Photosensitivity in Cutaneous Lupus Erythematosus

Abstract

Cutaneous lupus erythematosus (CLE) encompasses several different forms including acute, subacute, and chronic manifestations that may or may not occur in the setting of systemic lupus erythematosus (SLE). Ultraviolet radiation (UVR) is a well-known exacerbating factor for CLE, with photosensitivity comprising one of the American College of Rheumatology (ACR) diagnostic criteria for SLE. However, discerning true photosensitivity in this population is difficult due to the broad language utilized by the ACR and the delayed-onset nature of photosensitive lupus lesions. Photoprovocation testing provides a more objective method to measure photosensitivity, but photoprovocation trials demonstrate significantly varying results due to protocol variations. Despite UVR’s deleterious effect on lupus patients, UVA-1 may have therapeutic benefits as shown by some observations on murine and human lupus subjects. Accurately discerning photosensitivity has diagnostic implications for SLE and provides motivation for greater patient adherence to photoprotective measures.

Introduction

Cutaneous lupus erythematosus (CLE) has traditionally been sub-divided into acute, subacute, and chronic forms, according to the 1981 Gilliam and Sontheimer classification (1). Further distinctions have been made regarding chronic forms, such as discoid lupus erythematosus (DLE), lupus tumidus (LET), lupus panniculitis/profundus, and chilblain lupus, among others.

Population incidence measures show that approximately 4.3 per 100,000 are affected with CLE, and nearly two-thirds of patients meeting the diagnostic criteria for SLE will also have cutaneous manifestations of their disease. DLE remains the most common form of CLE, comprising over 75% of cases (2). While acute cutaneous lupus erythematosus is most frequently associated with active systemic disease, up to 17% of those presenting with DLE may eventually develop SLE (3).

For those with CLE, photosensitivity is a well-documented symptom in which ultraviolet radiation (UVR) is a major exacerbating factor in cutaneous lesion development. This increased risk of developing lesions due to UVR results in a profound impact on work-related disability and quality of life (4–6). Furthermore, investigations into photosensitive-positive patients have shown correlations with worsened disease activity (7). Patient understanding of the role UVR plays in the course of their disease is of importance in taking adequate photoprotective counter-measures to prevent or reduce the extent of their cutaneous manifestations.

This review will focus on: 1) the pathogenic roles that UVR has in instigating CLE lesions, 2) prior studies investigating photosensitivity in CLE patients by history and photoprovocation tests, 3) recommended photoprotective measures for CLE patients, and 4) UVA-1 treatment in systemic lupus.

Ultraviolet radiation and lupus

The association of UVR and cutaneous lesions in lupus has since spurred investigations into the possible pathophysiology behind this phenomenon. While the mechanisms of CLE continue to be elucidated, it is believed to be the manifestation of similar pathologic mechanisms involved in systemic disease with autoantibodies and immune complexes causing tissue damage. UVR promotes development of cutaneous lesions by augmenting lymphocytic recruitment and antibody-mediated cytotoxicity. Assessment of both ultraviolet-A (UVA) (320–400 nm) and ultraviolet-B (UVB) (290–320 nm) radiation suggest that each contributes via different mechanisms towards promoting cutaneous lesion development (Figure 1).

Figure 1.

Mechanisms of UVA and UVB radiation in cutaneous lupus. UVA and UVB have both distinct and overlapping actions in cutaneous damage contributing to CLE lesion development. UVB has wide-ranging effects on both cellular signaling through cytokines and chemokines and direct cellular damage. UVA also causes direct DNA damage and induces apoptosis and impaired immune function through ROS generation.

