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Ultraviolet radiation and systemic lupus erythematosus

M Barbhaiya and KH Costenbader
Lupus 2014 23: 588
DOI: 10.1177/0961203314530488

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 Lupus (2014) 23, 588–595
http://lup.sagepub.com

SPECIAL ARTICLE

Ultraviolet radiation and systemic lupus erythematosus

M Barbhaiya and KH Costenbader
Brigham and Women’s Hospital, Division of Rheumatology, Immunology, and Allergy, Harvard Medical School, USA

Exposure to ultraviolet (UV) radiation is among the environmental factors that have been
proposed and studied in association with systemic lupus erythematosus (SLE). While it is
known that UV radiation exposure may exacerbate pre-existing lupus, it remains unclear
whether UV exposure is a risk factor for the development of SLE. Experimental studies
show a significant immunomodulatory role for UV radiation, but strong epidemiologic data
regarding its role in triggering SLE onset are lacking. Further studies are needed to assess the
role of UV radiation in relation to development of incident SLE, yet they are challenging to
design due to difficulties in accurate exposure assessment, the heterogeneous nature of SLE,
and the challenge of assessing photosensitivity, a feature of SLE, which often precedes its
diagnosis. Lupus (2014) 23, 588–595.

Key words: Ultraviolet radiation; systemic lupus erythematosus; UV; SLE; vitamin D;
environmental exposure

Introduction immunomodulating effects, UV-B radiation could

potentially reduce the SLE risk.5–7 Further compli-
Environmental exposures, including infectious cating our understanding of the relationship
agents, cigarette smoking, exogenous sex hor- between UV radiation and SLE, a subset of UV
mones, silica exposure, hormonal and dietary fac- radiation, UV-A, is used as a phototherapy modal-
tors, and ultraviolet radiation, are hypothesized to ity to treat cutaneous forms of lupus.8 Based on
contribute to the development of systemic lupus current literature, strong epidemiologic evidence
erythematosus (SLE).1 The role of ultraviolet concerning the role of UV radiation in triggering
(UV) radiation in the development of SLE remains SLE onset is lacking.
controversial. Although UV radiation exposure The purpose of this article is to review the poten-
may exacerbate pre-existing SLE, it remains tial mechanisms whereby UV radiation exposure
unclear whether UV exposure plays a role in the could be related to SLE risk, review the back-
pathogenesis of SLE.2 In experimental studies, ground epidemiologic evidence suggesting an asso-
UV radiation has a number of immunomodulatory ciation between UV radiation and the pathogenesis
effects, up-regulating Th2 cells and down-regulat- of incident SLE, and to highlight the need for pro-
ing Th1 cells, and inducing interleukin-10 produc- spective studies related to the role of UV radiation
tion, an anti-inflammatory cytokine, and increased in the development of autoimmune diseases.
production of T-regulatory cells.3,4 UV-B exposure
is responsible for sunburn and skin damage and
may lead to worsened photosensitivity, skin
rashes, and even flare of systemic disease in Molecular effects of UV radiation
patients with pre-existing SLE. However, it has
been suggested that through the stimulation of UV radiation consists of three types, including
cutaneous vitamin D synthesis, which has known UV-A (wavelength range 320–400 nm), which is
abundant in terrestrial sunlight, but is not strongly
absorbed by protein and nucleic acids; UV-B
(wavelength range 290–320 nm), which is erythemo-
Correspondence to: M Barbhaiya, MD Division of Rheumatology,
genic and present in the terrestrial solar spectrum;
Immunology, and Allergy, PBB-3 Brigham and Women’s Hospital,
75 Francis Street, Boston, MA 02115, USA. and UV-C (wavelength range 200–290 nm).9 Given
Email: mbarbhaiya@partners.org that UV-C is absorbed by the Earth’s ozone layer,
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203314530488

