Photosensitivity in Lupus Erythematosus

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Percy Lehmann*

Department of Dermatology, Allergology and Environmental Medicine, HELIOS Klinikum Wuppertal,

University of Witten-Herdecke, Germany

1. Introduction

Lupus erythematosus (LE) represents an autoimmune disease with great clinical variability in which photosensitivity is a common feature for all forms and subsets. Cutaneous LE lesions often arise in sun-exposed areas and it is well reported and recognized that sun exposure may also exacerbate or induce systemic manifestations of this disease (Dubois and Tuffanelli, 1964; Nived et al., 1993; White and Rosen, 2003). The original concept of photosensitivity in LE dates back to the first description by Cazenave (1851) and early observations since the beginning of the 19th century, where the role of environmental factors were related to disease activity and even induction of the disease. Of the different external factors that have detrimental effects on disease activity, the sun's radiation has been best studied. Hutchinson (1888) reported in his Harveian Lectures on Lupus, that patients with LE did not tolerate the sun.

Pusey (1915) described a young lady with LE in which the first lesions appeared after some days of extensive golfing in the summertime. The lesions disappeared after sun avoidance, just to reexacer-bate the next summer after a golf tournament.

*Corresponding author.

Tel.: +49-202-896-5400; Fax: +49-202-896-5332 E-mail address: [email protected] (P. Lehmann).

Freund (1929) reported between 1920 and 1929 the prevalence of LE admissions to his Department of Dermatology in Berlin. He could show a significant increase of LE admissions during the months of May to July and concluded that climatic factors were responsible for this climax of new LE patients.

Additionally to these observations on natural sunlight it also became clear that artificial light sources were also detrimental in LE. Jesionek (1916), a famous German pioneer of phototherapy warned not to apply phototherapy in patients with LE.

The term ''Lupus erythematosus subacutus'' was first described by Fuhs (1929) when he described a patient whose disease broke out after irradiation with an artificial light source. Possibly, this is the first description of the exquisitely lightsensitive subset of LE, nowadays well known as subacute cutaneous lupus erythematosus (Gilliam and Sontheimer, 1982).

Despite those reports, the incidence of photo-sensitivity remained unclear and, therefore, since 1965 (Epstein et al., 1965) phototesting procedures were developed in order to reproduce specific LE lesions by exposure to standardized UV radiation.

In the following years, photosensitivity became a well-established factor in the pathogenesis of LE in clinical and experimental settings and was included as a discriminating factor in the revised criteria of the American Rheumatism organization (ARA) for the classification of systemic LE (SLE).

2. Pathophysiology of photosensitivity in LE

LE represents an autoimmune disease characterized by UV-sensitivity, apoptosis of keratinocytes, and an inflammatory infiltrate in superficial and deep dermal compartments (Casciola-Rosen et al., 1994; Crowson and Margo, 2001; Farkas et al., 2001; McHugh, 2002; White and Rosen, 2003).

Since clinical data, phototesting procedures, and experimental evidence demonstrate the detrimental effects of sun irradiation on LE patients, research on pathogenetic mechanisms of UV-induced LE has become an increasingly dynamic field in the past years, which was additionally supported by the immense progress of the disciplines of photo-immunology and genetics. Initiation and perpetuation of autoimmune responses by UV irradiation have been subjects of extensive in vivo and in vitro studies (Norris and Lee, 1985; Furukawa et al., 1990, 1997; Kuhn et al., 1998a,b, 2005; Lehmann, 2005; Meller et al., 2005). UV irradiation is a well-known trigger of apoptosis in keratinocytes, and there is growing consensus that abnormalities in the generation and clearance of apoptotic material is an important source of antigens in autoimmune diseases (McHugh, 2002; White and Rosen, 2003). Casciola-Rosen et al. (1994) have experimentally demonstrated the clustering of autoantigens at the cell surface of cultured keratinocytes with apopto-tic changes due to UV-irradiation. This localized concentration of autoantigens may be able to break self-tolerance, thus leading to autoimmunity.

Using a standardized photoprovocation protocol our group was able to detect increased numbers of apoptotic keratinocytes in cutaneous LE after UVA and UVB irradiation compared to control subjects (Kuhn et al., 1998). Since the cytokine in-ducible nitric oxide synthase (iNOS) is believed to play an important role in the course of autoimmu-nity and in the regulation of apoptosis (Kolb and Kolb-Bachofen, 1998), we have studied in further experiments the expression of iNOS at the mRNA and protein level in UV-induced LE. The results of this study (Kuhn et al., 1998) demonstrated a delayed iNOS-specific signal after UV irradiation in LE compared to normal controls. These data suggest that kinetics of iNOS and abnormalities in the apoptotic pathway play an important role in the pathogenesis of UV-induced LE.

