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Ultraviolet radiation and systemic lupus erythematosus M Barbhaiya and KH Costenbader Lupus 2014 23: 588 DOI: 10.1177/0961203314530488 The online version of this article can be found at: http://lup.sagepub.com/content/23/6/588
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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 Environmental exposures, including infectious agents, cigarette smoking, exogenous sex hormones, silica exposure, hormonal and dietary factors, and ultraviolet radiation, are hypothesized to contribute to the development of systemic lupus erythematosus (SLE).1 The role of ultraviolet (UV) radiation in the development of SLE remains controversial. Although UV radiation exposure may exacerbate pre-existing SLE, it remains unclear whether UV exposure plays a role in the pathogenesis of SLE.2 In experimental studies, UV radiation has a number of immunomodulatory effects, up-regulating Th2 cells and down-regulating Th1 cells, and inducing interleukin-10 production, an anti-inflammatory cytokine, and increased 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 patients with pre-existing SLE. However, it has been suggested that through the stimulation of cutaneous vitamin D synthesis, which has known
Correspondence to: M Barbhaiya, MD Division of Rheumatology, Immunology, and Allergy, PBB-3 Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Email: [email protected]
immunomodulating effects, UV-B radiation could potentially reduce the SLE risk.5–7 Further complicating our understanding of the relationship between UV radiation and SLE, a subset of UV radiation, UV-A, is used as a phototherapy modality to treat cutaneous forms of lupus.8 Based on current literature, strong epidemiologic evidence concerning the role of UV radiation in triggering SLE onset is lacking. The purpose of this article is to review the potential mechanisms whereby UV radiation exposure could be related to SLE risk, review the background epidemiologic evidence suggesting an association between UV radiation and the pathogenesis of incident SLE, and to highlight the need for prospective studies related to the role of UV radiation in the development of autoimmune diseases.
Molecular effects of UV radiation UV radiation consists of three types, including 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 erythemogenic and present in the terrestrial solar spectrum; and UV-C (wavelength range 200–290 nm).9 Given that UV-C is absorbed by the Earth’s ozone layer,
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its effects on human health appear negligible. UVB radiation, on the other hand, may be hazardous to human health by inducing skin cancer, premature 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 cutaneous lupus.8 However, other studies have demonstrated 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 systemic and cutaneous lupus erythematosus.16 In this section, we outline the specific molecular mechanisms 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 mitochondrial oxidative damage, which can result in generation 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 antiinflammatory 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 survival and decreased circulating anti-DNA antibodies, 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-specific immunotolerance.12,24,25 In particular, UV-B radiation induces antigen-specific immunotolerance
12
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 activated, regulatory T cells suppress immune responses by releasing the immunosuppressive cytokine IL-10.25 UV-B radiation may also result in a redistribution 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-transferase-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 overexpression of lymphocyte function associated antigen-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 immunosuppressive agent once metabolized to 1a,25 (OH)2D3, a steroid hormone. Evidence from animal models and prospective studies of RA, multiple sclerosis, and type-1 diabetes suggest an important role for vitamin D as a modifiable environmental factor in autoimmune disease.32,33 Furthermore, various animal models of autoimmunity – including collagen-induced arthritis, type I diabetes mellitus, inflammatory bowel disease, and SLE – have shown significant improvement and even disease prevention with vitamin D treatment.5,33,34 The role of vitamin D in SLE pathogenesis remains controversial, however. In numerous studies 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
