EPIDEMIOLOGY AND
PATHOGENETIC MECHANISMS
OF POLYMORPHIC LIGHT ERUPTION
The research described in this thesis was done at the department of dermatology, Leids Universitair Medisch Centrum, Leiden.
The studies described in this thesis were financially supported by the European Framework V program (project grant no. QLK4-CT01-0015).
Publication of this thesis was financially supported by Astellas Pharma Netherlands, Fagron BV, Galderma Nederland, Leo Pharma BV, Mölnlycke Health Care BV, Schering- Plough BV, Serono Benelux BV, Wyeth Pharmaceuticals BV, Firma Oldekamp, GlaxoSmithKline, Vichy, Louis Widmer and Beiersdorf.
Epidemiology and pathogenetic mechanisms of polymorphic light eruption Thesis, Rijksuniversiteit Leiden, the Netherlands
Copyright © 2008, Artiena Soe Janssens, the Netherlands
No part of this thesis may be reproduced, stored or transmitted without prior permission of the author.
ISBN 978-90-8891-0258
EPIDEMIOLOGY AND
PATHOGENETIC MECHANISMS OF POLYMORPHIC LIGHT ERUPTION
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus
prof. mr. P. F. van der Heijden,
volgens het besluit van het College voor Promoties te verdedigen op donderdag 17 januari 2008
klokke 15:00 uur
door
Artiena Soe Janssens
geboren te Seoul, Zuid-Korea in 1973
Promotiecommissie
Promotor prof. dr. R. Willemze Co-promotores dr. S. Pavel
dr. F. R. de Gruijl
Referent prof. dr. R. Roelandts (Katholieke Universiteit Leuven, België) Overige leden prof. dr. F. H. J. Claas
prof. dr. R. G. J. Westendorp
Voor Sarah
List of abbreviations
CD1a cluster of differentiation 1a
CDLE cutaneous discoid lupus erythematosus ELISA enzyme-linked immuno sorbent assay ICAM-1 intercellular adhesion molecule-1 IL interleukin
IL-1Ra interleukin-1 receptor antagonist LC Langerhans cell
MCP-1 monocyte chemotacting protein-1 MED minimal erythema dose
MIP-1 macrophage inflammatory protein-1 PBS phosphate buffered saline
PLE polymorphic light eruption
PLESS polymorphic light eruption severity score
RANTES regulated on activation, normal T expressed and secreted SLE systemic lupus erythematosus
SCLE subacute cutaneous lupus erythematosus SSR solar simulated radiation
TNF-α tumor necrosis factor-alfa UV ultraviolet
UVA ultraviolet A UVB ultraviolet B
Contents
Chapter 1 Introduction Chapter 2
Lifetime prevalence and characteristics of the ‘sun-allergy’ polymorphic light eruption in Europe
Chapter 3
UVB-induced leukocyte trafficking in the epidermis of photosensitive lupus erythematosus patients: normal depletion of Langerhans cells
Chapter 4
Normalised UV induction of Langerhans cell depletion and neutrophil infiltrates after artificial UVB hardening of patients with polymorphic light eruption
Chapter 5
Reduced IL1-Ra/IL-1 ratio in UVB-exposed skin of patients with polymorphic light eruption
Chapter 6
Susceptibility to UVA and UVB provocation does not correlate with disease severity of polymorphic light eruption
Chapter 7
Summary and discussion Appendices
Nederlandse samenvatting Curriculum vitae
Publicaties Dankwoord
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27
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51
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105 106 111 112 113
1
Introduction
Chapter 1
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Introduction
The research described in this thesis was initiated in 2002, when our group became member of the so-called SUNALL consortium. This was a multidisciplinary group of scientists from six different European countries interested in the pathogenesis of polymorphic light eruption (PLE). The scientific collaboration was funded by the European Commission. The main goal of the joint projects was to shed more light on pathogenetic mechanisms of PLE, but also to provide epidemiologic data, clues on mechanisms of (photo-) therapies and tools to improve diagnosis. A prerequisite was that all parties agreed on a definition of the studied subject. The clinical members of the SUNALL consortium reached consensus that polymorphic light eruption (PLE) is primarily a recurrent pruritic eruption comprising papules and/or vesicles and/or plaques, which occur on sun exposed skin sites, and which heal without scarring. We agreed to include patients with a classical history of PLE who also had positive ANA antibodies. However, the presence of antibodies against SSA and SSB was accepted as an exclusion criterion. Eczematous sun-induced lesions were not regarded as PLE.
In this introduction, recent insight into epidemiology, pathogenetic mechanisms, photo provocation procedures, differential diagnostic aspects and treatment of PLE are discussed, and questions addressed in this thesis are formulated.