Furthermore, UV irradiation may cause the formation of molecules by different epidermal and dermal cells. These molecules have the capacity to upregulate (PGE2, ROS, TNF-alfa, IL-1, ICAM1) or downregulate (IL-10, IL-1 receptor antagonist) inflammatory processes. Since genetic regulation is crucial for the induction of these molecules, a putative genetic polymorphism in LE may play an important role in the specific photosensitivity of LE (Von Schmiedeberg et al., 1996). The current genetic data suggest that increased amounts of TNF-alfa that induce apoptosis due to a UV sensitive TNF promoter polymorphism or to decreased clearance of apoptotic cells due to polymorphisms associated with decreased serum levels of collections such as C1q and mannose binding lectin (Bagglioni et al., 1998; Krutmann, 2000; Ronnblom et al., 2002, 2003).

Specific pathogenetic pathways in UV-induced autoreactivity have been demonstrated experimentally. Thus, Furukawa (1997) could demonstrate the cellular redistribution of the Ro antigen in absence of apoptosis upon UV radiation, which enables its presentation to the immune system as a possible first step in the autoimmune cascade. The four step model for the pathogenesis of UV-induced LE by Norris and Lee (1985) based on the translocation of the Ro antigen after UV injury has been widely referred to and agreed upon but, however, this model is limited to the Ro-positive forms of LE such as SCLE and neonatal LE (Kind et al., 1993; Lehmann, 1996, 2005).

The role of UV-irradiation in the induction of cytokine, mediator release and adhesion molecules in epidermis and dermal vessels have also been investigated. Adhesion molecules are not only induced secondary to cytokines, but also directly through transcriptional activation. This activation occurs by the formation of transcriptional factors like activator protein-2 in a singlet oxygen-dependent mechanism (Golan et al., 1994; Grether-Beck et al., 1996). Since there is a link between UVA sensitivity and free radical formation, free radical scavengers may be of special value in order to prevent UV-induced LE lesions (Tebbe et al., 1997; Lehmann and Ruzicka, 2001).

Although the relevant antigen in LE remains unknown, skin-infiltrating activated leukocytes are thought to play a crucial role in the induction and maintenance of this autoimmune disease (Bagglione M, 1998) Furthermore, skin-infiltrating memory T lymphocytes, which display the CD4 phenotype (Tebbe et al., 1995) dominate the inflammatory infiltrate in cutaneous LE.

Plasmocytoid dendritic cells (PDC) accumulate in cutaneous LE lesions, whereas they in systemic LE a decreased number of those cells are found in the peripheral blood. PDCs and their secreted products (interferon-alfa) play a crucial role in the pathogenesis of SLE (Ronnblom and Alm, 2002; Ronnblom et al., 2003). In a recent study our group (Meller et al., 2005) has studied the recruitment and activation pathways of skin infiltrating leukocytes in cutaneous LE. Meller et al. (2005) were able to show that UV irradiation induces the release and production of a distinct set of PDC-and T cell-attracting chemokines. In summary, these data show an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate recruitment and activation of autoimmune T cells and IFN-alfa-producing PDC's, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of LE lesions (Table 1).

Further elucidation of the various different factors which contribute to the UV initiation and perpetuation of LE autoimmunity may lead in future to the development of effective strategies in the prevention of LE induction by sunlight.

According to the present evidence it is conceivable that besides simple photoprotective measures, a further beneficial effect could be achieved by additional use of oxygen scavengers and, i.e., nitric oxide via chemical donors. Since DNA is a

Table 1

Series of published systematic phototesting in LE

primary target for UV insults, a very interesting photoprotection concept includes the addition of DNA repair enzymes into sunscreens (Stege et al., 2000). However, clinical data on this hypothetical treatment strategies for the prevention of UV-induced LE are still lacking.

3. Clinical photosensitivity and phototesting

Despite many anecdotal reports and the obvious clinical evidence showing the clear relationship between sunlight exposure and the manifestation of LE, no systematic studies existed on the photo-reactivity in patients with this disease until the early 1960s.Epstein et al. (1965) were the first to introduce the repeated exposure technique, which made it possible to induce specific LE lesions in 5 of the 25 treated patients by UVB radiation (Table 2).