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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 activity,38,40,41 whereas others did not confirm this finding.36,37 Furthermore, in a large prospective cohort of women, vitamin D intake from food and supplements did not appear to be associated with risk of SLE.7,42 In SLE patients, various other potential risk factors for vitamin D deficiency exist including avoidance of sun exposure, increased use of photoprotection methods, chronic steroid use, renal involvement, and use of hydroxychloroquine. Thus, it remains unclear whether vitamin D deficiency is a cause or consequence of the disease. As most of the prior studies have been limited by retrospective design and use of semi-quantitative questionnaires evaluating food frequency and supplement intake, as opposed to direct measurement of vitamin D serum levels, at present there is not sufficient evidence to establish a clear relationship 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 immunerelated 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 studies 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
vague, defined by the ACR as ‘a skin rash as a result of unusual reaction to sunlight’.45 The pathophysiology 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 erythematosus. Past studies have reported that nearly 50% of patients with cutaneous lupus developed non-specific inflammatory skin reactions or polymorphic 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 heterogeneous 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 measurement 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 cutaneous lesions induced or exacerbated by exposure to UV radiation.48 It has been shown in several epidemiologic studies 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 disease appears mainly on sun-exposed areas as macular, papular, or bullous lesions as well as classic erythema. SLE flares may also occur and are typically 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 studies 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 incidence of photosensitive rashes in the summer months,53,54 but other studies have shown increased
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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 photoprovocation with UV-A and UV-B in a subset of patients.58 Additionally, a retrospective study evaluating 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 populations 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 differences in the concentration of UV-B radiation.61 UV-B radiation for July showed the highest correlation with SLE mortality rates as compared to poverty level or Hispanic or African lineage, however these results were based on use of a limited dataset(61). In another study assessing whether the spatial variation in poverty, Hispanic ethnicity, and solar radiation explains the strong pattern of geographical clustering of mortality from SLE in the United States, after adjustment for Hispanic ethnicity 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 methodological study differences, and variations in climate and racial burden of the populations being
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 sunscreen 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 involvement, 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 literature.64 In a study of normal human volunteers exposed to a standard course of sun-tanning treatments in commercial tanning parlors, alterations in immune function were noted including decreased natural killer cell activity, depression of delayed type hypersensitivity responses to dinitrochlorobenzene, 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 epidemiologic 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 associated 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 Lupus
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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 blistering sunburn or a rash (OR 7.9, 95% CI 0.97–64.7); however, this may have been the result of differential 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 overall 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 genotypes 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 childhood, adolescence or adulthood. It is also not known whether UV-B exposure acts as an instantaneous hazard, triggering SLE onset very soon after exposure, or whether SLE risk is more related to cumulative lifetime exposure. Accurate assessment and quantification of individual exposure to UV radiation is critical to understanding its potential role in the etiology of SLE. However, studies to date have largely relied on subject recall or occupational categories to quantify past solar UVR exposures. 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 outdoors.71 Direct estimates of individual exposure to
