Drug-Induced Photosensitivity—An Update Forearms and Hands

Drug Safety https://doi.org/10.1007/s40264-019-00806-5 REVIEW ARTICLE Drug‑Induced Photosensitivity—An Update: Culprit Drugs, Prevention and Management Kim M. Blakely1 · Aaron M. Drucker1,2 · Cheryl F. Rosen1,3 © Springer Nature Switzerland AG 2019 Abstract Photosensitive drug eruptions are cutaneous adverse events due to exposure to a medication and either ultraviolet or visible radiation. In this review, the diagnosis, prevention and management of drug-induced photosensitivity is discussed. Diagnosis is based largely on the history of drug intake and the appearance of the eruption primarily afecting sun-exposed areas of the skin. This diagnosis can also be aided by tools such as phototesting, photopatch testing and rechallenge testing. The mainstay of management is prevention, including informing patients of the possibility of increased photosensitivity as well as the use of appropriate sun protective measures. Once a photosensitivity reaction has occurred, it may be necessary to discontinue the culprit medication and treat the reaction with corticosteroids. For certain medications, long-term surveillance may be indicated because of a higher risk of developing melanoma or squamous cell carcinoma at sites of earlier photosensitivity reactions. A large number of medications have been implicated as causes of photosensitivity, many with convincing clinical and scientifc supporting evidence. We review the medical literature regarding the evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing. Amiodarone, chlorpromazine, doxycycline, hydrochlorothiazide, nalidixic acid, naproxen, piroxicam, tetracycline, thioridazine, vemurafenib and voriconazole are among the most consistently implicated and warrant the most precaution by both the physician and patient. Key Points 1 Introduction Photosensitive drug eruptions, including both phototox- Photosensitive drug eruptions have been reported to repre- icity and photoallergy, have been reported for a number sent up to 8% of cutaneous adverse events from drugs [1]. of systemic medications. Such reactions, which can be classifed as either photoallergic or phototoxic, occur after exposure to a photosensitizing This review provides a comprehensive overview of medi- drug, either topically or systemically, and either ultraviolet cations implicated in such reactions, including the clini- (UV) or visible radiation. Importantly, for a drug eruption cal presentation for each medication and the evidence to be considered photosensitive, it must meet the following available to implicate them as true photosensitizers. criteria: (1) it occurs only in the context of radiation, (2) the Improved reporting, including randomized control tri- drug or one of its metabolites must be present in the skin at als, will help to better characterize these reactions and the time of exposure to radiation and (3) the drug and/or its provide a more comprehensive list of photosensitive metabolite(s) must be able to absorb either visible or UV medications for both the physician and patient. radiation. UVA radiation, which penetrates deeper into the dermis than UVB, is most commonly implicated in photo- * Cheryl F. Rosen sensitive drug eruptions, although UVB and visible light [email protected] have been reported for specifc medications [2]. Classically, photosensitivity reactions are classifed based 1 Division of Dermatology, Department of Medicine, on their proposed mechanism of action into photoallergic University of Toronto, Toronto, ON, Canada and phototoxic reactions (Table 1). Attempts to distinguish 2 Division of Dermatology, Department of Medicine, Women’s the two can be made using clinical history and physical College Research Institute, Women’s College Hospital, Toronto, ON, Canada examination, as well as histopathology and clinical tests including phototesting and photopatch testing. However, 3 Division of Dermatology, Toronto Western Hospital, Toronto, ON, Canada distinguishing between phototoxicity and photoallergy in Vol.:(0123456789) K. M. Blakely et al. Table 1 Diferentiating features between photoallergic and phototoxic drug-induced photosensitivity (adapted from Gould et al. [88]) Feature Photoallergy Phototoxicity Incidence Low High Pathophysiology Type IV hypersensitivity reaction Direct tissue injury Required dose of medication Low Usual dose to high Required dose of radiation Low High Onset after light exposure > 24 h < 24 h Clinical appearance Eczematous Exaggerated sunburn reaction Sensitization required Yes No Localization May spread outside exposed areas Only exposed areas Pigmentary change Unusual Frequent Histology Epidermal spongiosis, exocytosis of lymphocytes and a Necrotic keratinocytes, predominantly perivascular infammatory infltrate