UV recall

Ultraviolet (UV) reactivation reactions are rare and little known drug-induced dermatitic reactions that occur in areas previously exposed to varying degrees of UV irradiation. Such reactions have been observed primarily after administration of chemotherapeutics, antibiotics and other drugs (e.g. Suramin - Lowitt MH et al. 1995). Analogue radiation-associated drug reactions have been described as "radiationrecall" after radiation therapy and subsequent therapy with cytostatic drugs (other drug groups can also trigger such recall reactions). UV reactivation reactions can occur within days after UV exposure (e.g., after methotrexate), but also months later (e.g., after ampicillin).

The UV reactivation reaction is a special form of UV recall dermatitis, which is induced by earlier exposure to sunlight. It is an immunological reaction histopathologically characterized by epidermal spongiosis, by the appearance of intraepidermal apoptotic keratinocytes (Basile FG (2011). As this is a rare phenomenon, the pathophysiology of this reaction is not yet well characterized. It is assumed that non-lethal cell damage develops in dividing keratinocytes as a result of solar radiation, which becomes clinically evident in a later drug-induced immune reaction.

Numerous chemotherapeutic agents can cause UV reactivation reactions, such as taxanes, methotrexate, gemcitabine, etoposide, cyclophosphamide, paclitaxel, anthracyclines, docetaxel / cyclophosphamide (Burris H et al. 2010). Furthermore, several antibiotics have been identified as triggers of UV recall, including ampicillin, cephalosporins and gentamicin (Hil HZ et al. 2002).

Finally, the fixed drug reaction is also to be addressed as a "reactivation reaction" as it follows an analogous activation process.

The mechanisms underlying this reactivation response are still unknown. It is assumed that the epithelial cells are more responsive to epigenetic, transcriptional and metabolic programs after transient stimulation. This phenomenon is referred to as "trained immunity" or "innate immune memory". TI was first discovered in cells of the innate immune system, e.g. monocytes, macrophages and natural killer cells. However, TI has also been found in cells with a long lifespan, such as stem cells and fibroblasts (Naik, S et al. 2017). It has been shown that epithelial stem cells (EpSCs) can develop a long-lasting memory for previous inflammatory stimuli, e.g. topical imiquimod treatment, enabling the skin to respond quickly to subsequent damaging stimuli. After the initial stimulus, EpSCs retain chromosomal accessibility of several critical genes for the inflammatory response, enabling rapid transcription of AIM2 and its downstream effector genes upon a secondary stimulus, i.e. skin injury (Naik, S et al. 2017). This memory is mediated by the Aim2 gene encoding an activator of the inflammasome. The absence of the AIM2 protein or its downstream effectors, caspase-1 and interleukin-1beta, abolishes the memory of EpSCs for inflammation (Naik, S et al. 2017).

The treatment of the UV reactivation reaction is empirical. Most cases have been treated with topical steroids, and it is unclear whether or not they actually alter the clinical course or the risk of recurrence in subsequent chemotherapy cycles.

Typically, e.g. taxane-induced photo recall phenomena tend to weaken during subsequent treatments (Basile FG 2011). The therapeutic benefit of systemic steroids is still unclear.

UV reactivation reactions are rare, but clinically and medically important. Oncological patients are advised to explicitly avoid UV exposures during and several months after chemotherapy.

A 43-year-old premenopausal woman was diagnosed with T1bN0M0 estrogen receptor (ER) positive invasive ductal carcinoma of the right breast. The patient underwent breast-conserving surgery and decided to undergo adjuvant chemotherapy (docetaxel and cyclophosphamide) before radiation. Before starting the chemotherapeutic treatment, a long planned 1-week vacation in Florida was started. The UV exposures in Florida were without UV dermatitis. On day 5 of chemotherapy, the patient developed a maculo-papular exanthema on the previously light-exposed skin areas. Non-UV-exposed skin areas remained free. The patient received 100mg prednisolone i.v. for 5 days and externally a glucocorticoid cream of medium strength. The skin reaction subsided within 2 weeks. In the 2nd cycle of chemotherapy (no dose reduction), a similar but less severe skin reaction occurred again, but it was significantly less severe and no intervention was necessary.

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