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 protection factor (SPF) indices in recent years may also play a role. A recent large prospective study assessing the risk of UV-B radiation on the development of rheumatoid arthritis utilized the concept of UVB flux, a composite measure of mean UV-B radiation level based on latitude, altitude and cloud cover which is thought to represent ambient exposure 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 assessment has been largely based upon recall of jobs held for at least 12 months. However, shorterterm 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 radiation exposure relies on employing proxy or indirect 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 facilitate more accurate exposure assessment,75,76 prospective 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 exposure to UV radiation, would advance our understanding 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
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incidence and prevalence may also yield important clues to the etiology of disease, and may shed further light on a potential etiologic role for UV radiation. 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 epidemiologic studies to date suggest a possible etiologic role for UV radiation exposure in the pathogenesis of SLE, in particular cutaneous lupus, continued exploration of this potential trigger of SLE through large prospective cohort studies is warranted. It is challenging to interpret the current 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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52 Cooper GS, Wither J, Bernatsky S, et al. Occupational and environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents. Rheumatology 2010; 49: 2172–2180. 53 Amit M, Molad Y, Kiss S, Wysenbeek AJ. Seasonal variations in manifestations and activity of systemic lupus erythematosus. Br J Rheumatol 1997; 36: 449–452. 54 Haga HJ, Brun JG, Rekvig OP, Wetterberg L. Seasonal variations in activity of systemic lupus erythematosus in a subarctic region. Lupus 1999; 8: 269–273. 55 Krause I, Shraga I, Moland Y, Guedj D, Weinberger A. Seasons of the year and activity of SLE and Behc¸et’s disease. Scand J Rheumatol 1997; 26: 435–439. 56 Szeto CC, Mok HY, Chow KM, Lee TC, Leung JY, Li EK. Climatic influence on the prevalence of noncutaneous disease flare in systemic lupus erythematosus in Hong Kong. J Rheumatol 2008; 35: 1031–1037. 57 Schlesinger N, Schlesinger M, Seshan SV. Seasonal variation of lupus nephritis: high prevalence of class V nephritis during winter and spring. J Rheumatol 2005; 32: 1053–1057. 58 Hasan T, Pertovaara M, Yli-Kerttula U, Luukkaala T, Korpela M. Seasonal variation of disease activity of systemic lupus erythematosus in Finland: a 1 year follow up study. Ann Rheum Dis 2004; 63: 1498–1500. 59 Duarte-Garcı´ a A, Fang H, To CH, Magder LS, Petri M. Seasonal variation in the activity of systemic lupus erythematosus. J Rheumatol 2012; 39: 1392–1398. 60 Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 2006; 15: 308–318. 61 Grant WB. Solar UV-B radiation is linked to the geographic variation of mortality from systemic lupus erythematosus in the USA. Lupus 2004; 13: 281–282. 62 Walsh SJ, Gilchrist A. Geographical clustering of mortality from systemic lupus erythematosus in the United States: contributions of poverty, Hispanic ethnicity and solar radiation. Lupus 2006; 15: 662–670. 63 Vila´ LM, Mayor AM, Valentı´ n AH, et al. Association of sunlight exposure and photoprotection measures with clinical outcome in systemic lupus erythematosus. P R Health Sci J 1999; 18: 89–94. 64 Stern RS, Docken W. An exacerbation of SLE after visiting a tanning salon. JAMA 1986; 13: 3120. 65 Hersey P, Haran G, Hasic E. Alteration of T cell subsets and induction of suppressor T cell activity in normal subjects after exposure to sunlight. J Immunol 1983; 131: 171–174. 66 Hersey P, Bradley M, Hasic E, Haran G, Edwards A, McCarthy WH. Immunological effects of solarium exposure. Lancet 1983; 1(8324): 545–548. 67 Hersey P, Magrath H, Wilkinson F. Development of an in vitro system for the analysis of ultraviolet radiation-induced suppression of natural killer cell activity. Photochem Photobiol 1993; 57: 279–284. 68 Buller DB, Cokkinides V, Hall HI, et al. Prevalence of sunburn, sun protection, and indoor tanning behaviors among Americans: review from national surveys and case studies of 3 states. J Am Acad Dermatol 2011; 65(5 Suppl 1): S114–S123. 69 McGrath H, Martinez-Osuna P, Lee FA. Ultraviolet-A1 (340–400 nm) irradiation therapy in systemic lupus erythematosus. Lupus 1996; 5: 269–274. 70 Bengtsson AA, Rylander L, Hagmar L, Nived O, Sturfelt G. Risk factors for developing systemic lupus erythematosus: a casecontrol study in southern Sweden. Rheumatology 2002; 41: 563–571. 71 Vecchia P, Hietanen M, Stuck BE, van Deventer E, Niu S. Protecting workers from ultraviolet radiation. Oberschleißheim, Germany: International Commission on Non-Ionizing Radiation Protection, 2007. 72 Scotto J, Fears TR, Gori GB. Ultraviolet exposure patterns. Environ Res 1976; 12: 228–237. 73 Arkema EV, Hart JE, Bertrand KA, et al. Exposure to ultravioletB and risk of developing rheumatoid arthritis among women in the Nurses’ Health Study. Ann Rheum Dis 2013; 72: 506–511.