Epidemiology
The term polymorphous light eruption was first used by the Dane Rasch in 1900. 1 Before that time, several names were used to describe this idiopathic photodermatosis, such as eczema solare, summer prurigo, summer itch, solar dermatitis and benign summer eruption. PLE is the most common idiopathic photodermatosis. Epidemiological data on PLE are sparse, but the prevalence is estimated to be around 10-20% in the USA, England and Ireland. 2
The male/female ratio varies between 1:2 and 1:4 and the disease occurs preferentially in young women. Underlying genetic and/or hormonal differences together with the difference between women and men in seeking medical attention for dermatological problems seem to be likely causes of this gender difference. 3 A contributing role of the female sex hormone 17-oestradiol has been investigated to explain the gender differences of PLE. The role of 17-oestradiol on immunosuppression and contact hypersensitivity (CHS) caused by ultraviolet B (UVB) irradiation, was investigated in male mice intraperitoneally injected with the hormone and in female mice treated with anti-estradiol. 4 The results suggested that 17-oestradiol prevented UVB-induced suppression of the CHS response caused by lower concentrations of immunosuppressive cytokines (IL-10) produced by keratinocytes. Hormonal contraceptives can induce photosensitivity and are very widely used by women. These hormones could, as an exogenous factor, contribute to this female dominated prevalence of PLE. 5;6
Two studies based on interviews, conducted in the USA by Morison and Stern and in Sweden by Ros and Wennersten, have made clear that only 3-15 % of the responders with a history consistent of PLE, sought medical attention. 7;8 These surveys indicate that the prevalence of PLE is probably much higher than normally reported. PLE has a wide geographical distribution and it is believed to be more frequent in temperate than tropical climates. 9 In another epidemiological study, the prevalence and clinical characteristics of polymorphic light eruption were assessed by a questionnaire survey among 172, 196 and 182 subjects in Perth, Ballarat and London, respectively. The prevalence was 5.2% in Perth (latitude 32 degrees), 3.6% in Ballarat (37.5 degrees) and 14.8% in London (51.5 degrees). The age of onset (mostly diagnosed in the first three decades) and male/female ratio (1:3) were similar in all three areas. Development of tolerance during the summer was more common in Perth (66.7%) and Ballarat (71.4%) than in London (40.7%). 9
PLE is mainly a disease affecting the fair-skinned population. It is also believed that PLE occurs mainly in UV-unadapted skin. A study conducted among tourists visiting Hawaii illustrated that the cutaneous disorders of the Caucasian island visitors differed significantly from those observed in the local population. In the visitor group, over one-third of the diagnoses were light-induced conditions. The most common disease observed was the papulovesicular variant of polymorphous light eruption. 10 In another 10-year study conducted in Nigeria, light-sensitive dermatoses appeared not to be common among the black people. Only 64 cases (about 0.4% of all dermatological patients) had light-sensitive dermatoses. Two patients with polymorphic light eruption were visiting Caucasians. 11
Outline 1
To improve on the available epidemiological data, the SUNALL consortium has conducted a questionnaire survey among 6,895 individuals in 6 different European countries. We investigated the prevalence of PLE and its dependence on geographical latitude, gender, occurrence during springtime or sunny holidays and skin type. This survey is described in chapter 2.
Aetiology and pathogenetic mechanisms of PLE
The rash of PLE is induced by exposure to ultraviolet radiation (UVR). The evoking wavelengths apparently vary between patients, but typical lesions occurred following irradiation with broadband UV-B lamps (290-320 nm), UV-A (320-400 nm) or solar simulated radiation.12-16
Normal UV-induced immune reactivity
Our knowledge and understanding of the effects of UV radiation on human health and topical effects on the skin comes from studies that combine elements of photobiology, immunology and dermato-oncology. From photoimmunological
Chapter 1
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investigations it is recognized that UV irradiation suppresses cutaneous T-cell- mediated immunity in humans. 17 Most studies used the contact hypersensitivity (CHS) and delayed type hypersensitivity (DTH) responses to a variety of sensitising agents (such as di-nitrofluorbenzene (DNFB)) as a model to study the effects of UV radiation on immune responses. 18;19 In the CHS reaction, a hapten is applied onto the skin, and antigen-presenting cells (APC), mainly epidermal Langerhans cells (LC) take up the antigens and migrate to regional lymph nodes, where they interact with naïve T-helper cells to initiate the response. After expansion and differentiation, the T cells enter the circulation and upon a next contact with the same antigen on the skin, they cause local CHS response with symptoms of redness, itching and swelling. The DTH response is similar, except that the antigen is introduced by the intradermal or subcutaneous route. The initiation of UVR-induced immune suppression of the skin is accompanied by depletion of epidermal LCs, dermal and epidermal influx of CD11b+
neutrophils and macrophages and release of cytokines, in particular interleukin 10 (IL- 10). 18;20 UVR-induced immune suppression of CHS and DTH responses is achieved by a single or repeated low-dose UVB irradiation before the application of the antigen, leading to an absence of a visible response and possibly to tolerance to this antigen.
These immune suppressive responses take place in every healthy person. UV- induced suppression of cellular immunity can be thought of as a sound physiological reaction. What if the above mechanisms become disturbed or diminished? It is hypothesized that an imbalance of UV-induced pro-inflammatory reactions and immunosuppression could lead to a pathological skin reaction to a UVR-induced antigen (photoantigen), and that a UV-induced allergy e.g. PLE could develop.
Prior histological examination of PLE lesions revealed some features that were also found in DTH responses, such as the expression of intercellular adhesion molecule-1 (ICAM-1) and upregulation of major histo-compatibilty complex class II (MHC class II) on keratinocytes. 16 Also, the switch from a predominance of CD4+ lymphocytes in infiltrates of new PLE lesions to a predominance of CD8+ lymphocytes in older PLE lesions 13 resembled the change observed in a DTH response.
To unravel early pathogenetic mechanisms, other investigators focused on the pre-lesional UV-triggered skin responses in PLE patients. In 1999, Kölgen and co- workers reported that epidermal LCs of PLE patients persisted in the epidermis upon a high dose of UVB irradiation. 21 That contrasted with the depletion in healthy subjects.
