photosensitivity in lupus erythematosus

8
School in photodermatology Section Editor: Rik Roelandts Photosensitivity in lupus erythematosus Noah Scheinfeld, Vincent A Deleo St-Lukes Roosevelt Hospital Center, New York, NY, USA Background: Lupus erythematosus is a systemic disease process that may manifest with a variety of internal and cutaneous findings. Photosensitivity is one the most common manifestations of lupus erythema- tosus. In patients with lupus erythematosus, there is a relationship between exposure to ultraviolet light, autoantibodies, genetics and other factors in the development of photosensitivity. Methods: Literature was reviewed on the topics of lupus erythematosus and photosensitivity discussed together and separately. The suggested mechanisms for their relationship were reviewed and analyzed. Results: Photosensitivity’s relationship to and influ- ence on the systemic manifestations of lupus remain to be defined. Mechanisms for photosensitivity might include: modulation of autoantibody location, cyto- toxic effects, apoptosis induction with autoantigens in apoptotic blebs, upregulation of adhesion molecules and cytokines, induction of nitric oxide sythase expression and ultraviolet-generated antigenic DNA. Tumor necrosis factor a also seems to play a role in the development of photosensitivity. Conclusion: The basis for photosensitivity in lupus has yet to be fully defined. It is more commonly associated with subacute and tumid lupus erythematosus than with other variants. Anti-Ro antibodies appear to relate to photosensitivity. Tumor necrosis factor a polymorphisms appear to be important in some variants of lupus with photosensitivity. There is no sin que non antibody or mutation of photosensitivity in lupus. In patients with lupus, more work needs to be done to define the mechanisms of photosensitivity. Key words: anti-Ro antibody; photosensitivity; sub- actute lupus erythematosus; systemic lupus erythema- tosus; ultraviolet light. L upus erythematosus (LE) is a systemic disease process that may involve a variety of internal and cutaneous manifestations. Photosensitivity is one of the most commonly expressed of these criteria. There are several variants of LE. They include: systemic lupus erythematosus (SLE) discoid lupus erythematosus (DLE), medication induced lupus, neonatal lupus, tumid lupus (marked by indurated erythematous plaques) and sub-acute cutaneous lupus erythematosus (SCLE). A diagnosis of systemic lupus erythematosus (SLE) is made based on identifying in a patient manifestations of at least four of 11 criteria (Table 1). The science of photosensitivity began to be defined in the 1960s and early 1970s. An understanding of lupus and photosensitivity benefited initially from the work of Baer and Harber (1) and Everett and Olson (2). Tan (3) was the first to detect ultraviolet (UV)- altered DNA. Cripps and Rankin (4) helped to define the action spectra of LE and its immunofluorescence. Freeman et al. (5) investigated the induction by mono- chromatic light of cutaneous lesion of LE. The contri- butions of these researchers has been built upon in the last four decades although many questions remain. What are the cutaneous manifestations of lupus? In SLE, primary lesions include confluent erythema, edema and erythematous macules and papules espe- cially on the malar eminences and the nasal bridge. Bullae can be present as well as morbilliform macules and papules in a generalized photo-distributed pattern. In DLE, the primary lesion is an erythematous-brown papule or plaque with slight-to-moderate scaling, dilation of follicular openings with keratinous plugs (termed follicular plugging) and various degrees of atrophy. In the DLE lesion hypo-, de- and hyper- pigmentation may be present. The primary lesions of SCLE are minimally scaly erythematous papules, Photodermatol Photoimmunol Photomed 2004; 20: 272–279 Blackwell Munksgaard Copyright r Blackwell Munksgaard 2004 272

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Page 1: Photosensitivity in lupus erythematosus

School in photodermatologySection Editor: Rik Roelandts

Photosensitivity in lupus erythematosus

Noah Scheinfeld, Vincent A Deleo

St-Lukes Roosevelt Hospital Center, New York, NY, USA

Background: Lupus erythematosus is a systemic

disease process that may manifest with a variety of

internal and cutaneous findings. Photosensitivity is one

the most common manifestations of lupus erythema-

tosus. In patients with lupus erythematosus, there is a

relationship between exposure to ultraviolet light,

autoantibodies, genetics and other factors in the

development of photosensitivity.

Methods: Literature was reviewed on the topics of

lupus erythematosus and photosensitivity discussed

together and separately. The suggested mechanisms

for their relationship were reviewed and analyzed.

