Epidemiology and pathogenetic mechanisms of polymorphic light eruption

Epidemiology and pathogenetic mechanisms of polymorphic light eruption

Janssens, A.S.

Citation

Janssens, A. S. (2008, January 17). Epidemiology and pathogenetic mechanisms of polymorphic light eruption. Retrieved from https://hdl.handle.net/1887/12576

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License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

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6

Susceptibility to UVA and UVB provocation does not correlate

with disease severity of polymorphic light eruption

Soe Janssens¹, Stan Pavel¹, Tsui Ling², Sandra Winhoven², Lina Anastasopoulou³, Alexander Stratigos³, Christina Antoniou³, Thomas Diepgen⁴, Frank de Gruijl¹ and Lesley

Rhodes²

Archives of Dermatology 2007; 143: 599-604

1Leiden University Medical Center, the Netherlands

2Photobiology Unit, Dermatological Sciences, University of Manchester, UK

3A Sygros Hospital, University of Athens, Greece

4Department of Clinical Social Medicine, University of Heidelberg, Germany

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Abstract

We have examined whether the ease of disease provocation by UVA and/or UVB correlates with clinical features of polymorphic light eruption (PLE) including those indicative of disease severity. Provocation testing with broadband UVA and UVB lamps was conducted in 143 PLE patients. Additionally, a range of clinical characteristics of the disorder, including a 5-item PLE severity score, was assessed by questionnaire. We investigated the percentage of PLE rash induction by UVA and UVB provocation, differences between the skin types, correlation between the results of provocation and a range of clinical characteristics of the disorder, including a 5-item PLE severity score. Rash provocation was seen in 79% patients after UVA and in 47% after UVB exposure.

Neither UVA nor UVB provocation showed a significant association with the total 5-item severity score. UVB reactivity was associated with a high score of the severity item ‘number of months affected per year’ (p= 0.04), while UVA responsiveness showed a tendency for association with facial involvement (p=

0.06). We concluded that the objective assessment of UVA or UVB susceptibility in this large group of patients showed no significant relationship with clinical disease severity.

Introduction

Polymorphic light eruption (PLE) is a common photosensitivity disorder, which is believed to be of immune aetiology. ^1-4 Patients with PLE show considerable inter-individual variation in their disease presentation, including the severity of the disorder, but the factors influencing the clinical manifestations and severity are poorly understood. An objective way to determine severity of the disease may be by artificial photo provocation, in which the dose or number of ultraviolet (UV) irradiations needed to elicit PLE are recorded.

In the present study, we have assessed a range of clinical characteristics of PLE that may be indicative of PLE severity, against the easiness of rash provocation by UVA and UVB, in a large group of European patients. The main objective was to examine whether UV provocation response may be indicative of clinical disease severity.

Methods

Study centers

This investigation was effected by European Commission (EC) funded collaboration between 3 European university dermatology departments, during the period from 2001 to 2005. The centers involved were: (a) the Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. (b) the Photobiology unit, Dermatology Center, University of Manchester & Hope Hospital, Manchester, United Kingdom, and (c) the Department of Dermatology, University Hospital Athens, Greece.

Patients

The study received ethical approval from all local medical ethics committees and it complied with the Declaration of Helsinki 2000. A total of 143 patients participated (48 Dutch, 29 Greek and 66 British subjects). Patients aged 18-70 years were included. The diagnosis of PLE was based on a strict set of inclusion and exclusion criteria (see table 1).

Table 1. Inclusion and exclusion criteria for PLE diagnosis Inclusion criteria Exclusion criteria

Rash occurs following sun exposure Known coexistent photosensitivity disorder Rash occurs mainly on the photo exposed

skin (includes under light clothing) Rash with eczematous features

Rash is recurrent ENA antibody (anti-Ro, anti-LA) positive Rash is pruritic Markedly low MED to UVB or UVA Lesions are papules and/or vesicles

and/or plaques Histology incompatible with PLE Rash heals without scarring

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Photo provocation testing

Provocation testing was performed in the winter and spring months from the year 2002 to 2005 in the Leiden and Athens patients. Most provocation tests had been performed before 2002 in the Manchester group.

Both UVA and UVB testing were performed on the forearm skin for up to 3 consecutive days, but discontinued if a positive result was obtained sooner. All centers performed UVA testing (Leiden: 48 patients, Athens: 29 patients, Manchester: 66 patients). According to standard practice, a daily dose of 20 J/cm² was applied to a 20 x 5 cm area of the ventral surface of the forearm with a broadband UVA fluorescent source (Cleo Performance lamps (0,7% UV output in the UVB band, 280-315 nm), Philips Lighting, Eindhoven, The Netherlands). ⁵ At the Manchester center, the whole forearm was exposed.