Other investigators reported that CD11b+ macrophage-like cells infiltrate the epidermis 48 and 72 h after UV exposure in skin of healthy individuals. 19 The authors suggested that the ability to induce locally a state of in vivo tolerance is closely associated with the expansion of class II MHC+/CD11b+ monocytes/macrophages in the dermis and epidermis. 19 Kölgen et al. showed that these CD11b+ cells infiltrated the epidermis in PLE patients in lower numbers than in healthy control subjects upon a single high UVB exposure and that these cells were in fact neutrophils. 22 Furthermore, the neutrophils displayed cytoplasmatic expression of IL-4, IL-10 and TNF-α. 22
TNF-α and IL-1α have been linked to UVR-induced migration of LCs 23, and IL-10 to impaired antigen-presenting function of LCs. 24 IL-12 disposes the skin toward development of a Th1 response that is crucial for the induction of contact hypersensitivity, and it can abrogate the immunosuppressive effects of UVR. 25 However, no abnormalities were observed when measuring mRNA levels of TNF-α, IL- 1α, IL-10, and IL-12 in skin of PLE patients, at 6 and 24h after low dose solar simulated radiation (SSR) exposure.26
Two studies have been conducted to test functionally the hypothesis that UVB- induced immunosuppression fails in PLE. Van de Pas et al. tested PLE patients and showed that in contrast to healthy controls, a single dose of UVB radiation around 1 MED failed to suppress CHS in these patients. 27 Similarly, Palmer and Friedmann found that the induction of sensitisation to 2,4-dinitrochlorobenzene was less suppressed by UVR in PLE patients than in healthy controls. 28 These investigations confirm the hypothesis of failing UVB-induced immunosuppression in PLE patients and have thus contributed considerably to the clarification of some pathogenetic mechanisms in PLE.
Thus, the lower depletion of LCs and decreased infiltration of neutrophils together with a possibly disturbed cytokine expression and an unsuppressed CHS response after UV exposure are indicative of an imbalance of UV-induced immune responses in the skin of PLE patients as compared to healthy controls.
Outline 2
In chapter 3, 4 and 5 of this thesis, we describe three investigations to unravel the pathogenetic mechanisms of PLE: We have investigated whether the lower UV-induced epidermal LC migration and neutrophil infiltration was specific to PLE, or occurred also in a group of patients with photosensitive lupus erythematosus (LE). This would give evidence for a shared pathogenetic mechanism of photosensitivity in PLE and LE. The results of this study are described in chapter 3.
Furthermore, we wondered whether the supposed imbalance of UV-induced immune cell responses in PLE would shift towards a normal situation after a course of UVB therapy (chapter 4). A normalisation of cell responses in PLE patients after UV hardening would support a role of these cells in pathogenetic mechanisms of PLE.
The last research question was whether UVB irradiation would change the cytokine profile of PLE skin in such a way that it could explain underlying mechanisms of the impaired LC migration and neutrophil infiltration or of pro-inflammatory responses.
We expected to observe lower concentrations of LC and neutrophil recruiting cytokines.
The results of this investigation are described in chapter 5.
Chapter 1
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Clinical features of PLE
The appearance of PLE lesions is polymorphic. It ranges from papulo-vesicular lesions to multiple small and large papules that can coalesce to form plaques. 2;29 The lesions are moderately to severely pruritic, last for several days to weeks and heal without leaving scars. They mainly appear on sun-exposed skin areas, several hours to a few days after exposure. 2 Predilected areas are the neck, upper chest, dorsa of the hands, dorsolateral aspects of the upper arms, the legs and dorsa of the feet. In some patients, the process may generalize, with more severe lesions on photo-exposed sites. Flares of previously affected areas may occur when other parts are exposed to the appropriate radiation from the sun or artificial sources. 2
The time of sun exposure, necessary to induce PLE lesions, can vary from several minutes to several hours, sometimes on consecutive days. It would normally take one or two days after first sun exposure for the rash to appear, but appearance after some hours is also possible. If further exposure would be avoided from the beginning of the rash, lesions will resolve spontaneously after some days or some weeks. Since complete avoidance of sun exposure is not always possible, the lesions may stay on the skin for up to 6 months during spring and summer time. The lesions mostly emerge at the beginning of springtime when the first intense sunrays appear.
In the course of the summer, a gradual waning of lesions can be observed, as a result of UV-adaptation. 30 The time course of symptoms is likely to be dependent on geographic and climatologic factors. PLE has a chronic intermittently relapsing course.
In different long-term follow-up studies spontaneous remission was reported in 11- 23% after 7-32 years. 30;31
Figure 1. PLE lesions on the upper chest, one of the predilected areas
Differential diagnosis of PLE
PLE should be differentiated from photosensitive disorders like actinic superficial folliculitis 32, acne aestivalis, solar urticaria 33;34, photocontact dermatitis, phototoxic reactions, photosensitive eczema 35, hydroa vacciniforme and erythropoietic protoporfyria. Table 1 gives an overview of the most important differential diagnoses of PLE.
Distinguishing PLE from subacute cutaneous lupus erythematosus (SCLE), chronic discoid lupus erythematosus (CDLE) and photosensitive LE is sometimes very difficult and can remain a problem throughout the whole time course of the disease.
Therefore, the clinical features of these two diseases are given in more detail.
SCLE and CDLE
Previously, PLE was thought to be associated with lupus erythematosus (LE) but these diseases are now considered two distinct entities. 2;30;31 Skin lesions are found in up to 90 % of patients with systemic LE. 37 There is a clear relationship between sunlight and the manifestations of cutaneous LE. Up to 73 % of patients with systemic LE report photosensitivity. 37 Typical LE lesions occur on the face, the conchae of the ears and upper chest. They appear as round-oval or polycyclic erythematous plaques or annular lesions and after healing they leave central scars and atrophy.
Differentiation between PLE and LE is of high importance as desensitisation or UV hardening with PUVA or UVB is contradicted in LE. Antibodies to ENA, anti-Ro and anti-La are strongly associated with LE and SCLE, but not with PLE, and are therefore helpful in distinguishing between these disorders. The histology of SCLE may look identical to PLE but the follicular plugging and epidermal atrophy are important signs that only occur in SCLE and CDLE. Direct immunofluorescence may show IgG and IgM deposits scattered along the dermo-epidermal basement membrane zone in CDLE. It has been shown with photoprovocation tests in photosensitive LE patients that both PLE- and LE-like lesions can be induced with UV radiation. 38 Thus, the outcome of phototesting will not always lead to a better distinction between PLE and LE.
