View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repositório Institucional dos Hospitais da Universidade de Coimbra Phototoxic and Photoallergic Reactions 18 Margarida Gonçalo Contents 18.1 Introduction [AU1] 18.1 Introduction ............................. 1 Phototoxicity and photoallergy are different expressions 18.2 General Mechanisms of Photosensitivity . 2 of an abnormal skin reaction from the exposure to light, 18.2.1 Phototoxicity vs. Photoallergy . 2 usually enhanced by endogenous or exogenous sub- 18.3 Clinical Patterns of Photosensitivity ......... 3 stances that are selectively activated by solar radiation. 18.3.1 Acute Manifestations of Photosensitivity . 5 This can occur with artificial light sources (sun 18.3.2 Subacute Manifestations of Photosensitivity . 5 lumps used for aesthetic or therapeutic purposes or 18.3.3 Delayed and Late Effects of Photosensitivity . 8 ultraviolet (UV) sources in occupational settings), but 18.4 Main Topical and Systemic Photosensitizers . 8 mostly occur on sun exposure. From the solar spec- 18.4.1 UV Filters.. 9 trum that reaches the earth, UV radiation, and particu- 18.4.2 Plants Causing Phytophotodermatitis . 10 18.4.3 Photosensitive Drugs . 11 larly UVA (320–400 nm), is responsible for most cases of photosensitivity. Even though some chromophores 18.5 Conclusions ............................. 14 absorb in the UVB (290–320 nm) and UVB is more References..................................... 14 energetic, UVA penetrates the skin more deeply and, particularly for systemic chromophores, this is cer- tainly the most important spectrum for inducing photo- dermatosis [1]. Only exceptional reports have a well- documented exogenous photosensitivity exclusively from UVB [2]. Photosensitivity from topical agents, once frequent and often associated with persistent reactions to light, is now becoming rare [3, 4], as the main topical photosen- sitizers are removed from the market, or maybe photo- sensitivity is underreported or underdiagnosed [5]. On the other hand, and even though sun avoidance is rec- ommended in those exposed to known photosensitizers, new drugs are reported to have photosensitizing proper- ties, eventually associated with late problems. Therefore, photosensitivity is still a problem and a field on intense research. New photosensitizers are reported as a cause of skin disease, whereas others are M. Gonçalo used for phtnototherapy. Studies are still being under- Clinic of Dermatology, Coimbra University Hospital, University of Coimbra, Praceta Mota Pinto, taken on the mechanisms and chromophores, respon- 3000-175 Coimbra, Portugal sible for diseases associated with photosensitivity, e-mail: [email protected] such as HIV infection [6, 7]. J.D. Johansen et al. (eds.), Contact Dermatitis, DOI: 10.1007/978-3-642-03827-3_18, © Springer-Verlag Berlin Heidelberg 2010 M. Gonçalo 18.2 General Mechanisms exposed to fluorquinolones, diuretics [15], and voricon- 18 of Photosensitivity azole [16]. The chromophore responsible for the photo- sensitive reaction can be an endogenous molecule, like a porphyrin that accumulates in the skin due to an inborn Normal skin has several molecules that are activated metabolic error, or it can be an exogenous molecule that upon sun exposure and undergo chemical reactions – is applied on the skin or reaches the skin through the the chromophores – which are important for our sur- systemic circulation. In many diseases, the chromophore vival under the sun and necessary for our life. An has been identified, but there are many idiopathic photo- example is 7-dehydrocholesterol which, upon activa- dermatoses for which the main chromophore is still tion by UVB, forms provitamin D3 necessary for unknown. Some resemble exogenous photoallergic Vitamin D synthesis. reactions, like “Lucite Estivale Bénigne,” polymorphic Photosensitivity develops when an abnormal chro- light eruption, or chronic actinic dermatitis, whereas mophore, or a normal chromophore in exaggerated others have very typical clinical patterns, like hydroa amounts, is present in the skin. When excited by a photon, vacciniforme or actinic prurigo. Also, as sunscreens are these molecules suffer changes within the molecule itself, widely used to prevent skin lesions in these photoder- often also within neighboring molecules, in a cascade of matoses, these patients frequently develop allergic or events that result in skin damage and inflammation. This photoallergic contact dermatitis to UV filters [3, 4], can occur through the direct molecular modification thereby associating the effect of endogenous and exog- (isomerization, breaking of double bounds, oxidation) or enous chromophores. production