing criterion is a
guideline for the differential diagnosis from PMLE, which has the same localization, but
PMLE lesions usually appear between hours to days after sun exposure and generally take 2
to 6 days to disappear after its avoidance. In addition, the lesions are not limited to wheals.
Confirmation of the diagnosis of SU is given by phototesting, with transient itching or
burning erythema and whealing occurring at the immediate reading. Primary SU should be
differentiated by history from drug- or chemical-induced phototoxicity, which can also cause
a burning sensation within minutes of sun exposure.
Histology
There is dermal vasodilation and edema, while light-microscopic study of timed biopsies of
induced lesions of SU has demonstrated a dose-dependent increase, predominantly
perivascular, in upper dermal neutrophil and eosinophil numbers at 5 min and 2 h but not at
24 h. Endothelial cell swelling is also observed in early lesions, while late infiltration by
mononuclear cells is seen only following high doses of radiation. In addition, staining by
indirect immunofluorescence for eosinophil granule major basic protein shows extensive
extracellular deposition in the dermis at 2 and 24 h, suggesting eosinophil degranulation. 55
Diagnosis
Phototesting with an irradiation monochromator or broad-spectrum irradiation source
generally allows confirmation of the diagnosis and definition of the action spectrum of SU.
Several lamps can be used for phototesting, such as inexpensive fluorescent tubes or a more
sophisticated solar simulator, while the most detailed phototesting procedure involves a xenon
lamp combined with a monochromator; the urticarial reaction usually disappears in a few
minutes. It is very important to realize that a negative phototest from a single light source
does not exclude a diagnosis of solar urticaria, it being necessary to continue provocative
testing with other light sources, such as polychromatic light sources, a slide projector, or even
directly with sunlight.
Treatment
High-protection-factor sunscreens and appropriate clothing cover may be useful in UVBsensitive subjects, but are much less effective in those sensitive to UVA and particularly
visible light. However, nonsedating H 1 antihistamines may help significantly, increasing the
minimum whealing dose tenfold or more. The addition of H 2 blockers rarely may offer a
slight further advantage. In many patients chronically exposed skin, such as on the face and
the hands, becomes tolerant. Based on this observation, therefore, patients with SU can be
treated with repeated artificial UV exposures; this can be done with narrowband UVB,
broadband UVB, UVA alone, a combination of UVB and UVA, and even visible light. The
major disadvantage of phototherapy is that the tolerance obtained usually lasts only a few
days, although a more lasting effect is obtained with PUVA, the protection provided lasting
several weeks. Such regimens do not alter tissue histamine content or mast cell numbers,
however, and they may act via nonspecific photoinduced stabilization of the mast cell
activation mechanism or possibly through the persistent occupation of IgE-binding sites with
photoallergen. 55 Multiple exposures with increasing doses within a day (“rush hardening”)
also appear to be quite successful. 56 In addition, in patients with a detectable serum factor,
removal of this by plasmapheresis has resulted in clinical remissions persisting several
months. 57 , 58
CHRONIC ACTINIC DERMATITIS
Chronic actinic dermatitis is a persistent, generally eczematous, sometimes
pseudolymphomatous eruption, worse in summer, with corresponding histologic features. It is
induced and maintained by exposure to often very small amounts of UVB, often UVA, and
sometimes also visible radiation; rarely, UVA alone appears responsible. It most commonly
affects elderly men with outdoor interests, although many other subjects are also susceptible.
The syndromes of persistent light reactivity, actinic reticuloid, photosensitive eczema, and
photosensitivity dermatitis ( Table 135-2), each independently named more than 30 or more
years ago, are now all considered variants of the same condition. The disorder appears in all
respects to have the features of allergic contact dermatitis, and thus may be an acquired,
delayed-type hypersensitivity reaction to endogenous, photoinduced, epidermal antigen(s).
TABLE 135-2 Original Published Criteria for Eczematous Photosensitivity Disorders
Historical Aspects (See Table 135-2)
The possibility of persistent light reactivity appears to have been first mentioned in 1933 by
Haxthausen, who described continuing photosensitivity in a patient intravenously injected
with trypaflavine, following which Wilkinson, in 1961, reported an epidemic in older males
of a prolonged photoallergy to tetrachlorosalicylanilide, an antibacterial agent present in soaps
and hair toiletries. Jillson and Baughman then named this condition persistent light reaction.