Therapeutic possibilities for photosensitive cutaneous LE are to some extent similar to PLE, except for the artificial and natural hardening, which are contradicted in LE.
Diagnostic procedures of PLE
Diagnosis of PLE is based mainly on a combination of history taking and clinical symptoms. The definition of PLE as used in our studies is given in the introduction. In some cases, it is desirable to perform provocative phototesting to reproduce the photodermatosis in a controlled clinical setting.
Phototesting
Great variations in methods, UV-sources, irradiation protocols and positive reactions to provocative phototesting have been described since the early 80's. Percentages of
Chapter 1
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positive photo-provocation tests range from 48 to 100%. 12;15;39-47 Unfortunately, descriptions of the evoked skin rash after the provocation, are frequently absent. This in particular is very important for confirmation of the diagnosis. In contrast to former believe, there appears to be no difference in the ease of provocation between previously affected skin and previously unaffected skin of PLE patients. 15 In accordance with the protocol of SUNALL group, the provocation tests at our department are performed on a non-suntanned, non-lesional skin area on the flexor side of one forearm with a standardised dose of 20 J/cm2 UVA (Cleo Performance lamps).
Although > 95% of the UV output stems from the UVA band, it is important to note that 50% of the erythemal effective dose stems from the UVB band. The other arm is tested with 1 MED of UVB (TL12 lamps). The provocations were repeated on consecutive days, up to a maximum of three days. Reading is done 24 hours after every irradiation until a rash appears. An erythematous reaction with papules, plaques or vesicles is regarded a positive provocation and is suggestive of PLE. It is important to ask the patients about the resemblance between the provoked rash and the rash for which they sought medical attention. Artificially provoked lesions are always milder than the naturally occurring ones. The appearance of heavy sunburn, an eczematous rash or pustules does not support the diagnosis of PLE. The most suitable season for testing is assumed to be winter or early springtime, when environmental sunlight radiation is low and UV-adaptation is absent.
MED testing for UVB was performed using a device, first described by Diffey et al. 48 As depicted in Figure 2, we have adjusted this device for application onto the skin. The device contains ten holes with perforated meshes, with increasing permeability. In this way, a single UV irradiation will produce a UV range of 1:8 from the least permeable to the highest permeable hole, each subsequent hole increasing with a step of 26%. This tool for MED testing is used for most of our studies. An MED test range is also shown in figure 2.
A recent study suggests that high severity of the disease correlates with a positive outcome of UV-provocation testing. 49 However, this has never been tested in a large group of patients.
Outline 3
In chapter 6 we have investigated whether a severity score of PLE correlates with the outcome of UV provocation testing. We expected to find the highest severity scores in UV-A and UV-B susceptible patients. The provocation outcome would then be a reliable tool to predict the severity of PLE. This could also be of significance for the therapeutic advice to individual PLE patients.
Table 1. Differential diagnosis of photodermatoses DiagnosisAge of onsetAetiology & frequency Clinical features Polymorphic light eruptionadulthood idiopathic; very common Papules, vesicles, plaques on all UV-exposed areas. Starts 24-72 hours after UV-exposure; lasts 1-2 weeks, but can stay several months due to repeated UV-exposure. Actinic superficial folliculitis adolescence & adulthood Idiopathic; very rare Folliculitis on upper extremities and trunk. Starts 24-72 hours after UV-exposure; lasts 2 weeks. Acne aestivalis adolescence & adulthood idiopathic; history of acne vulgaris; very rare Papules, pustules and comedones on the face Starts 15-30 days after sun exposure; lasts 6 months Solar urticariaany age idiopathic; very rare Urticaria, can occur on the whole body. Starts within minutes after sun exposure; lasts max. 24 hours Photocontact dermatitis mainly adulthood chemical-induced delayed type contact hypersensitivity; common
Eczematous lesions, localisation depends on the application site of the chemical and on sun exposed areas. Starts 24-72 hours after sun exposure; lasts 2 weeks or several months. Phototoxic dermatitis mainly adulthood drug-induced; common Presents as heavy sunburn, on all sun exposed skin sites; starts within few hours after sun exposure; can last several days or months with repeated exposure. Hydroa vacciniformechildhood idiopathic; very rare Burning papules, bullae and crusts, on nose, distal limbs, leaving pock scars. Starts within hours, lasts several days. Erythropoietic protoporphyriachildhood inherited metabolic disorder of haem synthesis; rare Painful vesicular lesions, on nose, cheeks, fingers, leaving pitted scars. No protection from window glass. Starts within minutes, lasts a few days Photosensitive eczemaany age idiopathic, history of atopic eczema; rare Severe sun sensitivity and triggering of atopic eczema. Symptoms are mostly present year round with flare-ups during the summer Actinic reticuloid mainly adulthood idiopathic; very rarePersistent infiltrated papules and plaques on light-exposed skin, often with extension to covered areas or generalised infiltrated erythroderma; lymphoid infiltrate that resembles mycosis fungoides and is dominated by atypical CD8+ cells. 36 Chronic actinic dermatitis mainly above 50 years idiopathic; rareMainly affecting men. Chronic eczematous lesions with no clear seasonal dependency. Patients suffer from extreme photosensitivity, sometimes even to visible light. Associated with multiple contact allergies.