lymphocytic and neutrophilic dermal infltrate an individual patient can be difcult, and usually does not these adverse reactions, is an important aspect of patient care afect management. when using photosensitizing medications. Photoallergic drug eruptions, in addition to meeting all In this review, which is an update from our original article the criteria for photosensitivity reactions outlined above, published in 2011 [10], we discuss the diagnosis of pho- must demonstrate an immune-mediated mechanism of tosensitivity reactions, culprit drugs, as well as prevention action. Similar to other type IV hypersensitivity reac- and management of these eruptions. We have not included tions, not all persons exposed concurrently to both the reactions to topically administered drugs (e.g. sunscreens), drug and to radiation will experience the photosensitiv- and instead focus on reactions to systemically administered ity reaction. When a susceptible person does display a medications. We have also excluded drugs that cause pho- photoallergic reaction, typically it will present clinically tosensitivity as part of their desired mechanism of action as a predominantly eczematous eruption. Histopathologic (e.g. psoralens). features are identical to those seen in an allergic contact dermatitis, including epidermal spongiosis, vesiculation, exocytosis of lymphocytes and a perivascular inflamma- 2 Diagnosis tory infiltrate [3]. Phototoxic drug eruptions are much more frequent than Most cases of drug-induced photosensitivity can be diag- photoallergic reactions. Phototoxic drug eruptions are not nosed based on a detailed clinical history and physical immune-mediated, but instead result from direct cellular examination, as well as knowledge of the classic groups of damage. As such, phototoxic reactions will occur in all medications typically implicated in such reactions. That is, individuals exposed to sufcient doses of both the drug and specialized testing is not necessary to make the diagnosis radiation of the appropriate wavelengths. Classically, pho- for most patients. However, investigations including phototoxic eruptions appear as exaggerated sunburn reactions totesting may be important to diferentiate drug-induced with erythema, itching and burning. Histopathologically, photosensitivity from other causes of photosensitivity, par- necrotic keratinocytes are seen along with a predominantly ticularly where the relationship between onset of photosen- lymphocytic and neutrophilic dermal infltrate. Of note, sitivity and drug ingestion is not clear. For patients with a both phototoxic and photoallergic drug eruptions may have suspected photosensitivity eruption, as with any dermato- a dermatitic appearance. Other manifestations of photosen- logic presentation, a thorough clinical history and physical sitivity can include lichenoid eruptions, pseudoporphyria, examination should be performed. The interviewer should onycholysis, erythema multiforme, hyperpigmentation and pay particular attention to medication history, with special telangiectasia, as will be discussed in more detail with the consideration given to the temporal relationship of the erup- various culprit medications below. tion with the starting of any new medications. Additionally, Not only are photosensitive reactions a cause of signif- a general review of systems should be performed to screen cant morbidity in afected individuals, but in some instances, for diseases associated with photosensitivity, such as sys- pose a future risk for malignancy, specifcally melanoma temic lupus erythematosus. With photosensitive reactions, and keratinocyte carcinoma [4–9]. As such, awareness of physical examination will often reveal a photodistributed these culprit drugs, and using appropriate measures to avoid eruption involving the face, V of the neck and extensor Drug-Induced Photosensitivity—An Update forearms and hands. Areas typically spared include the rate secondary to skin irritation [15] and is not validated for upper eyelids, the base of skin folds (e.g. nasolabial folds), the majority of medications discussed in this review. as well as the submental and posterior auricular regions, as these areas are relatively protected from sun exposure. In cases where there is no prior literature to support a pho- 3 Photosensitizing Drugs tosensitive reaction to a given medication or where the diagnosis itself is in question, testing exists that may help In this updated narrative review, we discuss the drugs that to establish a diagnosis. Although several in vitro tests to have been reported, in the English-language medical lit- assess the photosensitizing potential of certain medications erature, to cause clinical photosensitivity. PubMed was the in cultured

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