Results: Photosensitivity’s relationship to and influ-

ence on the systemic manifestations of lupus remain to

be defined. Mechanisms for photosensitivity might

include: modulation of autoantibody location, cyto-

toxic effects, apoptosis induction with autoantigens in

apoptotic blebs, upregulation of adhesion molecules

and cytokines, induction of nitric oxide sythase

expression and ultraviolet-generated antigenic DNA.

Tumor necrosis factor a also seems to play a role in

the development of photosensitivity.

Conclusion: The basis for photosensitivity in lupus has

yet to be fully defined. It is more commonly associated

with subacute and tumid lupus erythematosus than

with other variants. Anti-Ro antibodies appear to

relate to photosensitivity. Tumor necrosis factor apolymorphisms appear to be important in some

variants of lupus with photosensitivity. There is no

sin que non antibody or mutation of photosensitivity in

lupus. In patients with lupus, more work needs to be

done to define the mechanisms of photosensitivity.

Key words: anti-Ro antibody; photosensitivity; sub-

actute lupus erythematosus; systemic lupus erythema-

tosus; ultraviolet light.

Lupus erythematosus (LE) is a systemic disease

process that may involve a variety of internal

and cutaneous manifestations. Photosensitivity is one

of the most commonly expressed of these criteria.

There are several variants of LE. They include:

systemic lupus erythematosus (SLE) discoid lupus

erythematosus (DLE), medication induced lupus,

neonatal lupus, tumid lupus (marked by indurated

erythematous plaques) and sub-acute cutaneous lupus

erythematosus (SCLE). A diagnosis of systemic lupus

erythematosus (SLE) is made based on identifying in

a patient manifestations of at least four of 11 criteria

(Table 1).

The science of photosensitivity began to be defined

in the 1960s and early 1970s. An understanding of

lupus and photosensitivity benefited initially from the

work of Baer and Harber (1) and Everett and Olson

(2). Tan (3) was the first to detect ultraviolet (UV)-

altered DNA. Cripps and Rankin (4) helped to define

the action spectra of LE and its immunofluorescence.

Freeman et al. (5) investigated the induction by mono-

chromatic light of cutaneous lesion of LE. The contri-

butions of these researchers has been built upon in the

last four decades although many questions remain.

What are the cutaneous manifestations oflupus?In SLE, primary lesions include confluent erythema,

edema and erythematous macules and papules espe-

cially on the malar eminences and the nasal bridge.

Bullae can be present as well as morbilliform macules

and papules in a generalized photo-distributed pattern.

In DLE, the primary lesion is an erythematous-brown

papule or plaque with slight-to-moderate scaling,

dilation of follicular openings with keratinous plugs

(termed follicular plugging) and various degrees of

atrophy. In the DLE lesion hypo-, de- and hyper-

pigmentation may be present. The primary lesions of

SCLE are minimally scaly erythematous papules,

Photodermatol Photoimmunol Photomed 2004; 20: 272–279Blackwell Munksgaard

CopyrightrBlackwellMunksgaard 2004

272

Page 2: Photosensitivity in lupus erythematosus

which may expand and merge to form either plaques

with scaling in the papulosquamous variant or

annular and/or polycyclic lesions in the annular

variant. Neonatal lupus typically manifests with an

erythematous rash over the face with exaggeration

around the eyes, which is sometimes called ‘owl eyes.’

Any of the skin lesions described above may occur in

LE confined to the skin or may be a part of the multi-

system disease seen in SLE.

What is photosensitivity?Different definitions of photosensitivity in lupus exist.

Millard et al. (6) defines it as an abnormal cutaneous

response to UV radiation. The American College of

Rheumatology explains that photosensitivity is a ‘skin

rash as a result of unusual reaction to sunlight, by

patient history or physician observation.’ It may mean

a sunburn occurring with lower than expected doses

of sun exposure (a decreased minimal erythema dose),

a sensation in the skin of burning, worsening of LE

internal manifestation, or provocation of the skin

manifestations of LE listed above. A patient might

informally define it as some reaction to sunlight,

which they perceive as out of the ordinary. Patients

who have LE sometimes complain that their skin

burns in sunlight with an unusual time course, either

earlier during exposure or in a delayed manner.

The differential diagnosis of photosensitivity is

large and includes genetic and metabolic diseases,

photochemical sensitivity, idiopathic photosensitivity

and other systemic and cutaneous diseases where

photosensitivity is a part of a larger symptom complex

as in LE.