In the same year, Everett and Olson (1965) demonstrated that 1 minimal erythema dose (MED) of hot quartz UV light exposure produced an increase in the size of skin lesions in patients with DLE. Baer and Harber (1965) administered phototests to 29 patients with LE by applying one to six times the MED of UVB in single exposures to multiple test sites. An abnormal reaction was detected in only one patient with SCLE, and it consisted of a markedly decreased erythema threshold dose and persistence of the erythema for 4 weeks. Wavelengths longer than 315 nm were not evaluated in this study. Freeman et al. (1969) used monochromatic light to determine the wavelength dependency of phototest reactions in 15

Table 2

Series of published systematic phototesting in LE

Table 2

Series of published systematic phototesting in LE

Lehmann et al. (1986,

n=

128

UVB, UVA

1990)

Nived et al. (1993)

n=

23

UVA

Van Weelden et al.

n=

16

UVB, UVA

(1999)

Leenutaphong et al.

n=

15

UVB, UVA

(1999)

Sanders et al. (2003)

n=

100

UVB, UVA

From Lehmann (2005). prolonged test protocol

From Lehmann (2005). prolonged test protocol patients with LE by also applying the repeated UV exposure technique, which became a valuable tool later on for photoprovocation tests in several photosensitive disorders, such as polymorphous light eruption (PLE) (Lehmann et al., 1986). However, the UVA doses used in only a few patients with LE were probably too low for positive photoprovocation reactions. Cripps and Rankin (1973) also used monochromatic light between 250 and 330 nm in an attempt to determine the erythema action spectrum; specific lesions of LE were reproduced in the UVB range by applying 8-13 times the MED. At 330 nm (UVA) only a persistent erythematous response but not LE lesions could be detected. Because of these studies, the action spectrum of LE was ascribed to the UVB range despite experimental evidence from in vitro and animal studies indicating that UVA irradiation also had specific detrimental effects in LE (Doria et al., 1996; Friou, 1957; Sontheimer, 1996; Zamansky et al., 1980). However, the clinical phototesting experiments had shortcomings in that either only a very limited number of patients had been tested or the UVA testing was insufficient (Cripps and Rankin, 1973; Epstein et al., 1965; Freeman et al., 1969; van Weelden et al., 1989).

The description by Gilliam and Sontheimer (1982) of SCLE as a very photosensitive subset marked a major step forward in the photobiology of this disease. Evidence of a role for UV irradiation in the pathogenesis of SCLE came from the observations of patients that sun exposure resulted in lesion formation, the limitation of SCLE lesions to sun-exposed skin, and the predilection for fair-skinned individuals with skin type I or II. The observation that certain photosensitizing drugs, such as thiazide diuretics and sulfonylureas, can induce SCLE is also an indication that sun exposure plays an important role in the pathogenesis of this disease. Further experiments evolving from these clinical results have led to the concept that keratinocytes damaged by antibody-dependent cellular cytotoxicity might be a mechanism in photosensitive LE (Norris and Lee, 1985).

In 1986, our group (Kind et al., 1993; Lehmann et al., 1986, 1990) was the first to demonstrate experimental reproduction of skin lesions by UVB and UVA irradiation using a standardized test protocol on a large number of patients with the disease (Tables 3 and 4). A total of 128 patients with different forms of LE underwent phototesting with polychromatic UVB and long-wave UVA irradiation, and characteristic skin lesions clinically and histologically resembling LE were induced in 43% of patients (Gif. 12.1). Subsequent investigations confirmed UVA reactivity in LE by photo-testing (Nived et al., 1993; Wolska et al., 1989). In the following years, this testing regimen received much attention because the reproduction of skin lesions in patients with LE by UVB and UVA irradiation is an optimal model for clinical and experimental studies (Beutner et al., 1991; Hasan et al., 1997; Kind et al., 1993; Kuhn et al., 1998a, b; Leenutaphong and Boonchai, 1999; van Weelden et al., 1989; Walchner et al., 1997). Meanwhile, provocative phototesting in patients with LE has become routine at our department, and protocols for phototesting have become optimized by taking into account multiple factors. Nonlesional, non-sun-exposed areas of the upper back or extensor aspects of the arms were used for performance of the phototest reactions because other parts of the skin might not react to the same extent, probably

Table 3

Lupus erythematosus Photoprovocation procedure

Table 3

Lupus erythematosus Photoprovocation procedure

Test site:

Back or forearms

Test area:

5 x 8 cm

Irradiation source:

UVASUN 3000 (Mutzhas)

Philips TL 20W/12 (Waldmann)

Dose:

3 x 60-100 J/cm2 UVA

3 x 1.5-fold MED UVB

Readings:

24, 48, 72 h and sometimes up to

3 weeks

From Lehmann (1990).

Table 4

Provocative phototesting In lupus erythematosus n = 432

43% of all lupus erythematosus patients showed a positive test result

For optimal results it is very important to extend the reading up to 14 days and more from Lehmann (2005).