60 Thus, following continuing cutaneous contact with photoallergens such as the halogenated
salicylanilides, musk ambrette, or quinoxaline dioxide, occasional patients developed a
photoallergic contact dermatitis to these substances, and a very few progressed to a persisting
abnormal photosensitivity of not just exposed skin but often also covered sites, despite an
apparent complete avoidance of exposure to the offending chemicals. Further, whereas the
action spectrum for the initiating photocontact reaction generally encompassed just the UVA
wavelengths, that of the persistent disorder generally included the UVB, and occasionally
visible light.
In 1969, Ive et al. 61 introduced the term actinic reticuloid to describe a similar, but
apparently more severe, dermatosis; in this case, however, there was no apparent prior
photoallergen. Nevertheless, the condition again affected mostly elderly males, and it was
characterized by infiltrated, erythematous plaques, on an eczematous background,
predominantly affecting exposed sites. The histopathologic features tended to resemble
cutaneous T cell lymphoma, and there were abnormal cutaneous photobiologic responses to
UVB, UVA, and, occasionally, visible radiation. Furthermore, although the authors noted a
resemblance to persistent light reactivity, photopatch tests to all common photoallergens were
negative in their patients. Similar, but purely eczematous variants of the condition, also
without overt preceding photoallergy, were also described, with action spectra limited to the
UVB (photosensitive eczema) 62 or UVB ± UVA (photosensitivity dermatitis). 63
In 1979, Hawk and Magnus 64 proposed that actinic reticuloid, photosensitive eczema, and
photosensitivity dermatitis be incorporated into the one syndrome of chronic actinic dermatitis
(CAD), the validity of which was supported by reports of the transition of actinic reticuloid to
photosensitive eczema, 65 and the occasional association of the clinicopathologic features of
actinic reticuloid with just UVB photosensitivity, a variant with no specific name.
Furthermore, in view of the close clinical, histological, and photobiological resemblances
between persistent light reactivity and CAD, the end-stage persistent light reactivity syndrome
and CAD also appear to be the same. Patients who do not demonstrate increased sensitivity to
UVB irradiation on covered skin in the absence of an external photoallergen are excluded,
however, thereby differentiating the persistent photosensitivity of CAD from the transient
light reactivity of photoallergic contact dermatitis, which may nevertheless rarely eventually
progress to CAD (see also Chap. 136).
Etiology and Pathology
The mechanism underlying the transition from photoallergy to CAD, in cases in which this
disorder is in fact a precursor, remains unclear. Any explanation needs to account for the
increased UVB, rather than just UVA, sensitivity of skin that has had no direct contact with
any relevant chemical. However, it seems very possible 66 that during the initial localized
photoallergic reaction, a normal skin constituent is altered to become antigenic, the induction
of the local response apparently beginning with UVA-dependent covalent photochemical
binding of hapten to endogenous protein, followed by an eczematous delayed-type
hypersensitivity response. In the localized reaction, hapten must be present, but with the
progression to CAD, UVB ± UVA irradiation alone may trigger the immune response at any
site, very possibly by the continuing formation of antigenic photoproduct from the ubiquitous
endogenous carrier protein alone. This outcome now also appears possible, and, in fact, usual,
without any prior photoallergy. Kochevar and Harber, 67 using an in vitro model with the
photosensitizer tetrachlorosalicylanilide, provided theoretical support for such a mechanism,
demonstrating that the phototoxic oxidation of histidine with the modification of carrier
protein into weak antigen was indeed possible. Although the chromophores for such putative
antigen formation have not been identified, the action spectrum for CAD induction resembles
that for sunburn inflammation, 68 at least in many instances, for which DNA is already
considered the most likely main target. Thus, perhaps DNA, or a similar or related molecule,
may also act as an antigen in CAD.
The histologic and immunohistochemical features of CAD, including adhesion molecule
expression, are essentially the same as those of persistent allergic contact dermatitis, 69 , 70
or, in more severe cases, cutaneous T cell lymphoma (CTCL). In particular, the dermal
infiltrate consists predominantly of T lymphocytes with a significant trend toward lower
CD4+/CD8+ ratios in patients with more florid histology, 69 features that may also all occur
in persistent, pseudolymphomatous forms of allergic contact dermatitis. Thus, the occurrence
of the actinic reticuloid variant of CAD may, in fact, reflect prolonged and marked
endogenous antigenic stimulation.