The most common genetic-metabolic disease involv-

ing photosensitivity in the United States is porphyria

cutania tarda. Other conditions include Bloom’s

syndrome, Cockayne’s syndrome, Hartnup disease,

Rothmund–Thomson syndrome, trichothiodystrophy

and xeroderma pigmentosum. Interestingly, some

genetic complement deficiency syndromes mimic

lupus and can manifest with lupus-like symptoms

including photosensitivity. Chemically induced photo-

sentivity includes photo-drug reactions and photo-

irritation and photo-allergic contact dermatitis. The

idiopathic photosensitivities include the most com-

mon of all photosensitivity eruptions, polymorphous

light eruption (PMLE) known by lay-persons as ‘sun

poisoning.’ In fact, the cutaneous reaction of that

condition can be mistaken for LE and many studies

trying to link this common reaction pattern with SLE

have been undertaken with little success. Other rarer

forms of idiopathic photosensitivity include hydroa

vacciforme, actinic prurigo, chronic actinic dermatitis

and solar urticaria. These conditions can be distin-

guished from lupus by clinical history, morphology,

laboratory testing and photo-biologic testing.

What kind of UV light engendersphotosensitivity?The radiation from the sun or artificial sources that is

capable of inducing the skin lesions and systemic

effects in LE is referred to as the ‘action spectrum’ of

the disease. Photobiologists endeavor to determine the

action spectrum for various skin lesions so as to learn

more about the mechanism of the reaction and also so

that strategies can be offered to patients to protect

them against the relevant radiation.

Light or non-ionizing radiation which is produced

by the sun and by artificial sources like indoor lighting

and sun-tan parlor radiation is generally divided into

spectra defined by the wavelength of the radiation.

This includes UV, visible, and infrared radiation

(Table 2).

Most photosensitivity in human skin is caused by

UV radiation and in some rare instances like the

porphyrias, by visible radiation (400–800 nm). UV

Table 1. Criteria for diagnosis of lupus (50)

Malar rash Erythermatous rash on cheeks covering the bridge of the nose

Discoid rash Red or brown plaques sometime with follicular plugging

Photosensitivity Pain or exanthem to exposure with ultraviolet light

Oral ulcers Small erosions on in the nose or mouth

Arthritis Pain in the joints of the hands, arms, shoulders, feet, legs, hips, or jaws. This can be migratory and

accompanied by heat, redness and swelling

Serositis Pleurisy – chest pain or abnormal sounds heard by physician Inflammation of the lining of the heart.

There can be abnormal EKG findings or heart sounds

Renal (kidney) Excessive protein and/or cellular casts in the urine

Neurologic Seizures and/or psychosis

Hematologic (blood) Decrease in red and white blood cells or platelets

Immunologic Immunologic positive anti-DNA test, Ro, La antibody test

Antinuclear antibody (ANA) ANA positive

273

Photosensitivity in lupus erythematosus

Page 3: Photosensitivity in lupus erythematosus

radiation is classically divided into short-wave UVC

radiation, mid-wave UVB radiation and long-wave

UVA radiation. UVC radiation is made up of

radiation with wavelengths of less than 290 nm. Such

radiation is absorbed by the ozone layer and no UVC

reaches the surface of the earth. UVB radiation, 290–

320 nm, is also called ‘sun-burn’ radiation since it is

the principle cause of inflammation in the skin of

normal persons induced by excessive sun exposure

and is also most responsible for photo-ageing and skin

carcinogenicity. UVA radiation, 320–400 nm, unlike

UVB radiation, penetrates window glass so that

human skin is exposed to this radiation indoors and

while individuals are traveling in automobiles. UVA

radiation is commonly sub-divided into UVA1 340–

400 nm and UVA2 320–340 nm.

One phototesting study noted that skin lesions of

various form of LE could be reproduced experimen-

tally and that the action spectrum of the induced

lesions was within the UVB range in 33% of patients,

in the UVA range in 14%, and in both the UVB and

UVA ranges in 53% (7).