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2 12
its effects on human health appear negligible. UV-
B radiation, on the other hand, may be hazardous
to human health by inducing skin cancer, prema-
ture skin aging, and possibly inflammatory diseases
such as SLE and dermatomyositis.10–12 UV-A has
been found to decrease clinical disease activity in
SLE patients and patients with subsets of cutane-
ous lupus.8 However, other studies have demon-
strated UV-A exposure inducing cutaneous lupus
skin lesions.13–15 Of significant interest, during the
last three decades, UV A1 phototherapy has
emerged as a specific phototherapeutic modality
for various indications including conditions such
as atopic dermatitis, localized scleroderma, and sys-
temic and cutaneous lupus erythematosus.16 In this
section, we outline the specific molecular mechan-
isms of UV-A and UV-B in relation to SLE.
Role of UV-A
Although daily exposure to UV-A is significantly
greater than UV-B, UV-A induced erythema
requires nearly 1000 times more energy than from
UV-B.9 UV-A radiation is of longer wavelength
and is thus able to penetrate the deeper dermis
and induce keratinocyte apoptosis via mitochon-
drial oxidative damage, which can result in genera-
tion of reactive oxygen species.17 Pro-inflammatory
effects of UV-A are likely related to stimulation of
IL-1 and IL-6 and modification of lymphocyte
function.18
However, UV-A is also shown to have anti-
inflammatory effects, allowing for its use as a
phototherapeutic agent, related to T and B cell
apoptosis and reduction of inflammatory cytokines,
including interleukin(IL)-4, IL-10, and interferon-g
levels.19,20 Phototherapy, which requires direct skin
irradiation, induces an autoregulatory response
that deactivates abnormal T-cells and alters T-cell
receptor specificity, and may modify lymphocyte
function with UV-A activated psoralens.21 In
mice, UV-A irradiation resulted in increased sur-
vival and decreased circulating anti-DNA antibo-
dies, postulated to occur as UV-A does not affect
Langerhans’ cell function, resulting in decreased
stimulation of B-cell activity.22,23
Role of UV-B
Numerous animal studies suggest that exposure to
UV-B radiation is potentially immunosuppressive.
At the molecular level, a major trigger for UV-B
induced immunosuppression derives from UV-B
induced DNA damage, which leads to antigen-spe-
cific immunotolerance.12,24,25 In particular, UV-B
radiation induces antigen-specific immunotolerance
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Ultraviolet radiation and SLE
M Barbhaiya and KH Costenbader
589
through the generation of regulatory T cells.
Induction of regulatory T cells by UV-B radiation
requires antigen presentation by UV-damaged
Langerhans cells in the lymph nodes.24 Once acti-
vated, regulatory T cells suppress immune
responses by releasing the immunosuppressive
cytokine IL-10.25
UV-B radiation may also result in a redistribu-
tion of nuclear antigens to the cell surface or in the
production of novel forms of autoantigens, effects
that may be relevant given the mechanisms thought
to be involved in SLE pathogenesis.26 Additionally,
UV-B radiation can damage keratinocytes and
other mammalian cells via numerous mechanisms,
including induction of reactive oxygen species,
which may damage DNA via strand breaks and
pyrimidine dimer formation.27,28 The metabolism
and detoxification of reactive oxygen intermediate
compounds involves the glutathione-S-transferase
family of enzymes, including glutathione-S-trans-
ferase-M1 (GSTM1), which has been associated
with increased SLE risk among Caucasians.29
Furthermore, as a potential DNA methylation
inhibitor, UV-B radiation may also stimulate over-
expression of lymphocyte function associated anti-
gen-1 (LFA-1), leading to increased production
of autoreactive T cells, shown to induce SLE in
syngeneic mice.30
Role of vitamin D
While exposure to solar UV radiation may trigger
SLE disease flares, UV light exposure is also the
main source of vitamin D production.31 Vitamin
D regulates the growth and differentiation of
immune system cells and acts as an immunosup-
pressive agent once metabolized to 1a,25
(OH)2D3, a steroid hormone. Evidence from
animal models and prospective studies of RA, mul-
tiple sclerosis, and type-1 diabetes suggest an
important role for vitamin D as a modifiable envir-
onmental factor in autoimmune disease.32,33
Furthermore, various animal models of auto-
immunity – including collagen-induced arthritis,
type I diabetes mellitus, inflammatory bowel dis-
ease, and SLE – have shown significant improve-
ment and even disease prevention with vitamin D
treatment.5,33,34
The role of vitamin D in SLE pathogenesis
remains controversial, however. In numerous stu-
dies of patients with existing SLE, vitamin D levels
have been found to be lower than in those without
SLE.35–38 This is also true of patients with many
Lupus
 Ultraviolet radiation and SLE
M Barbhaiya and KH Costenbader
590