Allergic contact dermatitis commonly coexists with CAD, often preceding the onset of any
photosensitivity, 71 reactivity to one or more allergens occurring in 75 percent of patients. 72
Sesquiterpene lactone extracts from Compositae plants are implicated most commonly, but
other allergens may include fragrance, colophony, rubber, and sunscreens. Such substances do
not cause positive photopatch test reactions, although they may cause phototoxic reactions in
vitro, 73 , 74 including the ability to oxidize histidine, and might contribute additionally to
altering endogenous protein to antigenic forms leading to CAD. As also proposed for
persistent light reactivity, the avoidance of such substances may conceivably result in gradual
resolution of the condition. 75 In addition, chronic cutaneous immunostimulation from
constant patient exposure to airborne allergens during simultaneous ultraviolet exposure, as in
gardening, may enhance cutaneous immune recognition of the putative, presumed weak,
endogenous photoallergen.
Although photoallergy may progress to CAD and then to the actinic reticuloid variant 76 in a
proportion of patients, there is often no evidence of preceding photoallergy. CAD is thus
likely to represent an end state that may arise from a number of predisposing conditions,
namely photoallergic contact dermatitis, allergic contact dermatitis to substances with
possible phototoxic potential, endogenous eczema, 77 perhaps photosensitivity from oral
medication, possibly polymorphic light eruption, and human immunodeficiency virus
infection. 78 Finally, CAD also appears not uncommonly to arise de novo in normal subjects.
Significant exposure to sunlight, both photoaging the skin and activating putative endogenous
photosensitizer, may lead to CAD in men such as gardeners, who are also regularly exposed
to important airborne antigens such as Compositae oleoresins. Aged skin may also be more
susceptible as a result of reduced barrier function and allergen removal. Finally, because only
small doses of UVR are needed to evoke the eruption, the increased melanin of black skin
does not apparently protect against the condition.
Clinical Features
Chronic actinic dermatitis usually affects the middle-aged or elderly throughout many areas of
the world, 74 , 78 , 79 approximately 90 percent of patients being male. Occurrence under 50
years of age is unusual, unless patients have coexistent atopic eczema. 77 The eruption is
usually worse in summer and after sun exposure, although patients may often fail to recognize
this, particularly if affected year-round. Patchy or confluent eczematous changes are present
on the exposed skin of the backs of the hands, face ( Fig. 135-7 and Fig. 135-8), scalp, and
upper chest, often with some degree of sparing of the skin of the finger webs, of the upper
eyelids, behind the ears, and in the depths of skin creases. Severely affected patients also
characteristically demonstrate shiny, erythematous, infiltrated papules or confluent plaques on
exposed sites, sometimes abruptly adjacent to patches of normal exposed skin. Irregular
hyper- and hypopigmentation, sometimes marked, may also occur. In addition, there is the
occasional progression to erythroderma, often, but not always, accentuated on exposed sites.
Large numbers (up to 20 percent) of circulating CD8+ Sézary cells may be found in such
patients without any suggestion of malignancy. 80 An association with lymphoma has,
however, been reported but such reports are rare and any association may be coincidental,
particularly because T cell receptor and immunoglobulin gene rearrangement studies fail to
demonstrate any evidence of clonal lymphoid proliferation. 81
FIGURE 135-7 Chronic actinic dermatitis. Infiltrated eczematous eruption on face.
FIGURE 135-8 Chronic actinic dermatitis. A, B. Severe involvement of face and neck with
marked eczematous dermatitis. C, D. In this instance, the disease resolved with a course of
oral PUVA photochemotherapy over several weeks. Oral corticosteroids were necessary
initially, however, to control the exacerbation induced by irradiation.
Histology
Histologic features 26 include epidermal spongiosis, acanthosis, and, sometimes, hyperplasia,
along with a predominantly perivascular lymphocytic cellular infiltrate confined to the upper
dermis, milder cases having the appearance of chronic eczema. Severe CAD, however, may
mimic CTCL histologically, with epidermal Pautrier-like microabscesses and a deep, dense
epidermotropic mononuclear cell infiltrate, sometimes with hyperchromatic convoluted nuclei
and giant cells, but no marked increase in mitoses.
Diagnosis
Phototesting of the skin is essential to confirm the diagnosis of CAD, and is characterized by
abnormally low erythemal thresholds with eczematous or pseudolymphomatous responses
characteristic of the disorder itself following irradiation with UVB, and, in the majority of
patients, also UVA. A minority of patients react also to the visible wavelengths, while a very
small number may be sensitive to UVA alone, although drug or chemical photosensitivity
must be carefully excluded in such instances. Such testing must be performed on uninvolved
skin not exposed to systemic or topical corticosteroid administration over the preceding 3 to 4
days to avoid false-negative results. Broad-spectrum or monochromatic sources may both be
effective at inducing abnormal responses, although the latter determine the action spectrum
for the disease more precisely. Light-exacerbated endogenous eczemas must be distinguished
by their differing clinical features and usually normal light tests, while CTCL may also rarely
be photosensitive, more commonly to UVA than UVB. Such photosensitivity, however, is
usually clinically mild.