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595 74 Fears TR, Bird CC, Guerry DT. Average midrange ultraviolet radiation flux and time outdoors predict melanoma risk. Cancer Res 2002; 62: 3992–3996. 75 Kowk RK, Linet MS, Chodick G, et al. Simplified categorization of outdoor activities for male and female US indoor workers – a feasibility study to improve assessment of ultraviolet radiation
exposures in epidemiologic study questionnaires. Photochem Photobiol 2009; 85: 45–49. 76 Chodick G, Kleinerman RA, Linet MS, et al. Agreement between diary records of time spent outdoors and personal ultraviolet radiation dose measurements. Photochem Photobiol 2008; 84: 713–718.
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Ultraviolet radiation and systemic lupus erythematosus M Barbhaiya and KH Costenbader Lupus 2014 23: 588 DOI: 10.1177/0961203314530488 The online version of this article can be found at: http://lup.sagepub.com/content/23/6/588
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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 Environmental exposures, including infectious agents, cigarette smoking, exogenous sex hormones, silica exposure, hormonal and dietary factors, and ultraviolet radiation, are hypothesized to contribute to the development of systemic lupus erythematosus (SLE).1 The role of ultraviolet (UV) radiation in the development of SLE remains controversial. Although UV radiation exposure may exacerbate pre-existing SLE, it remains unclear whether UV exposure plays a role in the pathogenesis of SLE.2 In experimental studies, UV radiation has a number of immunomodulatory effects, up-regulating Th2 cells and down-regulating Th1 cells, and inducing interleukin-10 production, an anti-inflammatory cytokine, and increased 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 patients with pre-existing SLE. However, it has been suggested that through the stimulation of cutaneous vitamin D synthesis, which has known
Correspondence to: M Barbhaiya, MD Division of Rheumatology, Immunology, and Allergy, PBB-3 Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Email: [email protected]
immunomodulating effects, UV-B radiation could potentially reduce the SLE risk.5–7 Further complicating our understanding of the relationship between UV radiation and SLE, a subset of UV radiation, UV-A, is used as a phototherapy modality to treat cutaneous forms of lupus.8 Based on current literature, strong epidemiologic evidence concerning the role of UV radiation in triggering SLE onset is lacking. The purpose of this article is to review the potential mechanisms whereby UV radiation exposure could be related to SLE risk, review the background epidemiologic evidence suggesting an association between UV radiation and the pathogenesis of incident SLE, and to highlight the need for prospective studies related to the role of UV radiation in the development of autoimmune diseases.
Molecular effects of UV radiation UV radiation consists of three types, including 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 erythemogenic and present in the terrestrial solar spectrum; and UV-C (wavelength range 200–290 nm).9 Given that UV-C is absorbed by the Earth’s ozone layer,
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its effects on human health appear negligible. UVB radiation, on the other hand, may be hazardous to human health by inducing skin cancer, premature 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 cutaneous lupus.8 However, other studies have demonstrated 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 systemic and cutaneous lupus erythematosus.16 In this section, we outline the specific molecular mechanisms 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 mitochondrial oxidative damage, which can result in generation 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 antiinflammatory 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 survival and decreased circulating anti-DNA antibodies, 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-specific immunotolerance.12,24,25 In particular, UV-B radiation induces antigen-specific immunotolerance
12
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 activated, regulatory T cells suppress immune responses by releasing the immunosuppressive cytokine IL-10.25 UV-B radiation may also result in a redistribution 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-transferase-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 overexpression of lymphocyte function associated antigen-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 immunosuppressive agent once metabolized to 1a,25 (OH)2D3, a steroid hormone. Evidence from animal models and prospective studies of RA, multiple sclerosis, and type-1 diabetes suggest an important role for vitamin D as a modifiable environmental factor in autoimmune disease.32,33 Furthermore, various animal models of autoimmunity – including collagen-induced arthritis, type I diabetes mellitus, inflammatory bowel disease, and SLE – have shown significant improvement and even disease prevention with vitamin D treatment.5,33,34 The role of vitamin D in SLE pathogenesis remains controversial, however. In numerous studies 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
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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 activity,38,40,41 whereas others did not confirm this finding.36,37 Furthermore, in a large prospective cohort of women, vitamin D intake from food and supplements did not appear to be associated with risk of SLE.7,42 In SLE patients, various other potential risk factors for vitamin D deficiency exist including avoidance of sun exposure, increased use of photoprotection methods, chronic steroid use, renal involvement, and use of hydroxychloroquine. Thus, it remains unclear whether vitamin D deficiency is a cause or consequence of the disease. As most of the prior studies have been limited by retrospective design and use of semi-quantitative questionnaires evaluating food frequency and supplement intake, as opposed to direct measurement of vitamin D serum levels, at present there is not sufficient evidence to establish a clear relationship 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 immunerelated 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 studies 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