Research in vivo and in vitro has buttressed the role

of UVA and UVB in evoking LE. Cultures of cells

taken from SLE patients showed a decrease of their

unscheduled DNA repair capacity following UVB

irradiation, whereas most controls did not (8). UVA

was involved in the development of lupus in a Swedish

study (9). One report has noted a woman with SLE

who worked as a photocopy technician who deve-

loped cutaneous LE of the hands, neck, face, and

chest. Her skin lesions improved when she discon-

tinued her employment. Testing of several photocopy

devices showed emission of small quantities of UVA,

but not UVB (10). Fluorescent lighting emitting UVB

can also evoke lupus (11). A practical consequence of

UVA sensitivity is that patients with LE are not

adequately protected by glass covers or by conven-

tional sunscreens, which mostly absorb UVB radia-

tion. Moreover, high-intensity UVA sources in

tanning salons might be dangerous for these patients.

Film to cover windows, which absorb or reflect UVB

and UVA radiation can aid LE patients (12).

Unlike the effect of UVB radiation in LE, which is

always believed to be detrimental, the role of UVA in

lupus is complex and may in rare circumstances be

beneficial. McGrath has reported that UVA1 (340–

400 nm) (13) improved lupus disease activity, de-

creased sDNA titers and reduced medication use in 3

weeks. Therapy with visible light had no effect in these

patients (14). In a related study, six patients got long-

term relief with UVA1 used one, two or three times a

week (15). The mechanism of this treatment is uncertain.

Photosensitivity and lupusPhotosensitivity’s relationship to and influence on the

systemic manifestation’s of LE is unclear. Some

patients have noted that sun exposure increases

disease symptoms (including weakness, fatigue and

joint pain). Fluctuation in an individual’s symptoma-

tology related to solar exposure using objective

variables has not been demonstrated in sizeable

cohort studies. Although cutaneous manifestations

of lupus are more common in the summer months,

systemic disease activity is increased in the 3–6

months following maximal potential sun exposure,

suggesting that summer UV light exposure may lead

to systemic flares several months later (16, 17).

SCLEOf particular interest in understanding the relation-

ship of photosensitivity and LE is SCLE. This LE

variant routinely manifests with photosensitivity and

serologically most affected individuals have Ro

antibodies, thought to be a marker for photosensitiv-

ity. SCLE has certain diagnostic criteria (Table 3).

Clinical features most characteristic of SCLE rather

than DLE are superficial, non-indurated, non-scarring

papules, macules and plaques, and a close associa-

tion with sun exposure. Histologic examination

of involved skin demonstrates a sparse, superficial

Table 3. Diagnostic criteria for subacute cutaneous lupus erythema-

tosus (51)

1 Characteristic lesions (scaly papules) in women, typical distri-

bution on sun-exposed areas, facial sparing

2 Extreme photosensitivity, frequent disease exacerbations in

spring and summer

3 Possible induction by drugs (thiazides, terbinafine, piroxicam,

penicillamine, glibenclamide, glyburide)

4 Anti-Ro/SSA antibodies (60 kDa peptide)

5 ‘Dust-like particles’ of IgG deposition in the epidermis

6 Strong association with the A1, B8, DR3 haplotype

7 Mild systemic involvement (especially kidney and CNS involve-

ment)

Table 2. Non-ionizing radiation spectra (nm)

UVC o290

UVB 290–320

UVA 320–400

UVA2 320–340

UVA1 340–400

Visible 400–760

Infrared 4760

274

Scheinfeld & Deleo

Page 4: Photosensitivity in lupus erythematosus

infiltrate in SCLE as compared with a denser, deeper

infiltrate in DLE. Direct immunofluorescence shows

particulate epidermal IgG deposition (18). Photore-

production (appearance of LE lesion in irradiated

skin) is significantly more frequent in patients with

SCLE then with SLE (19). Early lesions of SCLE may

be difficult to distinguish from polymorphous light

eruption (PMLE).

SCLE is intimately involved with antibodies to the

Ro antigen (SS-A). They are found in annular SCLE

(90%), papulosquamous SCLE (80–85%), SCLE with

vasculitis, Sjogren syndrome, or C2d deficiency

(495%) and mothers of newborns with neonatal

LE (490%) (20).

It is important to understand Ro/SS-A and La/SS-B,

when studying SCLE and photosensitivity. Ro-SSA is

actually a complex of three proteins referred to as Ro-

60, Ro-52 and calreticulin with respective molecular

weights (kDa) of 60, 52 and 46. Expression of

antibodies against Ro/SS-A is associated with SCLE,

Sjorgen’s syndrome and systemic sclerosis. Ro-60 and

Ro-52 represent the most antigenic polypeptides of

Ro/SS-A. La/SS-B is a protein of approximately

50 kDa. The presence of antibodies against La/SS-B is

frequently associated with neonatal Lupus and SCLE.