different chronic inflammatory diseases.39 A recent
systematic review,39 which assessed the effect of
vitamin D on the risk of developing autoimmune
diseases, showed that in some studies lower levels of
vitamin D correlated with more SLE disease activ-
ity,38,40,41 whereas others did not confirm this find-
ing.36,37 Furthermore, in a large prospective cohort
of women, vitamin D intake from food and supple-
ments did not appear to be associated with risk of
SLE.7,42
In SLE patients, various other potential risk fac-
tors for vitamin D deficiency exist including avoid-
ance of sun exposure, increased use of
photoprotection methods, chronic steroid use,
renal involvement, and use of hydroxychloroquine.
Thus, it remains unclear whether vitamin D defi-
ciency is a cause or consequence of the disease. As
most of the prior studies have been limited by retro-
spective design and use of semi-quantitative ques-
tionnaires evaluating food frequency and
supplement intake, as opposed to direct measure-
ment of vitamin D serum levels, at present there is
not sufficient evidence to establish a clear relation-
ship between vitamin deficiency and increased SLE
incidence or exacerbation of disease. Furthermore,
questions regarding optimal vitamin D dosing in
SLE patients and whether a certain amount of
UV radiation may actually be beneficial in helping
to maintain vitamin D levels remain unanswered.
Epidemiologic evidence linking UV radiation to
prevalent and incident SLE
Epidemiologic studies have sought to identify
potential factors involved in the development of
SLE in the genetically susceptible. However, most
of the current research pertaining to immune-
related effects of UV radiation focuses on its role
in disease exacerbation or flares in prevalent SLE.
In this section, we aim to: (1) discuss the role of
photosensitivity and highlight epidemiologic stu-
dies demonstrating the effect of UV radiation
exposure on prevalent SLE; and (2) examine the
current epidemiologic data suggesting a role for
UV radiation in the etiology of incident SLE.
Role of photosensitivity and the effect of UV
radiation on prevalent SLE
Photosensitivity, one of the American College of
Rheumatology (ACR) diagnostic criteria for SLE,
occurs in approximately 40–50% of SLE
patients.43,44 The definition of photosensitivity is
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vague, defined by the ACR as ‘a skin rash as a
result of unusual reaction to sunlight’.45 The patho-
physiology of photosensitivity in SLE is thought to
be related to the aberrant processing and clearance
of an increased number of apoptotic keratinocytes
induced by UV radiation.46 Photosensitivity is most
common in individuals with cutaneous lupus ery-
thematosus. Past studies have reported that nearly
50% of patients with cutaneous lupus developed
non-specific inflammatory skin reactions or poly-
morphic light eruptions, as opposed to cutaneous
lupus flares, after exposure to UV radiation.15,47
Reported rates of photosensitivity range from
27% to 100% for SCLE, 25% to 90% for discoid
lupus, and 43% to 71% for lupus tumidus.47 The
large variation in reported rates of photosensitivity
is likely due to imprecise definition, the delayed
onset of true photosensitive reactions, and hetero-
geneous and inconsistent methods of assessing
photosensitivity.
As patient history correlates poorly with the
presence or absence of photosensitivity due to the
delayed-onset time interval between UV exposure
and eruption of skin lesions, phototesting may be a
reliable way of diagnosing photosensitivity.48 Using
photoprovocation testing methods involving meas-
urement of the minimal erythema dose, one study
reported that over 90% of lupus patients, including
patients with SCLE, SLE, and discoid lupus, had
an abnormal reaction to UV radiation, with cuta-
neous lesions induced or exacerbated by exposure
to UV radiation.48
It has been shown in several epidemiologic stu-
dies that among patients with prevalent SLE,
increased UV radiation exposure may aggravate
pre-existing skin disease, often resulting in new
cutaneous lesions.49 Photo-induced cutaneous dis-
ease appears mainly on sun-exposed areas as macu-
lar, papular, or bullous lesions as well as classic
erythema. SLE flares may also occur and are typ-
ically reported as weakness, fatigue, fevers or joint
pain.50 Patient reported photo-induced cutaneous
or systemic disease does not appear to correlate
well with physician assessment or laboratory stu-
dies of SLE disease activity, however.50,51
Sunlight exposure likely acts as a trigger for SLE
onset and exacerbation, particularly among
people whose reaction to midday sun is typified
by sunburn with blistering or a rash.52
Studies examining a seasonal influence on SLE
disease activity have suggested a possible role for
UV radiation, although the results are conflicting.
A few studies have demonstrated increased inci-
dence of photosensitive rashes in the summer
months,53,54 but other studies have shown increased