UVB testing was performed at the Leiden (47 patients) and Athens (13 patients) centers, using broadband fluorescent lamps [TL 12 tubes (57,5% UV output in the UVB band, 280-315 nm), Philips Lighting, Eindhoven, The Netherlands]. The minimal erythema dose (MED, just perceptible erythema at 24 hrs) was firstly determined on the ventral side of the upper arm, by use of a photo testing device containing 10 apertures with increasingly permeable meshes, as previously described. ^6;7 A dose of one MED was then applied daily to a 20 x 5 cm area of the contra lateral ventral forearm.

A positive provocation response to UVB or UVA was defined as the development of clearly visible and palpable erythematous papules or vesicles on the irradiated field. The last reading was performed 24 hrs following the last provocation.

Clinical characteristics & severity assessment

Standardised forms were constructed following a panel discussion of participating clinicians experienced in photosensitivity diagnosis. The forms comprised 30 questions related to personal and disease characteristics. Patients were interviewed in person by a clinician trained in photo dermatology.

Five clinical characteristics selected from the standardised forms were used to devise a PLE severity score (PLESS), as described by Ling et al. ⁸ The clinical characteristics comprised (a) the total duration of symptoms in one year expressed in months, (b) the possible involvement of the face, (c) a visual analogue score for severity of itching, (d) the time taken for the rash to resolve and (e) the treatment history. As can be seen from figure 1, the PLESS ranged from 0 to 11.

Statistical analysis

For statistical analysis, Statistical Package for Social Sciences 12 (SPSS incorporate, Chicago, IL, USA) and SAS 9.1 for Windows (SAS Institute Inc., Cary, NC, USA) were used. Continuous data of the clinical characteristics were described using means, standard deviations, minimum, median and maximum

(see table 2). Dichotomous and categorical data of the clinical characteristics were described by absolute and relative frequencies (see table 2). Possible differences between patients with UVA/UVB-elicited rashes and patients without elicited rashes were tested (univariably) using Wilcoxon-Mann-Whitney U-test or Student's t-test in case of continuous data or scores and Fisher’s exact test in case of contingency tables. Multiple logistic regression analyses were performed for clinical characteristics with borderline significance (facial involvement, time needed for the rash to resolve and the number of months a patient was affected per year with PLE), to examine the common influence of disease characteristics (including age and sex) to the outcome of UVA and UVB provocation. The level of significance was set to < 0.05.

Results

UVA and UVB provocation

In total, 143 PLE patients were tested with UVA lamps. The overall positive response of UVA provocation was 79%, ranging from 69% in Leiden to 88% in Manchester. The number of exposures on consecutive days necessary to induce PLE and the number of elicited papules are given in table 3. In the majority of cases, papular responses with a variable intensity of erythema were observed (see figure 2).

A total of 60 PLE patients were tested with UVB lamps; a papular rash after UVB provocation was achieved in 28 patients (47%), comprising 69% of 13 Athens patients and 40% of 47 Leiden patients. Twenty three (38%) of 60 PLE patients had both a positive UVA and UV-B provocation. Thirteen patients (22%) did not develop a rash with either source, and 5 patients (8%) only responded to the UVB source. There was no difference in the UVA or UVB provocation results between countries, but there was a trend for a higher number of positive UVA provocations in the UK (where a larger surface area was challenged), and a lower number in The Netherlands.

Disease characteristics and PLESS

As depicted in table 2, a high percentage of patients (n= 64; 47%) was found in the moderate category, 33 patients (24%) belonged to the mild category and the remaining 38 (28%) patients were in the severest category. The distribution of PLESS categories differed between the countries. On average, PLESS was higher in Dutch than in Greek patients (6.3 r 2.0 vs 5.1 r 2.1; p= 0.017) and in UK patients (6.3 r 2.0 vs 4.7 r 2.0; p < 0.001), while the severity scores of Greek and UK patients were similar (p= 0.36).

An overview of the disease characteristics of the evaluated patient population is given in table 2. The described data are a selection of the most

relevant features obtained from the standardised interview. Skin type showed similar distribution between the countries (chi-square p= 0.22, data not shown).

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Table 2. Patient characteristics and PLESS obtained by standard interview.