The mechanism for the development of antibodies to

multiple antigens in affected individuals is usually

thought to be due to ‘epitope spread’ and the physical

association and similarity of these antigens. Ro itself

is found in the skin of patients with SCLE.

Anti-Ro, however, is not a sin qua non of

photosensitivity. Anti-Ro is not commonly found in

association with DLE. However, photosensitivity can

be found in patients with DLE, especially if general-

ized. Other cases of lupus can manifest with photo-

sensitivity without anti-Ro antibodies. Finally, a

lupus-like syndrome has been reported developing in

mice lacking the Ro 60-kDa protein (21).

Epidemiology of photosensitivity and lupusThe prevalence of photosensitivity in LE is not

uniform worldwide. It appears most commonly in

oriental countries such as China and less commonly in

black African countries (Table 4). Studies have shown

that in most cases the lighter the skin type, the greater

the prevalence of photosensitivity. Interestingly,

blacks have fewer cutaneous manifestations of lupus

and different antibody profiles than whites. In a series

of South African black patients, only 68% had

cutaneous findings (22). Interestingly, photosensitivity

in black Jamaican patients with SLE is not associated

with antinuclear–antibody specificity (23).

What is the mechanism for photosensitivity?A number of theories have been adduced as reasons

for the induction of lupus activity by UV radiation.

They include (1) modulation of autoantigen location,

(2) cytotoxic effects related to autoantigens, (3)

apoptosis induction with autoantigens in apoptotic

blebs, (4) upregulation of adhesion molecules and

expression of pro-inflammatory cytokines, (5) induc-

tion of nitric oxide synthase expression and (6) UV-

generated antigenic DNA.

Modulation of autoantigen location

Evidence exists for the promotion by UV light of the

migration of autoantigens to the cell surface. The

basis and significance of this process is unclear. UVB

but not UVA can induce the expression of Ro/SSA

antigen on keratinocyte surfaces in vitro (24). Golan

et al. (25) found enhanced binding of IgG autoanti-

bodies to the cell surface membrane, RNP, SSA/Ro,

SSB/La and Sm after UVB exposure of cultured

keratinocytes from patients with SLE. Kawashima et

al. (26) found that cellular and cell surface expression

of 46 kDa SSA/Ro (calreticulin) was increased in

response to exposure to UVB. Photosensitivity and

the presence and titers of circulating anti-SS-A/Ro

and anti-SS-B/La antibodies are both directly corre-

lated with the expression of accessible and immuno-

reactive SS-A/Ro and SS-B/La antigens in the skin

specimens of patients with LE (27). How these

antibodies act is uncertain. SSA/Ro, a ribonucleo-

protein antigen expressed on UVB irradiated kerati-

nocytes, may be recognized and presented to immune

cells by a direct cell-cell contact rather than circulated

in extracellular fluids (28).

Cytotoxic effects

Once autoantigens are located on the cell surface, they

can lead to cytotoxic attacks on expressing cells. The

Table 4. Worldwide epidemiological prevelence of photosensitivity

and malar rash in lupus

Photosensitivity

(%)

Malar

rash (%)

Taiwan (52) 90.9 86.1

Puerto Rico (53) 76.9 71.9

Kuwait (54) 48.8.8

United Arab Emirates (55) 40.5 35.75

Tunisa (56) 41 71

Greece (57) 50 37

Pakistan (58) 60

Singapore (59) 30

US, North Carolina – Whites (60) 53 44

US, North Carolina – Blacks 30 35

South African Blacks (61) 19

275

Photosensitivity in lupus erythematosus

Page 5: Photosensitivity in lupus erythematosus

subclass bound in the skin in SCLE is IgG1, a

subclass capable of mediating tissue injury via

complement or cellular effectors (29). The comple-

ment membrane attack complex (C5b-9) has been

identified in lesional but not in uninvolved skin of

patients with SLE or SCLE. These findings are

suggestive that the interaction between Ro and

UVB-irradiated keratinocytes can provoke the photo-

senstivitity and cutaneous eruptions in SLE and

SCLE through a cytotoxic mechanism.

