ULTRAVIOLET IRRADIATION IN SYSTEMIC LUPUS ERYTHEMATOSUS: FRIEND OR FOE?
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British Journal of Rheumatology 1996;35:1002-1007
CLINICAL REVIEW
ULTRAVIOLET IRRADIATION IN SYSTEMIC LUPUS
ERYTHEMATOSUS: FRIEND OR FOE?
M. R. COHEN and D. A. ISENBERG
Bloomsbury Rheumatology Unit I Division of Rheumatology, Department of Medicine, University College, London
SUMMARY
The long established notion that UV irradiation is always harmful to patients with systemic lupus erythematosus has been
challenged by some recent reports of benefit using a form of phototherapy with UV-A,. In the review we discuss the different
types of UV radiation, the links between certain forms of such radiation and clinical manifestations and consider the mechanisms
involved.
KEY WORDS: Systemic lupus erythematosus, Photosensitivity, Ultraviolet radiation, UV-A, UV-B.
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EXPOSURE to sunlight has long been associated with effects of UV-B radiation, with 30-50% of patients
exacerbation of systemic lupus erythematosus (SLE). developing a skin reaction upon phototesting [12-14].
Photosensitivity occurs in ~ 4 5 % of patients and Systemic disease is induced rarely, perhaps due to the
remains a diagnostic criterion of SLE [1,2]. Photo- small area of irradiation. Patients with a UV-B-in-
induced cutaneous disease appears mainly on sun- voked reaction develop erythema at the phototest site
exposed areas as macular, papular or bullous lesions as 24 h-3 weeks after irradiation, and this can persist
well as classic erythema [3]. Although new lesions may for weeks [15, 16]. Although UV-A may exacerbate
result from exposure to sun or fluorescent light, pre- skin disease, some studies report no effect
existing skin disease is more likely to be aggravated [12, 14, 15, 17-19]. In a study of 20 patients with SLE,
[4, 5]. Systemic flare may occur and is reported as characteristic lesions were reproduced in a quarter of
weakness, fatigue, fevers or joint pain, but this may not those irradiated, mainly with UV-B or UV-B with
be related to more severe overall disease and does UV-A, but in one patient with UV-A alone [14].
not necessarily correlate with physician or laboratory Moreover, a history of photosensitivity does not
parameters of increased disease activity [6]. necessarily predict positive reactions on phototesting.
Photosensitivity results mainly from ultraviolet (UV) One-third of patients with SLE will have no phototest
radiation rather than visible light [7]. UV wavelengths reaction despite a history of photosensitivity, whereas
consist of UV-C (200-290 nm; far UV, germicidal UV), positive phototests may occur in patients with no
UV-B (290-320 nm; midrange UV, sunburn radiation) previous photosensitivity [14].
and UV-A (320-400 nm; near UV, black light) (Fig. 1).
Because UV-C is absorbed by the Earth's ozone layer, PATHOGENESIS OF PHOTOSENSITIVITY
its effects are negligible [3, 5]. Daily exposure to UV-A Amongst the mechanisms that may determine
is much greater than to UV-B, although UV-A-induced photosensitivity following UV irradiation, circulating
erythema in normal skin requires 1000 times more antibodies to the Ro/SSA antigen [ribonucleoprotein
energy than from UV-B [5]. Different photobiological (RNP) particles linked to particular small cytoplasmic
effects from UV-A radiation are thought to be signifi- RNA species] have been associated with photoinduced
cant in the pathogenesis of photoinduced systemic lesions and may confer an increased risk compared to
disease; however, recent studies have shown that longer other antibodies [20,21]. There is no difference,
wavelengths of UV-A, but not UV-B, may be beneficial however, in the frequency of antibodies to Ro/SSA
in SLE and in the photosensitive lupus subset, subacute among patients with positive and negative phototest
cutaneous lupus erythematosus (SCLE) [8-11]. These reactions [15, 18, 21]. Photosensitivity is diagnostic for
surprising findings warrant a re-appraisal of light SCLE and 75% of patients have antibodies to Ro/SSA
exposure, photosensitivity and SLE. antigen, although titres do not correlate with skin
activity [22-24]. This strong association of Ro/SSA
CLINICAL EFFECTS antibody in SCLE has served as a model for
Typically, clinical investigation of photosensitivity is investigation of the immunopathogenic mechanism of
performed by phototesting small areas of skin with UV photosensitivity [25]. In human skin grafted onto nude
radiation. Most studies of SLE have examined the mice, injection of sera having anti-Ro/SSA antibodies,
but not anti-DNA antibodies, resulted in Ro antibody
Submitted 21 November 1995; revised version accepted 19 April
deposition in the skin [26, 27]. UV-B, but not UV-A,
1996. increases the expression and binding of autoantibody
Correspondence to: D. A. Isenberg, Bloomsbury Rheumatology to Ro/SSA and, to a lesser extent, RNP and Sm
Unit, Arthur Stanley House, 40-50 Tottenham Street, London antigens, but not to DNA, while concomitant radiation
W1P9PG. of UV-B with UV-A appears to have no effect on
© 1996 British Society for Rheumatology
1002COHEN AND ISENBERG: UV RADIATION IN SLE 1003
binding [28-30], In contrast, UV-B-irradiated keratin- radiation [42,43]. These proteins may serve as
ocytes from patients with SLE show no association of molecular chaperonins with a role in Ro/SSA
in vitro photosensitivity with a clinical history of translocation, although overexpression of hsp 70
photosensitivity or anti-Ro/SSA antibodies [29]. decreases UV-induced IL-1 and IL-6 release, and
Laboratory studies support a mechanism by which increases cell viability after UV-B irradiation [43].