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Figure 2 MED testing device (A) and MED test (B)
A
B
Histo-pathology
Histo-pathological examination of PLE lesions is only partly helpful in establishing the diagnosis of PLE. The characteristic features of PLE lesions include epidermal changes of variable intensity, such as parakeratosis, focal spongiosis and vacuolar degeneration of basal cells. In the dermis, a superficial and deep perivascular lymphocytic infiltrate with subepidermal edema is seen. In a papular PLE lesion, these features are most prominent. The morphological variants of PLE are characterised by the same histological pattern, although additional features may be present. For instance, in the vesiculo-bullous form of PLE, spongiotic vesicles and severe subepidermal oedema that leads to blister formation are present. 50
In experimentally provoked lesions, intercellular adhesion molecule I (ICAM-I), human leucocyte antigen class II molecule (HLA-DR) and OKM5 expression were found on keratinocytes in a high number of PLE patients. This contrasted with healthy individuals, in whom the antigens where not expressed. 16 These antigens are commonly considered to play a role in antigen presentation and elicitation of an immune response. 51;52 PLE displays an accumulation of CD4+ T cells within hours and CD8+ T leucocytes within days after sequential UVR exposure, a picture that mimics delayed type hypersensitivity reactions. 13;16 These observations support the theory of an immunological basis for PLE.
Serologic antibody testing
PLE can precede, coincide or overlap with photosensitive lupus erythematosus. It is therefore recommended to test for the presence of anti-nuclear antibodies (ANA) and more particularly antibodies against extractable nuclear antigens (A-ENA, anti-Ro (SSA) and anti-La (SSB) antibodies) in any patient with a presumed photosensitivity disorder. 53 As mentioned earlier in this introduction, a classical history of PLE, but with the presence of A-ENA was regarded an exclusion criterion in our studies. PLE patients with positive ANA serology, without other criteria suitable to the diagnosis of LE were regarded as having PLE and were included in our studies.
Treatment of PLE
Therapeutic possibilities are limited and only partly effective. Treatment is generally aimed at preventing the disease. A summary of therapeutic options of PLE is given in table 2.
Prevention
Patients are not advised to strictly avoid sun exposure, but to expose themselves for some minutes in the morning or the end of the afternoon, starting in early springtime under mild conditions. 54 This results in an adaptation of the skin to natural sunlight (so-called hardening). It is advisable to increase the sun exposure with 15 to 30 minutes per day each week. A useful tool for the patient is to keep a diary, to note down sun exposure time and any rash that occurs during hardening. This will increase the patients' understanding and confidence of the effects of sun exposure.
The use of sunscreens with high sun protection factors (SPF) seems a sound advice but can be misleading, since most of the sunscreens protect mainly against UVB, while UVA is also responsible for triggering PLE. Sunscreen use can even lead to exacerbation of PLE. 55 It has been shown that photosensitive patients fail to apply sunscreen in some prominently exposed sites and use less sunscreen than recommended by the manufacturer (2 mg/cm2). As a result of that, the degree of
Table 2. Therapy of PLE TreatmentPeriodDoseDurationSide effectsAdvantageDisadvantage Natural hardening Early spring and summer Start with 10-20 minutes twice daily, increment with 5-10 minutes
Whole sunny season
PLE rash Prevention. No hospital consultation
Highly dependent on local weather conditions Artificial hardening Early spring Starting dose 0.1 MED incremented with steps
6 weeks Sunburn, PLE rash Prevention Often regarded as time- consuming Hydroxy-chloro- quineEarly spring and summer 200 mg 1dd7 months Oculotoxicity Prevention. Lower tendency to sunburn Sun protection creams Early spring and summer > factor 20 7 months Effect on immune system unknown Prevention. Increases sun exposure time Prevents UV-hardening Clothing Early spring and summer Hat, long sleeved shirt, trousers No Prevention. Increases sun exposure time
Prevents UV-hardening. Rash can appear on body parts despite clothes. Undesirable with hot weather Topical steroids When rash appears Class 3 or 4 steroid 2 weeks No Downregulation of inflammation Only symptomatic, not always effective Antihistamines When rash appears By doctor's prescription2 weeks Sleepiness Decrease of some itchOnly symptomatic, not always effective Systemic steroids With severe rash 30 mg Usually 3-5 days Infection Quickly effective. Can also be used as preventive measure Systemic side effects of corticosteroids
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protection is much lower than anticipated from the stated SPF of the product. 56 Moreover, stringent use of sunscreens will hamper UV hardening of the skin.
Protective clothing can mostly prevent the development of skin lesions, but it is not always desired during sunny and warm days.
Artificial hardening can be achieved by serial and gradually increasing whole- body irradiation with UVB lamps or psoralen plus UVA (PUVA) for two times a week during 6 weeks. 57 This results in diminishing of symptoms but it should be repeated every year in the beginning of springtime. Without regular sun exposure after PUVA therapy, patients were shown to lose their photoprotection after 4-6 weeks. 58 Rucker and co-workers compared the effect of UVA lamps in a clinical setting with sunbeds and concluded that the use of sunbeds in well equipped tanning studios with appropriately educated staff is also a reliable setting for hardening therapy. 59 In a questionnaire among 68 Dutch PLE patients who received PUVA hardening for five years, 55% reported great benefit from the therapy, 34% noticed some improvement and 9% had experienced no benefit or even worsening of their symptoms. The symptom-free interval after PUVA hardening was longer than 6 months in 38% of patients and between one and six months in 15% (unpublished data). On average, patients who stated to benefit from PUVA therapy tended to use sunscreens with a lower SPF than patients who had experienced no effect. Artificial hardening was considered a burden by 60% of the responders.
Symptomatic approach
The skin lesions of PLE can be treated with moderate or potent topical steroids.
Indications for the use of hydroxychloroquine are insufficient effect of sunscreen preparations and failure of UV hardening. 60 Hydroxychloroquine can be given in a starting dose of 400 mg and a maintenance dose of 200 mg daily. The mechanism of action is unknown but this treatment results in a moderate reduction of skin rash and it has anti-inflammatory properties. Somewhat paradoxically, hydroxychloroquine can also induce photosensitivity. However, this is regarded a side-effect which occurs only in a few patients and with high dosages. Chloroquine is not an obligatory phototoxic drug. Oculotoxity may be a serious side effect of this treatment and therefore, yearly ophtalmologic check-up is advisable when daily doses higher than 200 mg per day are used.