Apoptosis induction with autoantigens in apoptotic

blebs

In vitro, UVB-irradiated keratinocytes from normal

individuals actively cleave their DNA and undergo

apoptosis (30) . Cells concentrate autoantigens such as

Ro, during apoptosis, the antigens recognized by

autoantibodies such as Ro/SSA and calreticulin are

concentrated in structures termed blebs or apoptotic

bodies found at the cell surface. Larger blebs arise

from the nucleus and contain Ro/SSA, La/SSB and a

variety of nuclear antigens. It has been suggested that

the bleb-associated antigens may then be phagocy-

tosed, packaged and presented to lymphocytes, there-

by facilitating immunological activation (31).

Apoptosis itself leads to the production of antigens

that autoantibodies target and the large volume of

such antigens might effect the immune system’s self

tolerance. Proteins phosphorylated during apoptosis

may be preferred targets for autoantibody production

in patients with SLE (32). Most autoantigens targeted

across the spectrum of human systemic autoimmune

diseases are efficiently cleaved by granzyme B in vitro

and during cytotoxic lymphocyte granule-induced

death, generating unique fragments not observed

during any other form of apoptosis (33). Recognition

of apoptotically and oxidatively modified forms of the

U1-70-kd autoantigen are associated with distinct

clinical rheumatic disease manifestations (34).

Upregulation of adhesion molecules and cytokines

UV light has manifold effects on adhesion molecule

and cytokine expression and function. ICAM-1, an

adhesion molecule, has increased expression in

keratinocytes exposed to UV light and TNF-a (35).

In SCLE, there is diffuse epidermal ICAM-1 expres-

sion, with occasional accentuation on the cell surface

of basal cells, a pattern induced by UV light, which is

consonant with the release of TNF-a. In vivo, in LE

patients, increased keratinocyte ICAM-1 expression

was found 1 week after UV provocation in biopsies in

cutaneous reactions that eventually developed into

long-standing LE lesions. It is possible that these early

changes reflect an underlying defect in the mechan-

isms that regulate adhesion molecule expression in

LE (36). Aberrant expression of heat shock protein

70 (HSP70) in skin lesions of SLE might contribute

to both skin lesions and antibody formation in SLE

(37). UV light induces the release of pro-inflamma-

tory epidermal and dermal mediators such as IL-1

and TNF-a that are thought to be involved in the

promotion of lupus as well.

Induction of nitric oxide synthase expression

Aberrant regulation of cytokine-inducible nitric oxide

synthase (iNOS) expression has also been noted in

photo-induced lesions of cutaneous lupus (38).

Healthy controls were shown to have short-term

expression of iNOS after either UVA or UVB

irradiation. The kinetics of iNOS induction as well

as the time span of local iNOS expression may be

critical to the development of cutaneous LE lesions.

Patients with cutaneous LE are noted to have

significantly delayed but prolonged expression of

iNOS. Both IL-1 and TNF-a promote the expression

of iNOS (39) and this abnormal expression in

cutaneous LE could be secondary to a genetic

dysregulation of these cytokines.

UV-generated antigenic DNA

UV light can generate reactive oxygen species in

human tissue. Mammalian experiments demonstrate

that DNA damaged by reactive oxygen species (ROS-

DNA) can be immunogenic. That is, ROS-DNA

inducing antibodies are produced that recognize both

native and ROS-DNA. For example, hydroxyl

radical, generated by UV irradiation of hydrogen

peroxide caused damage to native calf thymus DNA

leading to strand breaks, base modification and

decrease in melting temperature, and such ROS-

DNA was highly immunogenic in goats (40). UV-

altered DNA has also been found in LE patients. The

presence of UV DNA antibodies correlated well with

the presence of native DNA antibodies (41).

TNF-a, SCLE and photosensitivityTNF-a appears to play a key role in the pathogenesis

of SCLE and its concomitant photosensitivity. SCLE

is associated with polymorphism in the TNF allele

(42). Researchers have found an association of the

promoter polymorphism 308A of tumor necrosis

factor a with subacute cutaneous lupus erythematosus

and distinct photoregulation of transcription (43).

Compared with healthy controls, there was a sub-

stantially increased prevalence of 308A polymorphism

276

Scheinfeld & Deleo

Page 6: Photosensitivity in lupus erythematosus

in SCLE, an extremely photosensitive form of

cutaneous lupus erythematosus, but not in DLE. Ro

antibodies and nephritis have been associated with

TNF polymorphism (44).