Patch and photopatch tests are also essential in suspected CAD. Contact sensitivity to airborne
or other ubiquitous allergens such as Compositae oleoresins, perfume, or colophony are able
to mimic or coexist with CAD. In addition, secondary contact or photocontact sensitivity to
sunscreens or topical applications may also occur. Finally, photopatch testing may also detect
primary photoallergic contact dermatitis such as to the fragrance, musk ambrette.
Treatment
The treatment of CAD is usually difficult and often only partially effective. In the first
instance, the rigorous avoidance of UVR and exacerbating allergen exposure and regular
application of broad-spectrum topical sunscreens of low irritancy and allergenic potential
(e.g., containing microfine titanium dioxide) are essential but rarely adequate as sole
measures. Topical steroids and emollients and occasionally topical tacrolimus or
pimecrolimus may help, but, in approximately two-thirds of resistant patients, azathioprine,
50 mg twice or three times daily, achieves remission within several months, 82 following
which the drug dose may be reduced. However, recurrent therapeutic courses, generally each
summer, are usually necessary. Cyclosporine too has been used and may give excellent
results, 83 while mycophenolate mofetil can also be helpful. Finally, low-dose PUVA, and
perhaps narrow-band UVB therapy, may be effective (see Chap. 266), although potent oral
and topical steroid cover is generally necessary to avoid disease flares early on. As a result of
these interventions, most CAD patients can now lead a reasonable life, until, in due course,
many gradually recover from their disorder. 75
PHOTOEXACERBATED DERMATOSES
Photoexacerbated (or photoaggravated) dermatoses represent a heterogeneous group of
conditions that share one common feature: they can be precipitated or exacerbated by
exposure to sunlight or to therapeutic or cosmetic UVR in at least a proportion of cases (
Table 135-3). It is however important to recognize that these diseases are not true
photodermatoses because they commonly develop without exposure to radiation. The precise
underlying mechanisms of their exacerbations are generally undetermined, but UV irradiation
apparently contributes specifically to pathogenesis in some disorders, such as lupus
erythematosus, while in others, it may be just a nonspecific factor able to worsen the
condition. Some of the disorders most frequently and importantly affected in this way are
discussed below.
TABLE 135-3 Diseases Exacerbated by Ultraviolet Irradiation
Acne (See also Chap. 73)
Acne aestivalis, as first described by Hjorth et al., 84 was characterized by pruritic, 1- to 3mm, pink or pale, dome-shaped papules occurring after sun exposure, usually on the face,
neck, or trunk. Nieboer 85 then further reported two patients, describing the disorder as
actinic superficial folliculitis with a predominantly follicular, pustular, nonpruritic rash
occurring several hours after sun exposure, on the upper trunk and arms. Verbov 86 finally
described patients with overlapping features of both acne aestivalis and actinic superficial
folliculitis, suggesting the unifying term actinic folliculitis. The condition appears to be a
form of UVR-exacerbated acne, for which high-protection-factor sunscreens, standard acne
treatments, including topical retinoic acid, and topical and systemic antibiotics have not
generally been helpful. Oral isotretinoin was however prophylactic and highly effective in two
cases. 87
Darier's Disease (See also Chap. 54)
There are not many reports of photosensitivity in Darier's disease. However, controlled tests
with mainly UVB radiation have shown that lesions can be induced that exhibit the clinical
and histopathologic criteria of the disease. The exacerbation of Darier' s disease after sun
exposure is also well-documented, and one of the authors found exacerbation in two patients
experimentally treated with psoralen photochemotherapy (PUVA).
Disseminated Superficial Actinic Porokeratosis (See also Chap. 56)
Disseminated superficial actinic porokeratosis (DSAP) may be induced or exacerbated by sun
exposure, or by immunosuppression, 88 which suggests that the exacerbation by sunlight in
part reflects the UVR-induced impairment of local cutaneous immunity.