vague, defined by the ACR as ‘a skin rash as a result of unusual reaction to sunlight’.45 The pathophysiology 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 erythematosus. Past studies have reported that nearly 50% of patients with cutaneous lupus developed non-specific inflammatory skin reactions or polymorphic 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 heterogeneous 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 measurement 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 cutaneous lesions induced or exacerbated by exposure to UV radiation.48 It has been shown in several epidemiologic studies 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 disease appears mainly on sun-exposed areas as macular, papular, or bullous lesions as well as classic erythema. SLE flares may also occur and are typically 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 studies 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 incidence of photosensitive rashes in the summer months,53,54 but other studies have shown increased
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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 photoprovocation with UV-A and UV-B in a subset of patients.58 Additionally, a retrospective study evaluating 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 populations 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 differences in the concentration of UV-B radiation.61 UV-B radiation for July showed the highest correlation with SLE mortality rates as compared to poverty level or Hispanic or African lineage, however these results were based on use of a limited dataset(61). In another study assessing whether the spatial variation in poverty, Hispanic ethnicity, and solar radiation explains the strong pattern of geographical clustering of mortality from SLE in the United States, after adjustment for Hispanic ethnicity 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 methodological study differences, and variations in climate and racial burden of the populations being
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 sunscreen 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 involvement, 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 literature.64 In a study of normal human volunteers exposed to a standard course of sun-tanning treatments in commercial tanning parlors, alterations in immune function were noted including decreased natural killer cell activity, depression of delayed type hypersensitivity responses to dinitrochlorobenzene, 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 epidemiologic 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 associated 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 Lupus
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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 blistering sunburn or a rash (OR 7.9, 95% CI 0.97–64.7); however, this may have been the result of differential 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 overall 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 genotypes 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 childhood, adolescence or adulthood. It is also not known whether UV-B exposure acts as an instantaneous hazard, triggering SLE onset very soon after exposure, or whether SLE risk is more related to cumulative lifetime exposure. Accurate assessment and quantification of individual exposure to UV radiation is critical to understanding its potential role in the etiology of SLE. However, studies to date have largely relied on subject recall or occupational categories to quantify past solar UVR exposures. 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 outdoors.71 Direct estimates of individual exposure to
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 protection factor (SPF) indices in recent years may also play a role. A recent large prospective study assessing the risk of UV-B radiation on the development of rheumatoid arthritis utilized the concept of UVB flux, a composite measure of mean UV-B radiation level based on latitude, altitude and cloud cover which is thought to represent ambient exposure 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 assessment has been largely based upon recall of jobs held for at least 12 months. However, shorterterm 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 radiation exposure relies on employing proxy or indirect 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 facilitate more accurate exposure assessment,75,76 prospective 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 exposure to UV radiation, would advance our understanding 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
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incidence and prevalence may also yield important clues to the etiology of disease, and may shed further light on a potential etiologic role for UV radiation. 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 epidemiologic studies to date suggest a possible etiologic role for UV radiation exposure in the pathogenesis of SLE, in particular cutaneous lupus, continued exploration of this potential trigger of SLE through large prospective cohort studies is warranted. It is challenging to interpret the current 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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