Conclusion
Polymorphic light eruption is the most common photodermatosis with an unknown etiology. The course of the disease is intermittently recurring and it can persist for decades. The minority of the patients suffer from severe complaints that affect their normal daily lives. Differentiating PLE from photosensitive cutaneous LE can be difficult, the disorders can even co-exist. The therapeutic and diagnostic options in this photodermatosis remain limited as a result of its unknown pathogenesis.
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Therefore, further clinical and immunological research should also be aimed at improvement of the therapeutic and diagnostic possibilities.
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19. Hammerberg C, Duraiswamy N, Cooper KD. Temporal correlation between UV radiation locally-inducible tolerance and the sequential appearance of dermal, then epidermal, class II MHC+CD11b+ monocytic/macrophagic cells. J Invest Dermatol. 1996; 107: 755-63
20. Kang K, Hammerberg C, Meunier L et al. CD11b+ macrophages that infiltrate human epidermis after in vivo ultraviolet exposure potently produce IL-10 and represent the major secretory source of epidermal IL-10 protein. J Immunol. 1994; 153: 5256-64
21. Kölgen W, Van Weelden H, Den Hengst S et al. CD11b+ cells and ultraviolet-B-resistant CD1a+ cells in skin of patients with polymorphous light eruption. J Invest Dermatol 1999;
113: 4-10
22. Kölgen W, van Meurs M, Jongsma M et al. Differential expression of cytokines in UV-B- exposed skin of patients with polymorphous light eruption: correlation with Langerhans cell migration and immunosuppression. Arch Dermatol 2004; 140: 295-302
23. Cumberbatch M, Dearman RJ, Kimber I. Interleukin 1 beta and the stimulation of Langerhans cell migration: comparisons with tumour necrosis factor alpha. Arch Dermatol Res 1997; 289: 277-84
24. Enk AH, Angeloni VL, Udey MC et al. Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. J Immunol 1993; 151: 2390-8 25. Schwarz A, Grabbe S, Aragane Y et al. Interleukin-12 prevents ultraviolet B-induced local
immunosuppression and overcomes UVB-induced tolerance. J Invest Dermatol 1996;
106: 1187-91
26. Wackernagel A, Back B, Quehenberger F et al. Langerhans cell resistance, CD11b+ cell influx, and cytokine mRNA expression in skin after UV exposure in patients with polymorphous light eruption as compared with healthy control subjects. J Invest Dermatol 2004; 122: 1342-4
27. van de Pas CB, Kelly DA, Seed PT et al. Ultraviolet-radiation-induced erythema and suppression of contact hypersensitivity responses in patients with polymorphic light eruption. J Invest Dermatol 2004; 122: 295-9
28. Palmer RA, Friedmann PS. Ultraviolet radiation causes less immunosuppression in patients with polymorphic light eruption than in controls. J Invest Dermatol 2004; 122:
291-4
29. Jansen CT. The morphologic features of polymorphous light eruptions. Cutis 1980; 26:
164-70
30. Jansen CT, Karvonen J. Polymorphous light eruption. A seven-year follow-up evaluation of 114 patients. Arch Dermatol 1984; 120: 862-5
31. Hasan T, Ranki A, Jansen CT et al. Disease associations in polymorphous light eruption. A long-term follow-up study of 94 patients. Arch Dermatol 1998; 134: 1081-5
32. Nieboer C. Actinic superficial folliculitis; a new entity? Br J Dermatol 1985; 112: 603-6 33. Uetsu N, Miyauchi-Hashimoto H, Okamoto H et al. The clinical and photobiological
characteristics of solar urticaria in 40 patients. Br J Dermatol 2000; 142: 32-8
34. Ryckaert S, Roelandts R. Solar urticaria. A report of 25 cases and difficulties in phototesting. Arch Dermatol 1998; 134: 71-4
35. Yokel BK, Hood AF, Morison WL. Management of chronic photosensitive eczema. Arch Dermatol 1990; 126: 1283-5
36. Toonstra J. Actinic reticuloid. Semin Diagn Pathol 1991; 8: 109-16
37. Wysenbeek AJ, Block DA, Fries JF. Prevalence and expression of photosensitivity in systemic lupus erythematosus. Ann Rheum Dis 1989; 48: 461-3
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38. Hasan T, Nyberg F, Stephansson E et al. Photosensitivity in lupus erythematosus, UV photoprovocation results compared with history of photosensitivity and clinical findings.
Br J Dermatol 1997; 136: 699-705
39. Holzle E, Plewig G, Hofmann C et al. Polymorphous light eruption. Experimental reproduction of skin lesions. J Am Acad Dermatol 1982; 7: 111-25
40. Boonstra HE, van Weelden H, Toonstra J et al. Polymorphous light eruption: A clinical, photobiologic, and follow-up study of 110 patients. J Am Acad Dermatol 2000; 42: 199- 207
41. McFadden N, Larsen TE. Polymorphous light eruption: the properties of a UVA-induced PLME patient group. Photodermatol. 1986; 3: 36-40
42. Vaillant L, Muller C, Fauvel C et al. [Polymorphous light eruption induced by UVA]. Ann Dermatol Venereol 1990; 117: 963-4
43. Lindmaier A, Neumann R. [The patient with polymorphous light dermatosis. Skin type, hardening and other light-associated markers]. Hautarzt 1991; 42: 430-3
44. Mastalier U, Kerl H, Wolf P. Clinical, laboratory, phototest and phototherapy findings in polymorphic light eruptions: a retrospective study of 133 patients. Eur J Dermatol 1998;
8: 554-9
45. Das S, Lloyd JJ, Walshaw D et al. Provocation testing in polymorphic light eruption using fluorescent ultraviolet (UV) A and UVB lamps. Br J Dermatol 2004; 151: 1066-70
46. Bergner T, Przybilla B, Heppeler M. [Polymorphous light dermatosis. Clinical data and test results]. Hautarzt 1993; 44: 215-20