Several authors have also reported the induction of new lesions or exacerbation of preexisting
ones following exposure to artificial UVR radiation sources, in particular, during the longterm treatment of psoriasis, 89 , 90 and the disorder has also been aggravated by suntan parlor
exposure. Furthermore, in a study of potentially provocative wavelengths, UVB plus UVA
was more effective in inducing new or exacerbating preexisting lesions than either
wavelength alone. 91
Herpes Simplex (See also Chap. 214)
It is common knowledge that many patients experience herpes simplex eruptions after sun
exposure, particularly while sunbathing, mountain hiking, or skiing at higher altitudes. The
mechanisms for viral activation by UVR are unknown but may be related to localized UVR
immune suppression. However, several other nonspecific stimuli, such as fever, hormonal
changes (menses), or heat, can trigger herpes lesions. Reports on sunlight-induced erythema
multiforme may actually reflect the fact that herpes may precipitate erythema multiforme.
Finally, relapsing gluteal herpes simplex is not uncommon in patients treated with UVB or
PUVA (see Chap. 266).
Lichen Planus Actinicus (See also Chap. 49)
In addition to being able to trigger lichen planus as a Koebner reaction to sunburn injury, UV
irradiation in suberythemogenic doses can also induce a lichenoid reaction known as lichen
planus actinicus. 92 The condition most commonly affects dark-skinned subjects, particularly
from the Middle East, but patients have also been reported from India, Europe, and the United
States. Several clinical patterns have been described. The most common consists of annular,
hyperpigmented plaques predominantly on the face and dorsa of the hands. Others include
pigmented melasma-like patches on the face and neck, or skin-colored, closely aggregated,
pinhead papules particularly on the face and dorsa of the hands. 92 , 93 The peak age of onset
is the third decade, and the lesions are generally only mildly pruritic, developing mainly on
exposed sites during spring and summer and improving or remitting in winter. Experimental
reproduction of lesions was successful in one patient with UVB but not with UVA. 94
Histopathology is identical to classic lichen planus.
Eczema (See also Chap. 122 and Chap. 124)
Patients with atopic or seborrheic eczema occasionally report mild to oderate, nonspecific
exacerbation of their condition following sun exposure. Normal responses are generally
demonstrated on phototesting, thus allowing distinction from chronic actinic dermatitis.
However, the majority of patients with atopic dermatitis actually benefit from both sunlight
and artificial UV irradiation.
Lupus Erythematosus (See also Chap. 171)
Photosensitivity has been reported for several so-called collagen vascular diseases such as
lupus erythematosus or dermatomyositis. However, only in lupus erythematosus (LE) is the
correlation between sunlight exposure and the development of skin lesions well established.
Therefore, photosensitivity that results in a specific skin rash has been added to the American
Rheumatological Association (ARA) list of criteria to diagnose systemic lupus. The estimated
prevalence of photosensitivity in this disease ranges from 30 to 70 percent in the white
population. It is important to recognize that different subsets of lupus erythematosus show
different degrees of photosensitivity. Chronic cutaneous LE with typical discoid lesions is
usually not photoaggravated. However, discoid lesions occur primarily on sun-exposed areas
such as the face, scalp, and ears, and some patients with discoid LE will progress to systemic
LE. Whether such progression occurs in photosensitive patients only is unclear. In systemic
LE, the typical butterfly rash may appear suddenly after sun exposure. Also widespread
lesions may develop in other exposed skin areas associated with systemic exacerbation. The
subset that exhibits photosensitivity most strikingly is subacute cutaneous LE. About 50
percent of these patients fulfill the ARA criteria for systemic LE but systemic manifestations
tend to be milder than in patients with classical systemic LE. 95 , 96 Patients with subacute
cutaneous LE tend to have anti-Ro (SSA) antibodies that represent predictors of
photosensitivity. Thus, several studies have supported the hypothesis that UVB irradiation
may induce Ro antigens in the disease to translocate to the keratinocyte membrane by a
glycosylation and microfilament-dependent process. At the membrane, they are bound by Ro
autoantibodies, which leads to immunologic cell lysis, probably by antibody-dependent
cellular cytotoxicity. 97 , 98 and 99
The action spectrum for the induction of LE skin lesions includes both UVB and UVA and
there are reports about exacerbation during photochemotherapy for psoriasis. Lehmann et al.