Assessing photosensitivity in lupusPhototesting is a method for assessing the response

of skin to visible and UV light in patients suspected

of having photosensitivity. The skin is exposed to

defined wavelengths of light from various artificial

sources. In most studies of individuals with LE, it

has been necessary to treat the skin with multiples

of the MED (minimal erythema dose) and to do so

repeatedly. This is termed a photoprovocation test.

Test sites are evaluated 24, 48, 72 h and up to

4 weeks after the last irradiation. A follow up of less

than 3 weeks can miss positive results in some

patients. There can be a persistence of hyperpigmen-

tation and hypopigmentation for several months after

irradiation.

Phototesting can reproduce lesions in SLE (25–

85%), SCLE (50–100%), tumid Lupus (70–81%) and

DLE (10–64%). The more widespread the DLE, the

higher the rate the positive phototesting. The high

incidence of positive phototest reactions in correlation

with the clinical findings, history of photosensitivity

and antinuclear antibodies enable the classification of

erythematosus tumidus as the most photosensitive

type of LE (45).

However, phototesting is rarely necessary to make a

diagnosis of photosensitivity associated with the

various forms of LE. Clinical history, physical

examination, skin biopsy for routine histology and

direct immuno-fluorescence and serologic studies are

the standard for diagnosis.

Patient reports of photosensitivity correlate poorly

with results of phototesting using standardized pro-

tocols (46). There is a poor correlation between

personal history of photosensitivity and a decreased

MED. Interestingly, phototesting usually elicits a

papule rather than erythema with a frequency and

nature not unlike PMLE. The incidence of positive

phototest reactions in Oriental patients with LE seems

to be similar to or a little lower than in Caucasians

(47). There was no correlation between a positive

history for UV sensitivity and phototest reactions

(48). Nevertheless, phototesting can be useful to assess

photosensitivity in lupus patients (49). Since it is

possible that photoprovocation testing in individuals

with LE can induce long-standing skin lesions and

may theoretically at least worsen systemic symptoms,

such testing should be undertaken with care.

Millard has noted that the indications for photo-

testing for patients with lupus include:

(1) The objective demonstration of photosensitivity

where there is doubt from the history and where

such a demonstration would support a diagnosis

of lupus where the clinical picture is otherwise

equivocal.

(2) Phototesting can be used to exclude other causes

of photosensitivity in lupus patients, e.g. chronic

actinic dermatitis, solar urticaria and drug-in-

duced phototoxicity. Those conditions tend to

show characteristic phototesting results.

(3) Photo-provocation tests can be a useful research

tool with which to study the immunology of

evolving lesions of lupus-specific skin disease.

Future considerationsThe basis for photosensitivity in lupus has yet to be

fully defined. It is more commonly associated with

SCLE and tumid lupus than with other variants. In

this regard Ro antibodies appear to be important. The

complex effects that UV engenders in the skin

underlie the pathophysiology of photosensitivity of

lupus. TNF-a polymorphism appears to be important

in some forms of LE with photosensitivity. Photo-

sensitivity occurs worldwide but is less common in

those of African decent. A diagnosis of photosensi-

tivity is made based on clinical and physical examina-

tions. Phototesting is an interesting and sometime

helpful modality in assessing photosensitivity and

lupus. Explicating why phototesting fails to replicate

actual photosensitivity will be an important question

to answer. Improved animal models for photosensi-

tivity will help researchers improve our understanding

of photosensitivity. In sum, our understanding of

photosensitivity has increased but many important

questions remain.

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2. Everett MA, Olson RL. Response of cutaneous lupuserythematosus to ultraviolet light. J Invest Dermatol 1965;

44: 133–138.

3. Tan EM. Antibodies to deoxyribonucleic acid irradiated withultraviolet light: detection by precipitins and immunofluore-

scence. Science 1968; 161: 1353–1354.

4. Cripps DJ, Rankin J. Action spectra of lupus erythematosus

and experimental immunofluorescence. Arch Dermatol 1973;107: 563–567.

5. Freeman RG, Knox JM, Owens DW. Cutaneous lesions of

lupus erythematosus induced by monochromatic light. Arch

Dermatol 1969; 100: 677–682.

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Accepted for publication 11 February 2004

Corresponding author:

Noah Scheinfeld, MD

St-Lukes Roosevelt Hospital Center

1090 Amsterdam Avenue Suite 11D

New York, NY 10025

USA

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