Abbreviations: ICAM – intracellular adhesion molecule; ROS – reactive oxygen species; UVA-ultraviolet-A; UVB – ultraviolet-B; UVR – ultraviolet radiation; VCAM – vascular cellular adhesion molecule

UVB causes keratinocyte apoptosis by damaging DNA via strand breaks and pyrimidine dimer formation. Though prior results have shown some conflicting reports, enhanced keratinocyte apoptosis in lupus patients has been observed in skin biopsy samples and in vitro cultures after UVB radiation, suggesting an increased susceptibility of keratinocytes to UVB damage and defective clearance over healthy skin (8, 9). UVB is also thought to play other pathologic roles via modulation of immunologic function and recruitment and attraction of inflammatory cells. More specifically, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), intracellular adhesion molecule-1 (ICAM-1), and histocompatability class II molecules (e.g. HLA-DR) expression in the skin have all been noted to be augmented by UVB exposure (9–11). Other studies have suggested the enhanced translocation of lupus autoantigens to the cell surface of apoptotic keratinocyte blebs, aiding autoantibody exposure to these autoantigens, which are normally sequestered intracellularly (12, 13).

In contrast, longer wavelength UVA radiation achieves penetration into the deeper dermis and plays a role in keratinocyte apoptosis via mitochondrial oxidative damage (14). Generation of excess ROS and the resulting oxidative damage are believed to be the mechanisms behind the molecular alterations causing cellular dysfunction. In hairless mice testing, UVA damage depletes cutaneous catalase and glutathione reductases, causing membrane lipid peroxidation via lipid peroxide generation (15). Other pro-inflammatory effects are seen with UVA-induced damage. Pro-inflammatory cytokines such as IL-1α/β and IL-6 are elevated following UVA exposure (16). Similar to UVB, cyclobutane pyrimidine dimer formation is also seen (17). UVA augments the binding of autoantibodies to keratinocyte surfaces, though to a lesser degree compared to UVB sensitization. UVA was initially not thought to be part of the action spectrum of CLE since photoprovocation in a manner similar to UVB did not result in lesions (18). However, other studies have since demonstrated UVA exposure inducing CLE lesions (19–22).

Photosensitivity in lupus patients

Photosensitivity covers not only skin disease flares but also systemic symptoms such as fatigue and arthralgias (23). Thus, in addition to skin symptoms (e.g. rash, tingling), we recommend providers to ask questions about fatigue and arthritis occurring after extensive sun exposure. Whether noted from patient history or physician observation, photosensitivity remains one of the 11 diagnostic criteria for SLE as determined by the 1982 American College of Rheumatology (ACR) guidelines (24). With reported rates of photosensitivity ranging from 27–100% for SCLE, 25–90% for DLE, and 43–71% for LET (25), CLE demonstrates a clear link with photosensitivity. However, the wide variability of reported rates underscores the inconsistent methods of detecting photosensitivity. Much of the problem lies in the lack of a precise definition of photosensitivity. The ACR has defined photosensitivity as “a skin rash as a result of unusual reaction to sunlight” (24). This description has been subject to varying interpretations, resulting in the potential inclusion of patients who may have other skin disease such as polymorphous light eruption (PMLE) and dermatomyositis. It has also been shown that lupus patients can develop non-CLE lesions from UVR exposure. One study showed 49% of lupus patients likely have PMLE after UVR exposure rather than CLE (25). Moreover, Hasan et al found that 53% of the biopsied positive phototesting skin samples in lupus patients indicated non-specific inflammatory reactions or PMLE-like histology (20). Those that had positive lupus histology correlated well with having long-lasting reactions (e.g. >3 weeks) (20). Therefore, providers can better distinguish PMLE-like and LE-like reactions by asking about the duration of these lesions after prolonged sun exposure. A short duration of hours to few days would imply PMLE, whereas a longer duration of weeks would make CLE more likely.

Moreover, several photoprovocation studies have clearly demonstrated that the onset of true photosensitive reactions is often delayed, with one study reporting 78% of reactions occurring greater than one week after phototesting (26) and another showing the average onset occurring at eight days (10). In fact, positive reactions have been observed up to three weeks after phototesting (26). Thus, because patients may not consider flares that occur days to weeks after extended sun exposure, we encourage providers to ask patients about flares that happen up to three weeks after being outside for an extended period.