47. Ferguson J. Diagnosis and treatment of the common idiopathic photodermatoses.
Australas J Dermatol 2003; 44: 90-6
48. Gordon PM, Saunders PJ, Diffey BL et al. Phototesting prior to narrowband (TL-01) ultraviolet B phototherapy. Br J Dermatol 1998; 139: 811-4
49. Palmer RA, van de Pas CB, Campalani E et al. A simple method to assess severity of polymorphic light eruption. Br J Dermatol 2004; 151: 645-52
50. Hood AF, Elpern DJ, Morison WL. Histopathologic findings in papulovesicular light eruption. J Cutan Pathol 1986; 13: 13-21
51. Smolle J. HLA-DR-antigen bearing keratinocytes in various dermatologic disorders. Acta Derm Venereol 1985; 65: 9-13
52. Vejlsgaard GL, Ralfkiaer E, Avnstorp C et al. Kinetics and characterization of intercellular adhesion molecule-1 (ICAM-1) expression on keratinocytes in various inflammatory skin lesions and malignant cutaneous lymphomas. J Am Acad Dermatol 1989; 20: 782-90 53. Petzelbauer P, Binder M, Nikolakis P et al. Severe sun sensitivity and the presence of
antinuclear antibodies in patients with polymorphous light eruption-like lesions. A form fruste of photosensitive lupus erythematosus? J Am Acad Dermatol 1992; 26: 68-74 54. Norris PG, Hawk JL. Polymorphic light eruption. Photodermatol Photoimmunol Photomed
1990; 7: 186-91
55. Farr PM, Diffey BL. Adverse effects of sunscreens in photosensitive patients. Lancet 1989;
1: 429-31
56. Azurdia RM, Pagliaro JA, Diffey BL et al. Sunscreen application by photosensitive patients is inadequate for protection. Br J Dermatol 1999; 140: 255-8
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2
Lifetime prevalence and characteristics
of the ‘sun-allergy’
polymorphic light eruption in Europe
Michael Bock1, Soe Janssens2, Tsui Ling3, Lina Anastassopoulou4, Christina Antoniou4, François Aubin5, Thomas Bruckner1, Brigitte Faivre5, Neil Gibbs3, Christer Jansen6,
Alexander Stratigos4, Lesley Rhodes3 and Thomas Diepgen1
submitted
1Department of Clinical Social Medicine, University of Heidelberg, Germany
2Leiden University Medical Centre, the Netherlands
3Photobiology Unit, Dermatological Sciences, University of Manchester, UK
4A Sygros Hospital, University of Athens, Greece
5Department of Dermatology, University Hospital, Besançon, France
6University of Turku, Finland
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Abstract
Although polymorphic light eruption (PLE) is the most common idiopathic photodermatosis, epidemiological data are sparse. Former investigations led to the assumption that there is a latitudinal gradient in the prevalence of PLE, i.e. decreasing toward the equator. We performed a survey to evaluate the latitudinal impact on prevalence, the frequency of eruption in springtime and during sunny holidays, and further characteristics of PLE in Europe.
The study was conducted by 6 dermatology centres from Finland, Germany, the Netherlands, the United Kingdom, France and Greece (61-38° northern latitude). Data were obtained largely from indoor working hospital staff, using standardised questionnaires.
Eighteen percent of the 6,895 participants reported experiencing an itching rash/abnormal skin reaction after sun exposure that was distinct from sunburn.
Women were nearly three times more often affected than men, i.e. 23% vs 9%, but large differences were found between Athens (Greece), 26% vs 15%, and Turku (Finland), 14 % vs 2%. PLE rashes were reported to occur in springtime in 7-10% of the interviewees in each country, without any indication of a latitudinal gradient (highest frequencies in Finland and Greece). The frequency of PLE during sunny holidays was very low among participants from Finland (9%) in comparison to other countries (14- 20%). One out of 3 people with skin type I had experienced PLE, and this fraction dropped to 1 out of 10 with skin types IV-VI. Skin type distributions were similar between countries.
Apparently, photodermatoses are highly prevalent in Europeans and deserve greater recognition. There is no evidence of increasing prevalence toward higher latitudes, i.e. with greater seasonal modulation of ambient UV radiation. Strikingly, prevalence is highest in Greece, the most southern country. Our data show that gender, skin type and behavioural factors, namely exposure during sunny holidays, are of paramount importance to PLE prevalence.
Introduction
Sun-provoked skin reactions (photodermatoses) constitute one of the most prevalent forms of skin disease and have a medical and socio-economic impact on the lives of millions of people. The most common idiopathic photodermatosis is polymorphic light eruption (PLE or PMLE) which is currently poorly investigated, and largely neglected as a public health problem. There is evidence to suggest that PLE has an underlying immune aetiology 1, with a strong genetic influence. 2 The disorder is characterized by recurrent pruritic papules, vesicles and plaques. The type of skin lesion varies between patients, hence the term polymorphic. However, in each patient, a single morphology predominates and reoccurs. The rash appears with a delay of several minutes to hours after ultraviolet (UV) radiation exposure and it persists for a few days up to a couple of weeks. The rash subsides completely in the absence of further UV exposure, without scar formation. The V of chest, neck, and the upper and lower extremities are most commonly involved. Most patients suffer from this susceptibility to UV radiation for many years. 3;4
Although PLE is a common skin disease, published epidemiological data are sparse. From interviews conducted among 550 visitors of shopping malls in Perth and Ballarat (Australia) and in London (UK) the prevalence of PLE was estimated to be 5.2%, 3.6% and 14.8%, respectively. 5 In a survey among 397 employees of a Swedish pharmaceutical company, symptoms of PLE were reported to occur by 21%. 6 Finally, a study of 271 subjects conducted in Boston (USA) reported a prevalence of 11%. 7 These investigations led to the assumption that the prevalence of PLE is lower in countries nearer to the equator. However, reliable data concerning this hypothesis are lacking as well as data on characteristics and treatment of PLE. In the present large-scale cross-sectional study, we performed a standardized survey on prevalence, symptoms and treatment of PLE in five European countries at different geographical latitudes.
