Genetic modeling of abnormal photosensitivity in families with polymorphic light eruption and actinic prurigo

Actinic prurigo and polymorphic light eruption are two of the so-called idiopathic photodermatoses, resulting from abnormal cutaneous responses to ultraviolet radiation (photosensitivity). Whereas they are clinically distinct in most cases, there are sufficient similarities between them to suggest they may be related conditions. To take this further, we examined the prevalence of polymorphic light eruption in families ascertained through actinic prurigo probands, as evidence of a shared pathogenesis. We then determined the heritability of photosensitivity in 420 individuals from families ascertained through polymorphic light eruption and actinic prurigo probands using segregation analysis. Across 58 pedigrees the prevalence of photosensitivity in first-degree relatives was 20.9% compared with a population prevalence of 13.6%, giving a relative risk of 1.5 (confidence interval 1.15-2.0) and providing evidence of clustering within families. The prevalence of photosensitivity (predominantly polymorphic light eruption) in relatives of actinic prurigo probands was 23.7%, with a relative risk of 1.74 (confidence interval 1.24-2.36). Modeling for polymorphic light eruption across all pedigrees revealed a strong genetic component with polymorphic light eruption showing a dominant mixed mode of inheritance. The model parameters estimate that 72% of the U.K. population carry a low penetrance polymorphic light eruption susceptibility allele, but that among this highly prevalent genotype only 24% of susceptible females and 13% of susceptible males will have polymorphic light eruption. Expression of polymorphic light eruption in genetically susceptible individuals (intergenotype variance) is determined in large part by a polygenic component, with an important additional environmental component. In summary, this study provides clear evidence that polymorphic light eruption is an inherited condition. It also suggests that polymorphic light eruption and actinic prurigo share a common genetic background, supporting the view that actinic prurigo may represent a human leukocyte antigen-restricted subset of polymorphic light eruption.     

The heritability of polymorphic light eruption

Polymorphic light eruption is classified as an acquired idiopathic photodermatosis, yet it appears to cluster in families, suggesting a possible genetic component. In this study, we assess the heritability of polymorphic light eruption using the classical twin model. Polymorphic light eruption was investigated by a nurse-administered questionnaire in a sample of 420 pairs of adult female twins from St Thomas' Hospital UK Adult Twin Registry, including 119 monozygotic and 301 dizygotic pairs. Probandwise concordance for the presence and absence of disease was calculated and the heritability of polymorphic light eruption assessed by a quantitative genetic model fitting approach using Mx software. The prevalence of polymorphic light eruption was 21% and 18% in monozygotic and dizygotic twins, respectively. A family history of polymorphic light eruption in first-degree relatives (not including the cotwin) was present in 12% of affected twin pairs (where at least one twin had polymorphic light eruption) compared with 4% of unaffected twin pairs, providing evidence of familial clustering (p < 0.0001). The probandwise concordance for polymorphic light eruption was higher in monozygotic (0.72) than in dizygotic twin pairs (0.30), indicating a strong genetic effect. Quantitative genetic modeling found that a model comprising additive genetic (A) and unique environmental (E) factors provided the most parsimonious fit, although a dominant gene effect could also explain our data. In the AE model, 84% (95% confidence interval 65-94%) of the variance in susceptibility to polymorphic light eruption is attributed to additive genetic factors with the remaining 16% (95% confidence interval 6-35%) to unique environmental effects. These data establish a clear genetic influence in the expression of polymorphic light eruption and provide a basis for examining candidate genes that may be pathogenic in this common condition.     

UVB phototherapy and photochemotherapy (PUVA) in the treatment of polymorphic light eruption and solar urticaria

Forty subjects (36 with polymorphic light eruption and four with solar urticaria) were treated during the spring and early summer of the years 1982 to 1985 with either UVB phototherapy (a total of 54 treatment courses in subjects with polymorphic light eruption) or photochemotherapy (PUVA) (18 treatment courses in polymorphic light eruption and eight in solar urticaria patients). Both forms of prophylactic therapy were found to be effective in 90% of those with polymorphic light eruption, and PUVA in all those with solar urticaria. The optimum duration of treatment was 5 weeks. Adverse reactions, although common, were usually slight and rarely required alteration of the treatment regimen.     