Based on previous literature findings, we propose the definition for photosensitivity to be the presence of a skin rash suggestive of cutaneous lupus and/or systemic symptoms such as fatigue or arthritis occurring up to 3 weeks after extensive sun exposure and lasting at least for several days or even weeks. Large prospective studies need to be conducted to validate this statement.

Photoprovocation testing in lupus patients

UVR phototesting of lupus patients stems from experience with natural lesion exacerbation with sunlight exposure. As an objective tool to evaluate photosensitivity, phototesting in lupus patients began in the 1980s when Lehmann et al first documented positive reactions following controlled UV exposures in lupus patients (27). Lehmann attempted to create more standardized criteria for determining positive photoreactivity by requiring 1) induced lesions that clinically resemble lupus, 2) histopathological findings consistent with lupus, and 3) skin lesions that develop slowly and persist for at least several days (28). However, despite efforts to better define photoreactivity, significant areas of protocol design were not standardized. This has resulted in varying phototesting results in different photoprovocation studies, which are summarized in Table 1 (10, 18–22, 26, 28–30). Aspects of phototesting including schedule of administration, fluences, locations irradiated, size of test sites, light source, and follow-up intervals varied among these studies. Thus, because of these protocol differences, direct comparisons between studies have been difficult to conduct.

Table 1.

CLE Photoprovocation Studies

			Lupus Subtype				(+) Photoreactivity
Year	Author	Reactive Subjects/ Total #	DLE	SCLE	SLE	LET	UVA	UVB		Dosing Regimen & Schedule
1989	Wolska et al (18)	49/202 (24%)	18/111 (16%)	15/24 (63%)	16/67 (24%)	–	–	49/202 (24%)	UVA UVB	3 J/cm2 × 1 day 1–2 MED × 1 day
1989	van Weelden et al (19)	20/24 (83%)	7/9 (78%)	7/8 (88%)	6/7 (86%)	–	10/24 (42%)	20/24 (83%)	UVA UVB	Started at 2 MED/day × max 6 days‡ Started at 2 MED/day × max 6 days‡
1990	Lehmann et al (28)	55/128 (43%)	36/86 (42%)	14/22 (64%)	5/20 (25%)	–	*	*	UVA UVB	100 J/cm2/day × 3 days AND 1.5 MED/day × 3 days
1991	Beutner et al (29)	110/139 (79%)	38/54 (70%)	35/35 (100%)	37/50 (74%)	–	–	110/139 (79%)	UVB	2 MED/day × 1 day
1997	Hasan et al (20)	46/67 (69%)	32/50 (64%)	7/7 (100%)	7/10 (70%)	–	28/51 (55%)§	44/67 (66%)	UVA UVB	20–80 J/cm2/day × 3 days OR q2–3 days × 5–6 doses‡ 1–3 MED/day × 3 days OR q2–3 days × 5–6 doses‡
1999	Leenutaphong et al (21)	6/15 (40%)	4/9 (44%)	–	2/6 (33%)	–	2/15 (13%)	5/15 (33%)	UVA UVB	100 J/cm2/day × 3 days 1.5 MED/day × 3 days
2001	Kuhn et al (10)	175/323 (54%)†	33/74 (45%)	40/63 (63%)	12/20 (60%)	47/62 (76%)	110/323 (34%)	137/323 (42%)	UVA UVB	Started at 2 MED/day × max 6 days‡ Started at 2 MED/day × max 6 days‡
2003	Sanders et al (26)	93/100 (93%)	41/46 (89%)	30/30 (100%)	22/24 (92%)	–	*	*	UVA UVB	Started at 2 MED/day × max 6 days‡ AND Started at 2 MED/day × max 6 days‡
2011	Kuhn et al (22)	16/25 (64%)	1/5 (20%)	2/3 (67%)	–	13/17 (76%)	*	*	UVA UVB	60–100 J/cm2/day × 3 days AND 1.5 MED/day × 3 days
2011	Kuhn et al (30)	22/47 (47%)	7/20 (35%)	8/14 (57%)	–	7/13 (54%)	*	*	UVA UVB	MTD/day × 3 days AND 1.5 MED/day × 3 days

Abbreviations: DLE – discoid lupus erythematosus; LET – lupus erythematosus tumidus; MED – minimal erythema dose; MTD – minimal tanning dose; SCLE – subacute cutaneous lupus erythematosus; SLE – systemic lupus erythematosus; UVA – ultraviolet A; UVB – ultraviolet B.