100 investigated the reproduction of LE lesions with artificial UVR in 128 patients. They
found the development of lesions on exposure to UVA and UVB in 53 percent, on exposure to
UVA alone in 14 percent, and on exposure to UVB in 33 percent. Interestingly, lesions were
induced in 64 percent of patients with subacute cutaneous LE, in 42 percent of patients with
chronic discoid LE, and in only 25 percent of patients with systemic LE. 100 This strongly
supports the idea that discoid LE is photoaggravatable. In view of this study and several
previous investigations, photosensitivity to broadband UVR in LE is a well-documented
phenomenon. 101 Because exacerbations can be provoked by UVA and UVB, appropriate
broad-spectrum sun protection should be recommended for all forms of LE. 95
Pellagra (See also Chap. 145)
Pellagra is characterized clinically by skin abnormalities, gastroenteritis, and encephalopathy,
the cutaneous features often being sunlight-induced, appearing in the spring and summer and
improving in winter. Pruritus and erythema occur initially on exposed areas, followed by
vesicles, bullae, and essentially symmetric, chronic, scaly, hyperpigmented, thickened
sclerotic papules and plaques. Dusky erythema and powdery scaling of the nose, a scaling
collarette around the neck with sternal extension (Casal's necklace), glossitis, and mucous
membrane ulcerations are also typical. The inducing wavelengths are unknown, as no lesions
or other abnormalities have been demonstrated following artificial irradiation. It seems likely
that decreased availability of NADP and NADPH resulting from niacin deficiency may
prevent the oxidation/reduction reactions necessary for the normal repair of UVR-induced
epidermal damage.
Pemphigus (See also Chap. 59)
Pemphigus vulgaris is not clinically associated with photosensitivity, although artificial UVR
induction of lesions with typical acantholysis has been noted. Pemphigus foliaceus and
erythematosus may however be aggravated or induced by sun exposure, characteristic lesions
having also been produced in both variants with experimental UVR. 102 , 103
Bullous Pemphigoid (See also Chap. 61)
A few patients have been described who developed bullous pemphigoid lesions after UVB
exposure. However, more cases have been reported in which photochemotherapy (PUVA),
given for unrelated diseases, was the triggering mechanism. 104
Psoriasis (See also Chap. 42)
Some patients with psoriasis report exacerbation of their disease after sunbathing, particularly,
after sunburn. Several groups have also attempted to estimate the prevalence of
photosensitivity in psoriasis from surveys and questionnaires. Ros et al. sent questionnaires to
2000 patients with psoriasis in Stockholm, and after telephone interviews, considered the
prevalence of photosensitivity to be 5.5 percent. In this study, in addition, the light-sensitive
patients with psoriasis had a history of PMLE with a secondary exacerbation of their psoriasis
in 43 percent of cases, and were more likely to have skin phototype I, psoriasis affecting their
hands, a family history of psoriasis, and an advanced age. 105 Interestingly, despite
photosensitivity, such patients can be successfully treated with PUVA. It is thus very likely
that the phenomenon of photosensitive psoriasis represents a Koebner type of reaction to
either PMLE or sunburn in fair-skinned subjects.
APPROACH TO THE PATIENT WITH PHOTOSENSITIVITY
Clinical Features
History taking is frequently the most important element in diagnosis of the photodermatoses,
particularly of the intermittent conditions in which the eruption is often not present at the time
of consultation. The following features of the eruption are of particular importance.
Exposure:
Latent interval between exposure and eruption
Seasonal variation
Minimum exposure duration to elicit eruption
Response to irradiation through window glass or clothing
Eruption:
Duration
Distribution
Morphology
Accompanying or premonitory symptoms (such as pruritus, dizziness, burning sensation,
swelling)
Patient:
Age at onset
Sex
Occupation (outdoor or indoor, such as sailor, farmer, welder, roofer, gardener,
phototherapist)
Topical applications or contacts (such as cosmetics, sunscreen, plants, chemicals, perfumes,
sprays, aftershaves)
History of skin response to sun exposure (rash or susceptibility to sunburn)
History of effectiveness of sunscreens in prophylaxis
Systemic medications
Leisure activities such as gardening, outdoor pursuits
Family history
To establish the relationship between an eruption and UVR exposure, it is important in most
patients to determine whether the exposed sites are affected predominantly, whether the
condition is worse in summer, and whether the lesions develop only in association with UVR
exposure. If photosensitivity is present, the eruption tends to occur on the forehead; bridge of
nose; upper cheeks; chin; rims of ears; back and sides of the neck; upper chest; dorsa of the
hands and feet; and extensor surfaces of the arms and lower legs. On the other hand, sparing
characteristically occurs below the eyebrows; under the hair fringe; on the upper eyelids;
below the nose, lower lip, and chin; behind the earlobes; in the webspaces of the fingers; and
at the bottom of skin folds or creases. Involvement of the latter sites can sometimes occur,
however, if allergic contact dermatitis to airborne allergens or extreme photosensitivity is
present.