Methods
Study design and participants
Ethical approval for the study was gained at each participating institution. The study was designed as a multi-centre observational study with in-person interviews in a sample of the adult population. We agreed that each centre would include at least 1000 subjects. One or at most two researchers at each site conducted the interviews.
All studied subjects were indoor workers, mainly hospital staff of the participating centres including nurses, cleaning staff, craftsmen and kitchen staff. A group of factory workers (mainly males) was included in the data from Heidelberg. The participating centres were dermatological departments of the Universities in Athens (Greece), Besançon (France), Heidelberg (Germany), Leiden (the Netherlands), Manchester (United Kingdom) and Turku (Finland). The northernmost city was Turku with a geographical latitude of 60.5°, followed by Manchester with 53.5°, Leiden 52°, Heidelberg 49.5°, Besançon 47° and Athens 38°.
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The questionnaire
A standardized, simple and short one-sided questionnaire was developed by dermatologists with special expertise in photodermatology and dermatoepidemiology.
In the first part of this questionnaire the questions regarding skin type, age and sex were asked. The main question of this first part was whether participants had developed an itching rash/abnormal skin after sun exposure, which they did not regard as sunburn (a so-called ‘sun allergy’). If interviewees had not developed such a rash in their history, further interviewing was terminated. If they replied with ‘yes’ or
‘do not know’ they were asked to continue with another 13 questions which formed the second part of the questionnaire, including questions whether a photodermatosis has been diagnosed by a physician; questions on previous treatment of this photodermatosis; occurrence in springtime and during sunny holidays; the presence of itch; other family members afflicted; course of the disease; quality of life; age at first appearance of the rash; time of appearance after sun exposure; duration of the rash. Answers of the first part of the questionnaire were used to describe the study population and to calculate the prevalence. Analysis of the clinical features and treatment of PLE was performed using answers obtained from the second part of the questionnaire. All participants were personally asked whether they agreed to fill in a short anonymous questionnaire about sun allergies. In each centre the response rate was > 90%.
Statistics
To establish the accuracy of the findings, sample size estimations were performed. To estimate a prevalence of 10% with an accuracy of ± 2%, a sample size of about n=
1000 was needed. All data were collected between March 2003 and May 2004. Excel (Microsoft, Redmond, WA, USA) was used for data filing. All statistical analyses were performed in Heidelberg using SAS™ 9.1 Win (Cary, NC, USA). Categorical data were summarised by means of absolute and relative frequencies (number of counts and percents). The distribution of quantitative data was inspected by means of the following summary statistics: the number of observations, the arithmetic mean, and standard deviation, minimum, median and maximum. The observed prevalences were standardised by age and sex to take into account the difference between the samples and the population structure.
Results
Overall 6,895 subjects were included. Most of the subjects were women (4,163;
62.8%) and a smaller proportion were men (2,471; 37.2%). 261 answers on gender were missing. The mean age of the study participants was 37.5 ± 12.1 (standard deviation) years. This ranged from 28.9 ± 12.4 years in Besançon (F) to 42.9 ± 11.0 years in Turku (FI). Specified data per country are given in more detail in tables 1 and 2A and 2B.
Lifetime prevalence Total cohort
As shown in table 2, out of the total of 6,836 (59 missing due to incomplete questionnaires) included subjects, 1,235 gave a history consistent with the diagnosis of PLE. On the basis of these data, the suspected lifetime prevalence of PLE was 18.0% in the study population and 18.2% after age and sex standardisation.
Prevalence at individual centres
After standardising for age and sex, we found similar prevalences among centres ranging between 17 and 19.5%, apart from a low prevalence of 13.6% in Turku (FI), see table 2A (crude percentages ranged from 16.1 to 22.8, with a low of 12% in Turku).
PLE rashes during springtime were reported to occur (always or sometimes) by equal proportions of the total interviewed population per country (between 7 and 10%), without any indication of a latitudinal gradient (with the highest frequencies of 10% in Finland and Greece). The frequency of PLE during sunny holidays was strikingly low among Finnish participants (9%), compared to people from other countries, where it ranged between 14 and 20% (see table 2A). This explained the overall low prevalence of PLE in Finland. Among people with PLE, most (76 to 93%) suffered from the rashes during sunny holidays.
Gender
The life time prevalence of PLE among women, standardized for age, was 22.2%
(crude prevalence 23.3%) which was more than double the 9.8% (9.2%) found in men.
An exceptionally low prevalence among females was found in Turku (FI) (15.0%). The prevalence of PLE among men was exceptionally high in Athens (GR) (16.6%). This resulted in a relatively low female/male ratio (1.3) in Athens, compared to other countries (see table 2A).
Skin type
People with skin type I (according to Fitzpatrick) had the highest prevalence of PLE:
33.4% in women and 28.6% in men. These percentages declined in skin type II to 30.8% in women vs 15.0% in men, in skin type III to 18.9% in women vs 7.0% for men.
Subjects with skin type IV had the lowest prevalence with 11.2% in women compared to 4.0% in men. The prevalence among different skin types showed a significant trend (Cochran-Armitage Trend Test; p < 0.001).