Provocative phototesting In lupus erythematosus n = 432

43% of all lupus erythematosus patients showed a positive test result

For optimal results it is very important to extend the reading up to 14 days and more from Lehmann (2005).

owing to some kind of local predisposion of unknown nature other than UV irradiation, such as thickness of the stratum corneum, vascularization, presence of antigens, or distribution of antigen-presenting cells (Walchner et al., 1997). Furthermore, it is important to use a defined test area, which should be sufficiently large to provide reactions. The initial observable response following exposure to UV irradiation is an erythema reaction that most commonly arises with the normal time course. Although the duration of the erythema was not studied in particular, a prolonged erythema-tous response was not a conspicuous feature.

In contrast to other photodermatoses, such as PLE, the development of skin lesions in patients with LE is characterized by a latency of several days to 3 weeks or even longer, and it might persist in some cases for several months (Kuhn, 2001a; Lehmann, 1996) (Figs. 1a,b, and 2). In addition, phototesting has been crucial in further characterizing a highly photosensitive form of CLE, namely, LE tumidus (LET) (Kuhn et al., 2000; Kuhn et al., 2001b). LET was first described by Gougerot and Bournier (1930) and has since been somewhat 'forgotten' or rarely described and diagnosed. In 1990, Goerz et al. (1990) emphasized for the first

Lupus Rash Characteristics
Figure 1. Photoprovocation tests in SCLE. (a) Left, normal UVA-response. Right: beginning pathological response, 48 h after last phototesting.(b) Right test field: Pathological test-reaction corresponding to photo-induced SCLE, 2 weeks after last phototesting procedure.

50 1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Figure 2. Time course of positive photoreactions of LE compared to polymorpic light eruption. (From Kuhn (2001)).

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Figure 2. Time course of positive photoreactions of LE compared to polymorpic light eruption. (From Kuhn (2001)).

DDLE

Figure 3. Lupus erythematosus subgroups Positive photoprovocations 2004. From Lehmann (2005).

DDLE

Figure 3. Lupus erythematosus subgroups Positive photoprovocations 2004. From Lehmann (2005).

time that extreme photosensitivity is a major characteristic of LET. According to our experience, we regard LET to be an unusual clinical variant of CLE, and skin lesions of LET consist of sharply demarcated, smooth, red-violet, infiltrated plaques with hardly any scaling and no scarring. The lesions usually disappear on therapy with anti-malarials and sun avoidance. It could be shown that this form is even more UV sensitive than SCLE, which until recently, was believed to be the most photosensitive LE subset (Fig. 3). Using a standardized protocol, reproduction of characteristic skin lesions occurred in 76% of patients with LET, 63% with SCLE, 45% with DLE, and 41% with other forms of CLE, such as LE profundus and Chilblain LE (Kuhn et al., 2001).

Results of reported phototesting in patients with LE often differ between various groups because there are numerous technical differences between the studies that could explain the different findings (Beutner et al., 1991; Hasan et al., 1997; Kind et al., 1993; Kuhn et al., 2001; Lehmann et al., 1990; Nived et al., 1993; Van Weelden et al., 1989; Sanders et al., 2003; Walchner et al., 1997; Wolska et al., 1989). Varying factors are light source, energy dose, wavelength, time points of provocation and evaluation, and location and size of the test area. Most studies were conducted in white patients; however, there is one recent article on phototesting in 15 oriental patients with LE using exactly the same test protocol as our group (Leenutaphong and Boonchai, 1999). The incidence of positive phototest reactions in these patients seem to be similar to or a little lower than that in white patients, and there was no correlation between a positive history of UV sensitivity and phototest reactions. However, classification of positive test results might be difficult in some patients because persistent erythema can develop, which is even histologically hard to interpret. It is also unclear why skin lesions cannot always be reproduced under the same conditions several months after the initial phototest and why phototesting results are not positive in all patients with LE tested, providing indirect evidence for variant factors in the pathophysiology of this disease (Fig. 4).

Furthermore, a history of photosensitivity in patients with LE does not necessarily predict positive reactions on phototesting, and results of reported photosensitivity often differ between various groups (Kuhn et al., 2001; Lehmann et al., 2005). This might be because skin lesions after UV irradiation do not develop rapidly after sun exposure, and, therefore, a relationship between sun exposure and exacerbation of LE does not seem obvious to the patient. An additional factor might be age at onset of disease, as observed by Walchner et al. (1997), demonstrating that mainly patients younger than 40 years reported photosensitivity. Furthermore, the occurrence of photosensitivity varies among different types of LE, and some ethnic groups, such as African blacks, seem to be less photosensitive than others. Nevertheless, the term in ''photosensitivity'' (skin

UV-Irradiation

Skin

Apoptotic cells Necrotic cells

Recruitment

Apoptotic cells Necrotic cells

Recruitment

Skin

4

Apoptosis

r

Recruitment t

IFN-

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