joint activity and lupus nephritis flares in the winter
and spring seasons.55–57 In fact, a small study of 33
SLE patients from Finland demonstrated increased
non-cutaneous disease activity in summer months,
but no increase in skin symptoms even after photo-
provocation with UV-A and UV-B in a subset of
patients.58 Additionally, a retrospective study eval-
uating seasonal variation of non-cutaneous lupus in
Hong Kong demonstrated a U-shaped correlation
between the rate of SLE flares and the monthly
average environmental temperature, with higher
flare rate at extremes of temperature.56 However,
a recent large prospective, longitudinal study using
data from the Hopkins Lupus Cohort found that
both photosensitive rash and arthritis activity were
significantly more frequent in the spring and
summer months.59 As season of the year may be
associated with many factors besides UV light,
such as infections, diet, and vitamin D levels,
along with the methodological differences, and
variations in climate and racial burden of the popu-
lations being evaluated, interpretation of these
studies is limited.
In addition to studies of the seasonal variation of
SLE flares, SLE burden and mortality rates have
also been examined in relationship to geography
and season. In a review of the literature, SLE
prevalence by country was remarkably varied,
lowest in Northern Ireland, the United Kingdom,
and Finland, and the highest in Italy, Spain, and
Martinique.60 The lowest overall incidence rates
were reported in Iceland and Japan, and highest
in the USA and France. It has been suggested
that the pattern of increased mortality from SLE
in the United States is consistent with regional dif-
ferences in the concentration of UV-B radiation.61
UV-B radiation for July showed the highest correl-
ation with SLE mortality rates as compared to pov-
erty level or Hispanic or African lineage, however
these results were based on use of a limited data-
set(61). In another study assessing whether the spa-
tial variation in poverty, Hispanic ethnicity, and
solar radiation explains the strong pattern of geo-
graphical clustering of mortality from SLE in the
United States, after adjustment for Hispanic ethni-
city and poverty, SLE mortality rates among white
women were 37% higher in regions with the highest
UV-B levels than in regions with the lowest levels.62
Comparable increases in mortality relative to solar
radiation were shown for White and Black men in
this study. However, owing to the association of
seasonality with other factors such as infections,
diet, and vitamin D levels, along with the methodo-
logical study differences, and variations in climate
and racial burden of the populations being
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Ultraviolet radiation and SLE
M Barbhaiya and KH Costenbader
591
evaluated, exact comparisons between these studies
is challenging. While these results are interesting,
they do not point to any specific pattern implicating
latitude or UV radiation in the development
of SLE.
Furthermore, the roles of sunscreen, tanning,
and phototherapy in relation to SLE flares are
also unclear. It is not known whether use of sun-
screen lotion is protective against risk of SLE. In a
retrospective structured questionnaire study of 60
Puerto Rican SLE patients, those who regularly
used sunscreen had significantly less renal involve-
ment, thrombocytopenia, hospitalization, and need
for cyclophosphamide than patients who did not
use sunscreen (p < 0.05).63 Although this study
was limited by its retrospective design and small
sample size, future prospective studies should be
conducted to examine the role of sunscreen. Case
reports of SLE exacerbation after use of indoor
tanning methods (mainly UV-A) exist in the litera-
ture.64 In a study of normal human volunteers
exposed to a standard course of sun-tanning treat-
ments in commercial tanning parlors, alterations in