Skin testing with simple equipment in photodermatoses

We have reviewed 275 patients who were tested in the light testing clinic in the 10 years from 1972 to 1981. 151 patients (55%) were referred with eczematous changes of the skin attributed to light, while 76 (28%) had a history of polymorphic light eruption. Light tests gave abnormal results in 54(36%) of the dermatitis group, showing a photoallergy in 17 patients and UV sensitivity with or without sensitivity to visible light in 30 patients. 7 out of 10 cases with clinical reactions to phenothiazines also had abnormal test results.
Patients with polymorphic light eruption reacted normally in our test system. Abnormal tests were obtained in solar urticaria, in a few cases of non-eczematous phototoxic reaction, folliculitis of the acne type and systemic lupus crythematosus.
Additional patch tests with standard allergens revealed a high % of contact sensitivity in the 30 UV sensitive patients.     

Immunohistopathology of light-induced skin lesions in lupus erythematosus

Recently we have been able to induce pathological skin reactions with UVB, UVA and visible light in patients with lupus erythematosus (LE). The pathological skin reactions had the appearance of spontaneously developed LE lesions. In the present study, using patients with polymorphic light eruption as controls, we subsequently investigated what types of immunohistochemical abnormalities were found in these lesions. It was shown that in the induced skin lesions, phenotypically similar inflammatory cells were found as in spontaneously evolved lesions. Granular deposits of immunoreactants, as found in most spontaneously evolved LE lesions, occurred in 12 out of 16 LE patients 7-10 days after onset of the artificial irradiation. The dermal infiltrates in light-induced LE lesions differed mainly from those in polymorphic light eruption, by the amounts of CD1+ cells (Langerhans' cells). In polymorphic light eruption, the relatively large amount of these cells suggests an active migration of antigen-presenting cells, a mechanism apparently not operative in LE. Our results underline the importance of the pathogenic action of light in LE.     

Erythema multiforme following polymorphic light eruption: a report of two cases

We report two patients in whom episodes of polymorphic light eruption were followed by recurrent erythema multiforme on exposed and nonexposed sites. Treating the polymorphic light eruption with prophylactic PUVA and/or oral prednisolone or cyclosporin prevented the development of erythema multiforme, suggesting that the two events are related. It is possible that erythema multiforme develops as a response to the same causative antigen as polymorphic light eruption.     

New insights into the mechanisms of polymorphic light eruption: resistance to ultraviolet radiation-induced immune suppression as an aetiological factor

Abstract:  An abnormal immune response has long been thought responsible for the patho-aetiology of polymorphic light eruption, the most common photodermatosis. Recent evidence indicates that polymorphic light eruption patients are resistant to the immune suppressive effects of sunlight, a phenomenon that leads to the formation of skin lesions upon seasonal sun exposure. This immunological abnormality in polymorphic light eruption supports the concept of the biological significance and evolutionary logic of sunlight-induced immune suppression, i.e. the prevention of immune responses to photo-induced neo-antigens in the skin, thereby preventing autoimmunity and skin rashes. This article focuses on the immunological alterations in polymorphic light eruption and the pathogenic significance to the disease state and skin carcinogenesis.     

Papular polymorphic light eruption: an immunoperoxidase study using monoclonal antibodies

Biopsy specimens of papules taken from eight patients with polymorphic light eruption were examined by immunoperoxidase techniques employing monoclonal antibodies. In each case, most infiltrating mononuclear cells were T cells. The majority of T cells were T8-positive (cytotoxic/suppressor) in four cases and T4-positive (helper/inducer) in two. In two cases, approximately equal numbers of both T cell subsets were present. In only three cases were rare B cells identified by their reactivity with anti-IgM antibody. MI-positive mononuclear cells (macrophages) represented less than 5% of cells infiltrating the dermis. In five subjects, anti-T6 antibody stained increased numbers of dermal mononuclear cells considered to be Langerhans/indeterminate cells. The pathogenesis of papular polymorphic light eruption may involve injury to upper dermal venules mediated by T cells and Langerhans/indeterminate cells.     

