We thank Lecluse et al for their interest in our work. Their main concern is that high-molecular-weight molecules such as etanercept, infliximab, and adalimumab should not be able to penetrate the stratum corneum and cause positive patch test results, based on the “500 Dalton rule.”1 This molecular sieve modeling of the skin is probably more applicable to simple chemicals than to biological compounds, especially proteinaceous substances. Ever since it was first described by Leslie Roberts in 1899, the proteolytic activity of the epidermis is acknowledged.2 More recent work has shown the large repertoire of proteases and antiproteases secreted in the stratum corneum.3 Skin contact with large proteins (>50 kDa), including food, plant, and animal proteins—which are mostly recognized as atopens because of the large prevalence of IgE immune responses they can trigger—can induce contact dermatitis and positive patch test results.4 The mechanism and mode of penetration of large proteins to access the skin immune system is still debated; 2 possibilities are direct skin penetration or hydrolysis and second-step penetration of smaller peptides. Similarly, the role of hair follicles, sebaceous glands, and sweat glands in large protein penetration is not yet clarified. Despite these uncertainties, skin penetration of high-molecular-weight molecular biological compounds can be considered a reality that might also apply to large proteins such as anti–tumor necrosis factor (anti-TNF) blockers.
Seneschal J, Milpied B, Taïeb A. The Use of Patch Tests in Determining Hypersensitivity to Etanercept and Infliximab—Reply. Arch Dermatol. 2008;144(8):1071-1072. doi:10.1001/archderm.144.8.1071