immune function were noted including decreased
natural killer cell activity, depression of delayed
type hypersensitivity responses to dinitrochloro-
benzene, decreased Langerhans’ cell activity,
reduced lymphocyte counts, and an alteration in
the proportion of T cell subpopulations in
blood.65–67 Recent estimates in the US show that
15.2% of adults reported using indoor tanning in
the past 12 months, most commonly by younger
adults aged 18–29 years.68 Indoor tanning use was
most common among females and non-Hispanic
whites. However, there are no epidemiologic data
concerning indoor or outdoor sun-tanning and risk
of SLE. Despite promising results from epidemio-
logic and randomized controlled trials that suggest
that UV-A1 phototherapy appears to be safe and
effective in patients with SLE,16 given the known
detrimental effects of UV-B radiation on SLE,8,69
further studies are necessary to evaluate the role of
phototherapy in cutaneous and systemic lupus.
Studies of UV radiation and incident SLE
While the link between UV radiation exposure and
SLE exacerbation is more firmly well established,
only few studies suggest an association between UV
radiation and the development of incident SLE. In
a case-control study of consecutive female incident
SLE cases in Sweden, elevated SLE risk was asso-
ciated with a having a history of more than one
serious sunburn before the age of 20 years
(odds ratio (OR) 2.2, 95% CI 1.2–4.1) and
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 Ultraviolet radiation and SLE
M Barbhaiya and KH Costenbader
592
sunburn-susceptible skin type (OR 2.9, 95% CI
1.6–5.1).70 Given that photosensitivity due to SLE
could be present for several years before diagnosis,
this association may be due to reverse causation. In
a Canadian case-control study of 258 patients with
SLE, an association was seen with outdoor work in
the 12 months preceding SLE diagnosis (OR 2.0,
95% CI 1.1–3.8), although there was no association
with total number of years of outdoor work.52 This
study also suggested effect modification by sun
reaction, with the strongest effect among people
who reported reacting to midday sun with a blister-
ing sunburn or a rash (OR 7.9, 95% CI 0.97–64.7);
however, this may have been the result of differen-
tial misclassification of exposure. In contrast, in the
Carolina Lupus Study, a large population-based
study of recently diagnosed SLE patients that
used cumulative months of occupational sunlight
exposure as a proxy for past UV exposure, no over-
all association with SLE risk was observed.29
However, a threefold increased risk (OR 3.1, 95%
CI 0.9–10.8) of SLE was seen among Caucasians
who had the GSTM1 null genotype who had 24 or
more months of occupational sun exposure among.
While this could be a chance finding in a smaller
subgroup, it does suggest that having certain geno-
types may modify the effect of occupational sun
exposure on the risk of SLE in Caucasians.
Challenges relating to UV exposure assessment
One of the major unanswered questions related to a
potential role of UV radiation in the development
of SLE is when the relevant susceptibility window
for UV-B exposure is: in utero, at birth, in child-
hood, adolescence or adulthood. It is also not
known whether UV-B exposure acts as an instant-
aneous hazard, triggering SLE onset very soon
after exposure, or whether SLE risk is more related
to cumulative lifetime exposure. Accurate assess-
ment and quantification of individual exposure to
UV radiation is critical to understanding its poten-
tial role in the etiology of SLE. However, studies to
date have largely relied on subject recall or occupa-
tional categories to quantify past solar UVR expos-
ures. Factors which appear to influence the amount
of UV radiation to which an individual is exposed
largely have been described as dependent upon
three variables including: (1) solar ambient UV