Polymorphic light eruption may be associated with cigarette smoking and alcohol consumption

BACKGROUND: Although the genetic influence on polymorphic light eruption (PLE) is well established, the role of lifestyle factors is less well defined. METHODS: A retrospective case-control study was conducted that included 74 PLE patients and 102 controls. Each participant was interviewed about demographic, disease and lifestyle characteristics such as smoking, alcohol consumption and use of medications. Multivariate logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared with the controls, patients with PLE were significantly more likely to be younger females (P<0.05). Univariate analysis did not show a significant association between any of the smoking-related questions and PLE. However, after adjusting for gender and drinking alcohol, patients with PLE were significantly more likely to smoke 15 cigarettes or more daily [adjusted OR=4.06 (95% CI=1.19, 13.80) compared with 0 daily cigarettes] than controls. Participants who consumed six or more drinks a week were less likely to have PLE [adjusted OR=0.24 (95% CI=0.07, 0.80)]. In contrast, women who used oral anticonceptives for a longer period were four-fold more likely to have PLE [adjusted OR=4.74 (95% CI=1.33, 16.86)]. CONCLUSION: Several lifestyle factors may be associated with PLE, but further studies are warranted to confirm these retrospective findings.     

Determination of zinc, copper, manganese, and iron in blood from patients with light-sensitive skin diseases

It is known that some trace elements have an influence on the repair of UV light induced DNA damage. We have detected certain alterations in the excision repair of patients with photodermatoses. In these investigations of screening character the levels of zinc, copper, manganese, and iron were measured by means of atomic absorption spectrophotometry in the whole blood of 31 patients with polymorphic light eruption and 27 patients with cutaneous porphyrias. In active stage of polymorphic light eruption decreased zinc, copper, and iron concentrations and an increased manganese content were found. In remission only the zinc level was lower. In the active stage of cutaneous porphyrias a decreased zinc and iron content as well as an increased manganese level could be detected. A presumable connection between the findings and the rate of the excision repair is discussed.     

Juvenile spring eruption of the ears: a probable variant of polymorphic light eruption

We report 18 cases in which a pruritic, erythematous, papular and vesicular eruption developed on the ears following sun exposure. Four of these patients had, on other occasions, suffered from typical polymorphic light eruption. The clinical features, histological changes, and results of phototesting suggest that juvenile spring eruption of the ears is a localized form of polymorphic light eruption.     

Polymorphic light eruption limited to areas of vitiligo

Two patients are described with clinical and histological features of polymorphic light eruption (PLE) limited to areas of vitiliginous skin. This phenomenon has not been reported previously and provides evidence for the protective role of melanin in PLE.     

Polymorphic light eruption sine eruptione

We describe seven patients, four female and three male, who developed intense pruritus on sun-exposed skin without visible change. The clinical features resembled those of polymorphic light eruption (PLE) without rash. Four patients also occasionally developed typical PLE upon sun exposure, but sun-induced pruritus alone occurred most frequently. No patient was taking any drug therapy. One patient developed similar pruritus following solar simulated irradiation, and one following PUVA therapy. All other laboratory investigations were negative. Treatment with low dose UVB phototherapy or PUVA therapy was effective. The condition, which we have called polymorphic light eruption sine eruptione (PLESE), appears to be a variant of PLE not previously reported.     

An immunoelectron microscopy study of the relationship between herpes gestationis and polymorphic eruption of pregnancy

Five patients with typical bullous herpes gestationis and five patients with polymorphic eruption of pregnancy were studied. Shave biopsies were taken from both involved and uninvolved skin and examined by routine immunofluorescence. They were also examined by immunoelectron microscopy employing a multistep peroxidase-antiperoxidase technique which has been shown to be more sensitive than immunofluorescence. Despite the increased sensitivity of immunoelectron microscopy all cases of polymorphic eruption of pregnancy were completely negative. Although there is a considerable clinical and histopathological overlap between herpes gestationis and polymorphic eruption of pregnancy our findings indicate that these conditions are pathogenetically distinct and should be classified as separate disorders.     

Effect of therapeutic sunscreen cream on phototest reaction in polymorphic light dermatosis

In 15 patients with polymorphic light eruption, we tested the protective action of a therapeutic sunscreen agent containing both UVB and UVA filters. The photoprovocation test showed that the preparation successfully suppressed the development of skin lesions in both wavelengths.     

Lupus-like phototriggering in a young woman with benign summer light eruption

We report the case of a young woman with a single history of benign summer light eruption (BSLE) who developed delayed onset annular lupus-like lesions triggered by a polychromatic phototest, 6 weeks after the irradiation. BSLE of French authors is an idiopathic photodermatosis that corresponds to the minor form of polymorphic light eruption (PLE) of Anglo-Saxon authors. This patient may develop a true lupus erythematosus in the future as indicated by this lupus-like phototriggering and in view of the high prevalence of PLE in lupus patients.     