anti-Ro/SSA antibodies might recognize the normally While prostaglandin production and release may be
intracellular antigen in epidermal cells [25]. Thus, enhanced by UV light, UV-irradiated antibodies to
following UV-B irradiation, keratinocytes become Ro/SSA may contribute to changes in vascular
apoptotic with Ro/SSA antigen expression in discrete dilatation and may increase blood flow [44, 45].
surface blebs which appear to be associated with sites Unlike cutaneous photosensitivity, the pathogenesis
of oxygen modification [31]. Photoinduced epidermal of systemic photosensitivity is not clearly understood,
damage is likely to occur as a result of antibody-de- and may be due to causes other than Ro/SSA
pendent cell-mediated cytotoxicity (ADCC) after autoantibody and ADCC (Fig. 2). In contrast to
autoantibody binding to Ro/SSA antigen, whereby Ro/SSA antigen-antibody binding, the binding of
effector cell attachment to the Fc receptor of the anti-DNA antibodies to DNA is not increased after
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Ro/SSA antibody on keratinocytes results in cell lysis UV-A or UV-B irradiation [46]. UV-B radiation
[32]. Indeed, destruction of basal keratinocytes, those induces thymine dimers as products of DNA damage,
above the dermal-epidermal junction, is a consistent while UV-A induces single-strand DNA breaks
finding in cutaneous lupus and may be particularly [47, 48]. Antibodies to UV-altered DNA (UV-DNA)
prominent in SCLE [32-34]. are increased in sera of patients with SLE compared
With the current knowledge that Ro/SSA exists in with normal controls, but again this does not correlate
several forms, the question of the precise specificity of with a history of photosensitivity [49, 50]. Interestingly,
anti-Ro antibody in this context would be well worth i.v. injection of UV-DNA can result in glomerulo-
examining. Ro/SSA antigen is a system of multiple nephritis (GN) in New Zealand albino rabbits with
polypeptides with different binding properties, and anti-DNA glomerular deposition [51]. Effects of direct
these differ among cell types. The 60 kDa Ro/SSA UV irradiation on animal models of SLE are variable,
antigen has binding sites for RNA and DNA, and may although generally there is increased morbidity and
play a role in transcriptional regulation, while the antibody production [52]. Furthermore, UV effects on
52 kDa antigen may be a DNA-binding protein [35]. cutaneous immune function may contribute to systemic
Clinically, high-titre antibodies to 60 kDa Ro/SSA photosensitivity. UV-induced cytokine production by
antigen have been demonstrated in SCLE patients, keratinocytes may result in systemic inflammation,
while anti-52 kDa Ro/SSA antibodies occurred only in while UV-B can activate a skin-derived mediator,
association with the anti-60 kDa antigen [36]. No cLs-urocanic acid, which results in profound suppres-
increase in 52 or 60 kDa antigen, however, has been sion of systemic cell-mediated immunity [53]. UV-B
reported after UV-B irradiation of keratinocytes, but may affect Langerhans cells (LC) in several ways, e.g.
rather, a selective expression of calreticulin, a 46 kDa by decreasing the number of these cells or changing
peptide bound by some anti-Ro antibodies [37]. their morphology and function, and decreasing their
Yet Ro/SSA antibodies may not be necessary for ability to stimulate T cells, particularly CD4 + T h l , thus
cutaneous damage, particularly in other forms of resulting in unopposed Th2 cell stimulation of B cells
photosensitive lupus with predominantly dermal rather [54,55]. In addition, UV-B-irradiated epidermal
than epidermal damage [16,25]. UV irradiation macrophages activate CD4 + CD45RA + suppressor-in-
triggers TNF-a, IL-1 and IL-6 release, resulting in local ducer cells which results in a predominantly suppressor
inflammation and enhancing ICAM-1 expression on effector T-cell response in circulating lymphocytes [56].