radiation levels, (2) the fraction of ambient UV
exposure received on different anatomical sites,
and (3) behavior and duration of time spent out-
doors.71 Direct estimates of individual exposure to
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UV radiation by measurement using UV radiation
sensitive dosimeters can be challenging to obtain,
whereas indirect measures rely on measurement or
modeling of the three variables mentioned above.
Use of sunscreen lotions with increasing solar pro-
tection factor (SPF) indices in recent years may also
play a role. A recent large prospective study assess-
ing the risk of UV-B radiation on the development
of rheumatoid arthritis utilized the concept of UV-
B flux, a composite measure of mean UV-B radi-
ation level based on latitude, altitude and cloud
cover which is thought to represent ambient expos-
ure better than geographic region.72,73 UV-B flux
has been shown to be associated with risk of skin
cancer, suggesting that it is a reliable proxy for sun
exposure.74
In the current literature on UV radiation risk in
SLE, occupational UV radiation exposure assess-
ment has been largely based upon recall of jobs
held for at least 12 months. However, shorter-
term occupational exposures, sunscreen use, and
recreational sunlight exposure have not been
included, and thus exposure estimates may not
accurately capture actual exposure to sunlight.
Furthermore, reconstruction of lifetime UV radi-
ation exposure relies on employing proxy or indir-
ect measures such as self-report of time spent
outdoors and the use of questionnaires to assess
past UV radiation exposures, which may introduce
recall bias. Although efforts have been made to
develop questionnaires and diary records to facili-
tate more accurate exposure assessment,75,76 pro-
spective cohort studies that combine self-report of
sunlight exposure with dosimetry of sun exposure
or proxy measures such as UV-B flux, along with
biomarkers of genotoxicity, and serial testing of
autoantibodies are needed to further elucidate the
risk assessment related to UV radiation exposure
and the development of SLE. Finally, small
sample sizes and difficulty in measurement of UV
radiation exposure in past studies have limited the
ability to investigate a dose-response relationship
between sun exposure and SLE risk.
Conclusion
The identification of modifiable environmental risk
factors for the development of SLE, such as expos-
ure to UV radiation, would advance our under-
standing of disease pathogenesis and could lead to
strategies to prevent disease, in particular for those
individuals at high risk. Further assessment of the
true geographic and seasonal differences in SLE

incidence and prevalence may also yield important
clues to the etiology of disease, and may shed fur-
ther light on a potential etiologic role for UV radi-
ation. Given the current paucity of prospective
epidemiologic evidence linking UV radiation with
the development of incident SLE, rheumatologists
must await further studies before considering UV
radiation as a risk factor for the development of
SLE in the population. Given that animal and epi-
demiologic studies to date suggest a possible etio-
logic role for UV radiation exposure in the
pathogenesis of SLE, in particular cutaneous
lupus, continued exploration of this potential trig-
ger of SLE through large prospective cohort studies
is warranted. It is challenging to interpret the cur-
rent literature due to methodological difficulties in
assessment of UV exposure, the heterogeneous
nature of SLE, and the fact that photosensitivity
is a common manifestation of SLE and may
develop prior to SLE clinical diagnosis.
Funding
This work was supported by the National
Institiutes of Health (grant number T32
AR055885-06).
Conflict of interest statement
The authors have no conflicts of interest to declare.
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