^*Combined UVA+UVB photoprovocation

^‡Dose varied depending on previous dose reaction (modified repeat exposure technique)

^†104 with various other forms of LE

^§16 subjects not phototested with UVA

However, a recent European multi-center photoprovocation study of cutaneous lupus patients using a similar protocol demonstrated reproducibility in the phototesting results across seven different sites. In this study, 47 CLE and 13 normal subjects underwent three consecutive days of minimal tanning dose (MTD) for UVA and 1.5 × minimal erythema dose (MED) of UVB. 47% of CLE subjects and none of the normal subjects had lesions induced by phototesting, with 86% of them being histologically consistent with CLE. Minimal side effects were reported in this study (30). The ability of these investigators to successfully reproduce their photoprovocation protocol across multiple sites imply that this procedure could be potentially implemented universally.

Phototesting results have not correlated well with patients’ and physicians’ subjective assessments of photosensitivity. Kuhn et al demonstrated those reporting a positive history with photosensitivity had a 62% concordance with positive photoprovocation testing, while those with a negative history had nearly the same rate of positive photoprovocation tests at 58% positive (10). Moreover, 44 SLE patients and 31 normal controls were questioned about photosensitivity and received phototesting. 57% and 79% were considered photosensitive by both questionnaire and phototesting, respectively, with poor agreement in SLE patients (κ=0.01) (31).

Photoprotection for lupus patients

Photoprotection remains the primary method to reduce photosensitivity in lupus patients. This consists of education on the association of UVR exposure with cutaneous symptoms and counseling on sunlight exposure reduction methods. Physicians should encourage sun avoidance during the hours between 10 AM to 4 PM. Patients can use a broad-spectrum sunscreen with a minimum sun protective factor (SPF) of 30 on a daily basis, even on cloudy days. Sunscreen should be reapplied every two hours and after swimming or excessive sweating. Tight woven clothing and wide brimmed hats can also be used to block out UVR.

Controlled trials of photoprovocation comparing sunscreen-protected skin versus unprotected skin show striking differences in cutaneous reactions, which stresses the importance of photoprotection in lupus patients. A recent randomized, vehicle-controlled, double-blinded photoprovocation study assessing sunscreen efficacy in preventing photosensitive cutaneous lupus reactions showed a reduction in skin lesions from 64% and 56% of the untreated and vehicle-only treated skin patches, respectively, to none in the sunscreen-protected patches (22).

In addition to the traditional methods of sun protection, anti-malarials, which are first-line oral treatments for CLE patients, may also have photoprotective properties. A trial investigating 43 SLE patients and 32 controls taking chloroquine found that MED increased, and post-UVB erythema decreased after chloroquine use. It was postulated that this could be due to chloroquine’s ability to decrease cytokine levels such as TNF-α and inflammatory cells (32).

While adequate photoprotection is an important measure in helping to control symptomatic CLE, CLE patients are at risk for deficiency in vitamin D, whose levels could further decrease with chronic corticosteroid use. Assessments of 25-hydroxyvitamin D levels in patients with CLE have been found to be significantly lower than controls, particularly in those with lighter skin (33, 34). Providers should be encouraged to address concerns of vitamin D insufficiency to maintain adherence to photoprotection. The Endocrine Society Clinical Practice Guidelines advocates vitamin D screening of populations at risk for deficiency. Testing is currently recommended using serum circulating 25-hydroxyvitamin D levels with the suggestion all deficient adults be treated with 50,000 IU vitamin D₂ or D₃ once a week for 8 weeks (35). Alternatively, the current Institute of Medicine recommendation for daily vitamin D intake is 600 IU for those between 1–70 years, and 800 IU for those older than 70 years (36).