Association with the results of UVA and UVB provocation.

data as means wih standard deviation between brackets or as percentage

1 association with provocation with UVA or UVB

2 according to Fitzpatrick

3 skin type I vs skin type IV and V

4 posterior neck, anterior neck, V of chest, dorsal hands, arms, legs, dorsal feet, back, abdomen

5 thyroid disease, diabetes mellitus type I, arthritis

6 questions of clinical features included in the severity score

Characteristics n frequencies of answers UVA¹ UVB¹

Male ; female 14

3 33 ; 110 n.s. n.s.

Age at study entry, yrs 14

1 43 (12) n.s. n.s.

Age at onset of PLE, yrs 14

1 28 (14) n.s. n.s.

Duration of PLE, yrs 14

1 15 (11) n.s. n.s.

MED to UVB, mJ/cm² 60 116 (50) n.s. n.s.

Skin type² 13

5

I: 11.9%; II: 35.6%; III: 38.5%;

IV: 12.6%; V: 1.5% p= 0.04³ n.s.

Provocation of rash behind window glass

11

7 yes: 48% n.s. n.s.

Number of body sites ever involved⁴ 12

5 4.8 (2) n.s. n.s.

PLE in first line family 12

5 yes: 26% n.s. n.s.

History of auto-immunity⁵ 12

2 yes: 6% n.s. n.s.

Improvement of rash during summer (adaptation)

10

9 yes: 31% n.s. n.s.

Time of sun exposure to provoke rash on a sunny day in own country

11 8

< 1 hour: 53%

> 1 hour: 47% n.s. n.s.

Time for the rash to appear after sun exposure

12 0

< 1 hour: 9%

> 1 hour: 91% n.s. n.s.

Number of months of the year affected⁶

13 7

up to 1 month: 16%

1-4 months: 18%

4-6 months: 42%

more than 6 months: 23%

n.s. p= 0.04

Face involved with PLE⁶ 13 6

never: 45%

sometimes: 29%

always: 27%

n.s.

(p= 0.06) n.s.

VAS itch (score 0-10)⁶ 13 6

score 0-4 (mild): 13%

score 4-7 (moderate): 22%

score 7-10 (severe): 65%

n.s. n.s.

Time taken for the rash to resolve⁶ 13 7

up to one week: 46%

1-2 weeks: 26%

more than 2 weeks: 29%

n.s. n.s.

Treatments previously used⁶ 12 5

creams/antihistamines only: 60%

phototherapy/systemic steroids:

35%

systemic immunosuppression: 4%

n.s. n.s.

PLE severity score (PLESS) 13 5

score 0-3 (mild): 24%

score 4-6 (moderate): 47%

score 7-11 (severe): 28%

n.s. n.s.

Figure 1. A questionnaire for the determination of PLE severity score (PLESS)

Figure 2. Papules on the anterior forearm induced during the UV provocation

PLE severity score (PLESS)

1. How many months of the year are you affected? Score

† up to 1 month 0

† 1-3 months 1

† 4-6 months 2

† more than 6 months 3

2. Is your face included

† never 0

† sometimes 1

† always 2

3. Indicate on the line the severity of your itching, where 0 is no itch and 10 is the worst imaginable itch

0  10

† 0-3 0

† 4-6 1

† 7-10 2

4. How long does your rash take to resolve?

† up to 1 week 0

† 1-2 weeks 1

† more than 2 weeks 2

5. Which treatments have you previously received?

† creams/histamines only 0

† phototherapy/systemic steroids 1

† systemic immunosuppression 2

Total

Severity score 0-3 mild; 4-6 moderate; 7-11 severe

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Association between UV provocation and PLESS

As shown in table 2, we have examined the association between UV provocation and PLESS. Overall, neither the UVA nor UVB provocation response showed any significant association with PLESS. In UVA non-responsive patients PLESS did not differ significantly from that of UVA responsive patients (4.7 vs 5.5; p= 0.09).

Similar results were also found in case of UVB provocation.

Analysis of individual features included in PLESS revealed a borderline significant association between facial involvement and time needed for the rash to resolve with UVA provocation. A high number of months a patient was affected per year, was associated with a positive UVB provocation (p= 0.04).

Further analysis of clinical characteristics not included in PLESS showed only a significant association between a positive UVA provocation and sun reactive skin type I. This correlation was not found in case of UVB provocation.

The examination of a potential relationship between the disease characteristics revealed that facial involvement was associated with a longer rash resolution time (p= 0.03) and with a higher number of months affected with PLE per year (p= 0.02).