Central to the diagnosis of the acute intermittent photodermatoses is the time course of the
eruption following sun exposure. Thus, onset within 5 to 10 min with resolution in an hour or
so is typical of solar urticaria and photosensitivity due to certain drugs such as benoxaprofen
(which has been withdrawn from the market) or amiodarone. A delay of 20 min to several
hours with lesions lasting for several days is characteristic of PMLE, HV, erythropoietic
protoporphyria, subacute cutaneous LE and other light-exacerbated dermatoses, and
xeroderma pigmentosum, as well as drug photosensitivity to, for example, thiazide diuretics.
A description of the morphology of the eruption is also of great diagnostic importance.
Patients with SU describe raised pruritic wheals, sometimes confluent, whereas those with
erythropoietic protoporphyria or drug photosensitivity to amiodarone or previously
benoxaprofen complain of an often severe, painful, burning sensation with initially no visible
signs. Later they may develop diffuse swelling and erythema of the exposed sites with
prolonged exposure. HV is differentiated from PMLE by its characteristic blistering response
always leading to varioliform scarring. Helpful in distinguishing PMLE from subacute
cutaneous LE are the usual lack of pruritus and the presence of discrete scaling plaques in the
latter, although an eruption indistinguishable from PMLE has also been described in some
subacute cutaneous LE patients.
Photoexacerbated dermatoses must be distinguished by their morphologies and distribution.
Xeroderma pigmentosum and most drug-induced photosensitivity, on the other hand, can lead
to an exaggerated sunburn-like response, which, in the case of xeroderma pigmentosum, may
not reach its peak until 48 to 72 h after exposure.
In patients who report a more persistent, apparently photosensitive eruption, the morphology
of lesions should be carefully considered. Persistent pruritic papules, occurring mostly on
exposed sites but also involving the upper limbs and sometimes buttocks, are suggestive of
AP. An eczematous eruption accentuated on or limited to the exposed sites suggests CAD,
particularly if there is a history of exposure to potential airborne contact allergens such as the
Compositae oleoresins or colophony, but this must be differentiated from light-aggravated
endogenous eczema and perhaps eczematous drug-induced photosensitivity (e.g., thiazideinduced) (see Chap. 136), although the latter seems rare. Fragility and blistering with scarring
of the exposed skin, worse in the summer, suggests a hepatic porphyria or pseudoporphyria,
particularly if drug or excessive alcohol ingestion, or frequent sunbed exposure, has occurred
(see Chap. 149).
Other important general points in the history, often helpful in diagnosis, include the age at
onset—young girls most often suffer from AP, children from HV, young women from PMLE,
and elderly men from CAD. A family history of photosensitivity is sometimes present in AP,
PMLE, and the porphyrias. Finally, a reaction to sun exposure through window glass may
assist in diagnosis and treatment by suggesting the action spectrum of the eruption, as UVB
radiation is absorbed by glass. Certain occupations or leisure activities may permit exposure
to allergens or photocontact allergens, such as in outdoor workers or enthusiasts, in whom
CAD is possible. Deterioration in the condition despite regular sunscreen application should
suggest the possibility of allergic contact dermatitis to one of the sunscreen constituents.
Laboratory Studies
Unless the diagnosis is otherwise certain, important investigations in all cases of
photosensitivity include measurement of the circulating antinuclear factor, anti-SSA (Ro) and
anti-SSB (La) antibody titers, and of blood, urine, and stool porphyrin concentrations.
Lesional skin histology, particularly in PMLE, HV, and CAD, may also be helpful, but rarely
diagnostic. Direct immunofluorescence, however, can assist in the diagnosis of LE. On the
other hand, phototesting of unaffected skin, usually of the back with narrow-waveband or
monochromatic irradiation, may induce the eruption and thus define the action spectrum in
certain disorders. This type of testing is however only moderately reliable overall, while solar
simulating and broad-waveband irradiation are more effective eruption inducers but give less
idea of the action spectrum. In eczematous photosensitivity, patch and photopatch testing are
also important to identify any inducing or exacerbating allergens. Finally, special techniques,
such as the measurement of DNA excision repair or the rate of recovery of RNA synthesis in
cultured fibroblasts following UV irradiation, are also required to make the diagnosis in
certain genophotodermatoses.
Phototesting
Phototesting of the unaffected skin, usually on the back, may assist in the diagnosis of
photosensitivity and help to identify the responsible wavelengths by demonstrating reduced
erythemal thresholds or reproducing the typical lesions. Table 135-4 lists the disorders in
which such testing is likely to be helpful. Several suitable protocols have been described,
either relatively simply with broad-spectrum light sources and filters if necessary, or,
preferably, for precise definition of the action spectrum, with an irradiation monochromator.