UVA-1 therapy for lupus patients

Despite the conventional understanding that UVR is a major trigger of CLE, promising data exists on the potential effects of UVA-1 therapy in SLE patients. While producing wavelengths between 340 and 400 nm, UVA-1 phototherapy devices have evolved over the years. Early implementation UVA-1 light sources generate infrared radiation that results in increased heat production. Several of these trials fit UVA-1 emitting fluorescent tubes in either canopy sunbeds or specially constructed cabinets (37, 38). The fluorescent tubes were also either coated with strontium borate phosphor or used in conjunction with UVASUN-pink filters to screen out other wavelengths (37–39). Newer models with higher intensity metal halide bulbs contain novel cooling systems and blue lights that reduce heat and increase patient comfort (40, 41). The anti-inflammatory effects of UVA-1 are thought to be related to T and B cell apoptosis through the production of singlet oxygen species and superoxide anions (42). UVA-1 also can reduce levels of IL-4, IL-10, and interferon (IFN)-γ (43).

The potential for UVA-1 treatment in SLE originated from a study showing that UVA-treated lupus-prone NZB/NZW F1 mice had better rates of survival, decreased anti-DNA antibody production, and augmented lymphocyte responses to foreign antigens compared with untreated mice (44). UVA-1 radiation in lupus-prone MRL-lpr mice also prevented development of CLE-like skin lesions (45). Based on these findings, UVA-1 was tested in SLE patients in varying dosing regimens in case report, open-label, and randomized control trial settings (Table 2) (37–41, 46–50). In these trials, UVA-1-treated patients demonstrated decreased systemic symptoms and disease activity scores (e.g. SLE disease activity index [SLEDAI], systemic lupus activity measure [SLAM] scores), and minimal adverse events. Improvement in other areas such as neurological symptoms, pulmonary function, and cutaneous lesions was also reported. These trials also reported clinical improvement in two subacute cutaneous lupus (SCLE) patients using subjective measures (40, 48). Decreased levels of circulating T_H1 and T_C1 cells in UVA-1-treated SLE patients suggest a potential mechanism of action, as these cells produce IFN-γ, which has been implicated in SLE pathogenesis (18). Increased apoptosis of skin-infiltrating white blood cells has also been reported following UVA-1 radiation (51). Furthermore, attenuated B-cell immunoglobulin production and lower anti-dsDNA titers were found with UVA-1 exposure in vitro (52).

Table 2.

UVA-1 Radiation Trials for Lupus Patients

Year	Author	N	Study Type	UVA-1 Regimen	Comments
1993	Sönnichsen et al (46)	1	Case report	186.1 J/cm2 over 9 weeks	Clinical improvement in a 71 y.o. female with SCLE having contraindications to corticosteroid and immunosuppressive therapy
1994	McGrath et al (47)	15	Open-label	6.5 J/cm2/day: 5 days/wk × 3 weeks	Disease activity scores decreased
1994	McGrath et al (48)	10	Open-label	6 J/cm2/day: 5 days/wk × 3 weeks	Disease activity scores decreased, and one SCLE patient’s skin lesions improved
1996	McGrath et al (37)	26	DB-RCT (cross-over)	6 J/cm2/day: 5 days/wk × 3 weeks (or visible light)	SLAM scores & dsDNA autoantibodies significantly decreased with UVA-1 radiation group
2001	Polderman et al (40)	11	DB-RCT (cross-over)	6 J/cm2/day: 5 days/wk × 3 weeks (or visible light)	SLAM & SLEDAI scores decreased in both groups, but no significant difference between groups
2003	Menon et al (38)	1	open-label (case report)	16 J/cm2/day: 3 days/wk × 24 weeks (minus 12–14)	Clinically significant improvement seen by week 2–3 of UVA-1 treatment, brain function improvement on PET paralleled reversal of cognitive dysfunction
2004	Polderman et al (41)	12	DB-RCT (cross-over)	12 J/cm2/day: 5 days/wk × 3 weeks	SLAM & SLEDAI scores significantly decreased in UVA-1 group vs. placebo group, one SCLE patient’s skin lesions improved
2005	Szegedi et al (39)	9	Open-label	6 J/cm2/day: 5 days/wk × 3 weeks, then 3 days/wk × 3 weeks then 4 days/wk × 3 weeks	SLEDAI scores declined significantly, decrease in IFN-γ producing TH1 and TH2 cells, decreased ratio of TH1:TH2 and TC1:TC2
2005	McGrath (49)	1	Case report	10 J/cm2/day: 2 days/wk × 30 weeks	Elimination of anticardiolipin antibodies and termination of cognitive decline in SLE patients
2010	Jabara et al (50)	1	Case report	8 J/cm2/day: 2 days/wk × 5 years	Incidental improvement of interstitial lung disease and pulmonary hypertension