Table 3. Photoprovocation responses across three European centers: The Netherlands (NL), Greece (Gr) and the United Kingdom (UK)

UV sourc e

NL (n=48)

Gr (n=29)

UK (n=66)

Total (n=143) UVA no. positive

responses

33 (69%) 22 (76%) 58 (88%) 113 (79%) no. exposures to

elicit rash

1 2 3

12%

36%

49%

14%

23%

64%

31%

31%

38%

elicited papules

< 10 10-50

> 50

64%

21%

15%

90%

5%

5%

n.a.*

NL (n=47)

Gr (n=13)

UK (n=0)

Total (n=60) UVB no. positive

responses

19 (40%) 9 (69%) n.a.* 28 (47%)

no. exposures to elicit rash

1 2 3

13%

17%

70%

33%

33%

33%

n.a.*

elicited papules

< 10 10-50

> 50

74%

21%

5%

100%

- -

n.a.*

* not analysed

Discussion

Polymorphic light eruption is a common disorder of unknown pathogenesis that shows a high variability in its clinical characteristics and severity. We have examined whether the ease of disease provocation by UVA and/or UVB correlates with clinical features of the disorder, including those indicating disease severity.

In our examined group, PLE induction was found in 79% of patients after UVA and in 47% after UVB irradiation. The UVA results are consistent with the data of published studies but our UVB responses are higher and there are large variations in irradiation protocols. ^3;9-13 The distribution of PLESS in our PLE population showed a normal spreading with 24%, 47% and 28% found in the mild, moderate and severe category of PLE severity, respectively. We originally assumed that the outcome of photo provocation would be a reliable tool to demonstrate an individual's clinical severity. To our surprise, the present PLE severity score, PLESS, showed no significant association with either UVA or UVB provocation. Our findings thus indicate that the provocation results are not predictive for the clinical severity of PLE.

Our results differed from those reported by Palmer et al. who concluded that the clinical severity of PLE was correlated to the ease of provocation to solar simulated radiation (SSR). ¹⁴ The difference between the results could be attributable to large differences in group size (n= 9 versus n= 143), differences in the UV-source used, (with elicited PLE lesions in different subsets of PLE patients), or to the method of severity scoring. The number and types of questions included in our scores differed substantially from Palmer et al.’s method. Nevertheless, both their and our questions of the severity score showed internal consistency. ^8;14

This lack of correlation between UV-provocation and PLESS was observed in all three participating countries. The outcome of provocation testing was similar in the three centers, but the PLESS scores were higher in Dutch patients. This was attributable to higher scores on the visual analogue score of itch, more facial involvement among Dutch patients and a relatively large proportion of Dutch patients that scored high on treatment history. Differences in answers about previous treatment could have been influenced by the moment of inclusion in the study in relation to the duration of the disease. The average duration of PLE at inclusion in this assessment among Dutch patients was 19 years, while among UK and Greece patients it was 12 years.

Clinical features of PLE that have been reported previously to correlate with (UVA) photo provocation testing are the duration of the disease, the persistence of naturally occurring lesions, and the time interval from accidental exposure to the development of lesions. ¹⁵ In the present study, we only found correlations with UV provocation and facial involvement of PLE, with a high

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number of months a patient was affected with PLE during one year and with sun reactive skin type I. Positive photo provocation in patients with PLE has varied among reported studies between 0-100 percent over the last 20 years. ^9-12;16-21 This large variation can be attributed to differences in UV source used, number and total dose of exposures, and possibly some patient characteristics.Our data confirm that UVA lamps give the highest positive responses and are therefore the most suitable sources for confirming the disease. However, with still a large proportion of false-negative responses in patients with a classical history of PLE, the outcome of UVA testing can not be regarded the golden standard and essential for making the diagnosis, but it can be helpful in some cases. The gain for clinical practice of UVB provocation testing is even smaller. However, the results of UVB provocation testing might provide information that helps to unravel pathogenetic mechanisms of the disease. We already showed in another study that the UVB-induced migration of epidermal Langerhans cells and neutrophils differs between patients that develop PLE rashes after UVB and UVA provocation. ⁶

Based on our results, we suggest that UVA and UVB testing have only a limited role in clinical practice. The clinical severity and the provocation test outcome were both regarded important for therapeutic advice to PLE patients.

However, since they are not correlated with each other, it should be investigated how they could contribute to therapeutic decisions (e.g. choice of light source for UV-hardening and/or preventive measures).

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