of free radicals, dependent or not on oxygen, In some patients, photosensitivity develops because which modify unsaturated lipids of cell membranes, aro- of a deficiency in the capacity to repair UV aggression, matic amino acids of proteins, or DNA or RNA bases of due to a genetic problem (xeroderma pigmentosum, nucleic acids. If the repair mechanisms do not act imme- Bloom’s syndrome) or a transient imbalance of antioxi- diately, there is damage and/or death of skin cells and dant skin defense (in pellagra due to reduced levels of inflammatory mediators are produced (prostaglandins, niacin in diet or alcohol consumption), or because the IL-1, 6, 8, other cytokines, and chemokines) with conse- natural mechanisms of skin protection are deficient (vit- quent skin lesions – this is briefly the mechanism of pho- iligo, albinism) [1, 17]. totoxicity [1]. In some circumstances, the energy of the photon can be used by the chromophore to transform itself into a new molecule (photoproduct) or to bind an Core Message endogenous peptide and, therefore, form a hapten or an › allergen that can be recognized by the skin immune sys- UV activation of an endogenous or an exogenous tem. In these cases, photoallergy may develop with a sen- skin chromophore can induce an inflammatory sitization phase and effector phase similar to allergic reaction (phototoxicity) or a T-cell-mediated contact dermatitis (see Chap. 8 for more details). reaction (photoallergy). Apart from the capacity to generate free radicals responsible for phototoxicity, several phototoxic sub- stances, such as psoralens, chlorpromazine, and fluo- rquinolones, have shown to induce chromosomal 18.2.1 Phototoxicity vs. Photoallergy damage in the presence of UVR. Therefore, both in vitro and in animal studies, they were photomutagenic and photoimmunosuppressive, with consequent implica- In theory, it is easy to differentiate photoallergy, a tions in photocarcinogenesis [8–12]. Epidemiological T-cell-mediated hypersensitivity reaction to an aller- studies and recent reports are showing this may also be gen formed upon UV exposure, from phototoxicity, significant for humans. In 1999, the group of Przybilla that represents an exaggerated inflammatory response showed an association between actinic keratosis and the to the sun enhanced by an exogenous chromophore. use of potentially photosensitizing chemicals [13]. More Classically, photoallergy develops only in a limited recent data tend to confirm an increased risk in patients number in individuals, needs previous sensitization but on long-term PUVA treatments [14] and, also in those is extensive to cross-reactive chemicals, is subject to 18 Phototoxic and Photoallergic Reactions flare-ups, is not dependent on the dose of the exoge- Also, although it is considered that photoallergy does nous chromophore and needs low UV exposure, not occur on a first contact due to the need for previous appears as eczema that can spread to nonexposed sites, sensitization, this may not be necessary if you have and on skin biopsy, there is mainly spongiosis as in already been sensitized by contact to a similar molecule. eczema. Phototoxicity is more frequent and considered This occurs in patients who are allergic to thiomersal, to develop in every individual, as long as enough pho- namely to its moiety thiosalicylic acid, who develop tosensitizer and sun exposure are present; occurs even photosensitivity to piroxicam on the first intake of the on a first and single contact, with no flare-ups or cross- drug. Upon UVA irradiation, piroxicam is photodecom- reactions; and appears mainly as well-demarcated ery- posed into a molecule very similar antigenically and thema exclusively on sun-exposed areas (mimicking structurally to thiosalicylic acid, responsible for piroxi- sunburn); and on histology, apoptotic keratinocytes cam photoallergy [23–25]. (sunburn cells) are abundant (Table 18.1). Also, although phototoxicity is considered to occur But, even though there are typical aspects of these in every patient as long as enough chromophore and two polar types of photosensitivity, some molecules sun are present at the same time, there is also individual may induce both phototoxic and photoallergic dermati- susceptibility to phototoxicity from drugs and phyto- tis. Although rare, this can occur with plant furocou- photodermatitis, even though the parameters that char- marins (Ruta graveolans, Ficus carica, Umbeliferae) acterize this susceptibility are not precisely known. or during photochemotherapy, as individuals become Therefore, and although, in theory, we can separate reactive to very low concentrations of psoralens [18]. these two mechanisms – phototoxicity