Abbreviations: DB-RCT – double-blinded randomized control trial; SCLE – subacute cutaneous lupus erythematosus; SLAM – systemic lupus activity measure; SLEDAI – SLE disease activity index

Despite these promising results, UVA-1 radiation in SLE patients is not a common therapeutic modality. UVA-1 radiation is offered in a limited number of dermatology offices, and providers are wary of the risk of potential lupus flares, given the previous data on UVA radiation exacerbating CLE lesions (19–22). However, the introduction of small mobile low-dose UVA-1 units and larger randomized controlled trials that demonstrate efficacy would aid in promoting UVA-1 treatment in lupus patients.

Conclusions

Cutaneous manifestations of lupus pose significant difficulties for affected individuals with photosensitivity having a considerable impact on their quality of life (7). Despite the well-known association of lupus with UVR exposure, varying results from multiple investigations into photosensitivity have underscored the challenge in accurately assessing for photosensitivity in lupus patients. Self-patient reporting, which tend to miss delayed onset of lesions after sun exposure, and the broad definition of photosensitivity per the ACR guidelines play roles in confounding accurate reporting. Providers can help improve detection of photosensitivity by asking about duration of flares, flares occurring up to three weeks after prolonged outdoor time, and other extracutaneous symptoms such as fatigue and arthralgias. Phototesting has been shown to be a more objective standard to measure photosensitivity. While standardized protocols will likely improve consistency of results, cost and time are limiting factors that could prevent universal use of this method. Nonetheless, optimizing methods of detecting photosensitivity in lupus patients will improve our ability to diagnose SLE, motivate patients to adhere better to photoprotective measures, and reduce disease flares. UVA-1 studies, to date, may suggest possible therapeutic benefits in lupus patients. However, as the data is derived mainly from animal experiments, case reports, or small clinical trials, larger randomized controlled trials will be needed in verifying its efficacy in lupus patients.

Summary Statement.

Photosensitivity, in which exposure to ultraviolet radiation (UVR) can exacerbate skin lesions, is widespread in cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) patients. Because of variations in history taking and phototesting protocols, accurate accounting of photosensitivity rates in this population has been difficult to attain. We present a review on photosensitivity in CLE to help clinicians understand the difficulties in evaluating photosensitivity in these patients. We also provide recommendations for improving detection of photosensitivity by patient history and for photoprotection, and a review on the potential treatment of ultraviolet A-1 in CLE.

Abbreviations

ACR

American College of Rheumatology

CLE

cutaneous lupus erythematosus

DLE

discoid lupus erythematosus

ICAM

intracellular adhesion molecule

IFN

interferon

IL

interleukin

LET

lupus erythematosus tumidus

SLEDAI

systemic lupus erythematosus disease activity index

MED

minimal erythema dose

MTD

minimal tanning dose

PMLE

polymorphous light eruption

SLAM

systemic lupus activity measure

SLE

systemic lupus erythematosus

TNF

tumor necrosis factor

UVA

ultraviolet-A

UVB

ultraviolet-B

UVR

ultraviolet radiation