Polymorphic light eruption sine eruptione

Seven patients, four female and three male, who develop intense pruritus without visible skin changes in light-exposed areas after sun exposure are reviewed. Onset in all cases has been in childhood or adolescence and the condition has persisted indefinitely except in one patient who has been in remission-for I year and one who was in remission for 5 years before relapse. Itching occurs on sun-exposed areas within 45 min to 24 h and lasts for 1–5 days. No patient has taken photosensitizing medications or suffered from any significant systemic illness. There is a positive family history of polymorphic light eruption (PLE) in one, and of sunlight-induced pruritus in another.
Porphyrin studies and antinuclear factor titres are normal. Cutaneous phototesting of the back by monochromator is normal in the UV-B, UV-A and visible light ranges. Irradiation from a xenon arc solar simulator in one patient induced intense pruritus with no visible skin changes on the tested sites of the anterior forearm and back in a time course mimicking that of sun-induced symptoms.
Treatment by sun avoidance, topical sunscreens and antihistamines has been only partially effective.
Two patients have subsequently developed occasional typical PLE upon sun exposure, but sun-induced pruritus alone occurs most frequently. This suggests that polymorphic light eruption sine eruptione is a variant of PLE and, to our knowledge, is the first report of this condition.     

The photosensitivity dermatitis and actinic reticuloid syndrome (chronic actinic dermatitis) occurring in seven young atopic dermatitis patients

Seven young patients with atopic dermatitis (AD) who presented with a marked photoexposed site dermatitis have been investigated in detail. The results of phototesting, patch testing and other investigations were compatible with the diagnosis of photosensitivity dermatitis/actinic reticuloid syndrome (PD/AR) (chronic actinic dermatitis). It is known that AD patients may have photoaggravation of their dermatitis or exacerbation secondary to a photodermatosis, such as polymorphic light eruption, actinic prurigo or drug-induced phototoxicity. The patients we describe, however, appear to be an uncommon AD subgroup affected by PD/AR. We recommend that all AD patients who have a history of sunlight-induced exacerbation or marked intolerance of PUVA or ultraviolet B phototherapy should have phototesting and patch testing conducted.     

Benign summer light eruption and polymorphic light eruption: genetic and functional studies suggest that a revised nomenclature is required

New research indicates that polymorphic light eruption (PLE) is an autoimmune disease against an ultraviolet radiation-induced cutaneous antigen. PLE may even confer some protection against skin cancer later in life. This new information demands a reassessment of the precise nature and nomenclature of PLE. Benign summer light eruption (BSLE) (lucite estivale bénigne) is the name used in continental Europe, and particularly France, to describe a clinically short-lived, itchy, papular eruption particularly affecting young women after several hours of sunbathing at the beginning of summer or on sunny vacations. Clinically more prolonged forms of solar eruption, starting early in spring and persisting for long periods, have been known in France as polymorphic light eruption (PLE) (lucite polymorphe) ('European PLE'). Investigative studies, however, now suggest that BSLE and some cases of 'European PLE' are part of the same spectrum. In the Anglo-Saxon literature, they are lumped together as PLE ('Anglo-Saxon PLE'). The other cases of 'European PLE', which do not fall within the compass of 'Anglo-Saxon PLE', are, in the Anglo-Saxon literature, classified as either actinic prurigo (AP) (a genetically determined, prolonged, excoriated form of Anglo-Saxon PLE), or chronic actinic dermatitis (CAD) (a sunlight-induced eczema precisely resembling allergic contact dermatitis, apparently to an ultraviolet radiation-induced antigen). It is therefore proposed that: i. the European term BSLE be dropped and that these patients be reclassified within the spectrum of (Anglo-Saxon) PLE, ii. the European use of the term PLE ('European PLE') be discontinued, iii. those previously diagnosed as having 'European PLE' be reclassified as (Anglo-Saxon) PLE, AP or CAD, as appropriate. The benefits of such a change in nomenclature would be twofold, firstly a uniformity of terminology and secondly, and more importantly, terminology would then correlate better with our recently improved understanding of the pathogenesis of these disorders.     

Induction of UV light tolerance by PUVA in patients with polymorphous light eruption

A tan induced by 8-methoxypsoralen-long wave ultraviolet light has proved an effective photo- protective sunscreen in 5 patients with long wave ultraviolet light-induced polymorphic light eruption.