Sunlight with filters may also be used in some parts of the world but is generally too
unpredictable for regular and reliable use (for references see Ref. 106 and Ref. 107 ).
TABLE 135-4 Phototest Responses in Photosensitivity Disorders
Solar simulators produce imitation sunlight from xenon arc lamps; excitation of the highly
compressed gas produces a continuous emission spectrum approximating fairly closely that of
terrestrial sunlight after the unwanted wavelengths shorter than 285 nm and longer than 700
nm have been removed by appropriate filters. Such sources most reliably induce the typical
eruption of the photodermatoses, enabling confirmation of the diagnosis, while further filters
can also be used to enable some degree of action spectrum determination.
An irradiation monochromator (normally incorporating a xenon arc source, input slit,
collimating mirror, and output slit) is required to establish precise action spectra, but the
experience necessary for its correct use and the appropriate interpretation of results is such
that this sophisticated and expensive equipment is not generally available. The apparatus
emits any chosen narrow waveband with reliable purity, although usually relatively low
irradiance, which may be accurately quantified with an appropriate radiometer such as a
thermopile.
A number of other less expensive, more versatile, and more robust radiation sources have also
been used to investigate patients with photosensitivity. For example, mercury vapor arc lamps
emit throughout most of the solar spectrum but with superimposed isolated lines of relatively
high output, rather than the smoothly continuous spectrum produced by the xenon arc. Thus,
the Kromayer lamp has been a widely available, convenient, mobile, medium-pressure source
emitting mostly in the UVB and UVC regions, but the difficulty in precise determination of
the wavelengths and doses of light emitted have made it useful mainly for rapid
nonquantitative studies or occasionally treatment. Fluorescent lamps on the other hand are
low-pressure mercury arc glass tubes coated on their inner surfaces with fluorescent
phosphors made of alkaline earth salts, which then convert the internally emitted 254-nm
mercury line into a variety of external broadband outputs, for example, UVA or UVB. Such
lamps can be used for phototesting in relatively inexpensive and easily constructed systems, if
necessary with filters. However, they are even more useful for phototherapy and, in the case
of UVA lamps, also for photopatch testing.
Phototesting is usually performed on the unaffected skin of the back, although the attempted
induction, for example of PMLE, is best undertaken on previously involved skin. Systemic
glucocorticoids in high doses should not have been administered nor test sites treated with
topical glucocorticoids in the preceding few days in order to avoid false-negative results.
Furthermore, both patient and investigator must wear protective goggles.
Photopatch Testing (See also Chap. 136)
Photopatch testing is a well-established method to use for identifying phototoxic or
photoallergic substances. It should be performed whenever a phototoxic reaction or
photoallergic contact dermatitis is suspected. Diseases of the CAD spectrum are also
indications for testing. In the latter, contact sensitivity may also be noted to airborne allergens
such as plant oleoresins, which may have an inducing or exacerbating role in CAD. Other
photodermatoses, such as PMLE, HV, SU (see above), or porphyrias, are diagnosed according
to specific criteria of these entities and do not represent an indication for the photopatch test.
For patients who present with unclear photoreactions that cannot be associated with a genuine
photodermatosis, photopatch testing should also be performed. This holds true in particular
for patients with eczema in a photodistribution, or those with exacerbated sunburn reactions.
Such lesions are suspicious for photoallergic or phototoxic reactions, respectively, and a
careful history should evaluate all drugs and topical preparations. Among those, the
photosensitizer should be identified in the photopatch test. Following such stringent criteria
for photopatch testing, unnecessary test procedures are avoided and the positive test reactions
obtained are likely to be highly relevant for the patients. Test materials are applied to the back
in a duplicate set, one for irradiation, the other as a control. Patches to be irradiated are left on
the skin for 24 h; control patches are applied for either 24 or 48 h. Nonirradiated patches are
used as controls to exclude nonphotoinduced plain contact sensitivity. Test sites are evaluated
before and immediately after irradiation as well as 24, 48, and 72 h later. Control sites are
read shortly after removal of the patches as well as 24 and 48 h later.
Until the early 1980s, the photopatch test procedure was not standardized. Differences
between the recommended test procedures included variations in the range of test substances,
the irradiation doses, the precise irradiating wavelengths, the timing of the irradiation, the
irradiance used, and the delay before reading the responses. The first attempt to devise a
standard method was initiated by the Scandinavian Photodermatitis Research Group (SPRG).
108 Following this example, the German photopatch test working group was founded in 1984
in Germany, Austria, and Switzerland. This group also established a standardized protocol for
photopatch testing. 109
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