keratinocytes which, in turn, may facilitate cellular That UV-A has different photobiological effects than
interaction, recognition and subsequent cytotoxicity UV-B may be significant in systemic photosensitivity
[25, 38-40]. Similarly, UV irradiation increases E-se- (Table I). Unlike UV-B, UB-A penetrates the dermis
lectin in dermal endothelial cells which may promote and dermal vasculature, and may have a more direct
migration of memory and activated T cells [41]. effect on systemic immunity. Although lymphocytes
Members of the heat shock protein (hsp) 70 family, cultured from patients with SLE showed increased
72 kDa and 70 kDa proteins, are increased by UV susceptibility to UV-B irradiation as well as decreased
uv-c UV-B UV-Aj UV-Ai Vmbte ll^ht
200-290 290-320 320-340 340-400 400-700
1 1 1
200 250 300 350 400 700
Wmvetenjth (mnometen)
Fio. 1.—The spectrum of UV radiation, by wavelength. The diagram is not to scale.1004 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 35 NO. 10
Ro/SSA
antigen antibody
expression — ^ "
translocation
epidermal macrophages
cir-urocanic acid
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Fio. 2.—Diagram of the grouped effects of UV-A and UV-B. The large balloon denotes UV-B, the smaller shows UV-A, with some overlap.
Arrows show presumed cause and effect. ADCC, antibody-dependent cell-mediated cytotoxicity.
DNA repair synthesis, UV-A had either no effect or membrane damage upon subsequent UV-A exposure,
increased DNA repair synthesis [57]. Although UV-B and haem oxygenase 1 and ferritin may mediate this
may be more efficient in causing damage to DNA adaptive response [60].
through direct absorption, UV-A has little effect on
DNA without sensitization or activation of a THE BASIS OF PHOTOTHERAPY
secondary molecule ('chromophore') which forms a The principle of chromophore activation is the basis
DNA cross-linking agent that may inhibit lymphocyte of photochemotherapy, and has been used in the
proliferation [7]. In skin as well as in lymphocytes, investigation and treatment of SLE. Photochemother-
chromophore action is partly mediated by activated apy induces an autoregulatory response in the recipient
oxygen species which may contribute to damage of cell that may deactivate abnormal T-cell idiotypes and alter
membranes or DNA [7, 58, 59]. Splenocytes from SLE T-cell receptor specificity [61-63]. Modification of
murine models appear to be more sensitive to lymphocyte function with UV-A-activated psoralens
UV-A-induced oxidative stress than normal spleno- (PUVA) is the most common form of photochemother-
cytes [8,9]. Interestingly, pre-irradiation of skin apy, but requires direct skin irradiation.
fibroblasts with UV-A results in decreased oxidative Most intriguing is that UV-A alone may be beneficial
without a known chromophore. UV-A irradiation of
(NZB x NZW)F| mice resulted in increased survival
TABLE I and decreased circulating anti-DNA antibodies [64]. A
Comparison of the effects of UV-A and UV-B mechanism for the beneficial effect of UV-A is unclear,
Specific effects UV-A UV-B although it may be due to the absence of a
Location of maximum effect dermis epidermis chromophore and subsequent lack of effect on DNA.
Phototest response mixed positive Furthermore, longer wavelengths of UV-A, UV-A,
Ro/SSA (340-400 nm), do not affect LC function, perhaps
Antigen expression no effect increased
Antibody binding no effect increased
resulting in decreased stimulation of B-cell function
Langerhans cells [65].
Number no effect (UV-A,) decreased
Morphology no effect (UV-A,) altered EFFECTS OF PHOTOTHERAPY
T-cell stimulation no effect decreased In SLE, extracorporeal photochemotherapy (photo-
DNA damage minimal without increased pheresis) has been used in order to avoid potentially
chromophore
Role of Oi radical damage + harmful effects of direct light exposure. Photopheresis
+ + +
Antioxidant response increased unknown of MRL/1 mice and a murine model of lupus-like
DNA repair synthesis increased or decreased graft-versus-host disease resulted in delayed pro-
unchanged gression of autoimmune disease [63,66]. In anCOHEN AND ISENBERG: UV RADIATION IN SLE 1005
uncontrolled trial of photopheresis in eight patients 6. Wysenbeek AJ, Block DA, Fries JF. Prevalence and
with SLE, seven had significant clinical improvement, expression of photosensitivity in systemic lupus eryth-
including decreased joint scores, improved skin lesions, ematosus. Ann Rheum Dis 1989;48:461-3.
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was maintained up to 1 yr after treatment. ultraviolet radiation on microorganisms and animal cells.
In: Biological effects of ultraviolet radiation with emphasis
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SUMMARY clinical disease activity and autoantibodies in patients
with systemic lupus erythematosus. Clin Exp Rheumatol
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