by modulating nuclear transcription. Unlike biologics, which require the RES system for drug clearance, small molecules undergo hepatic or renal clearance and may require decreased dosages for severe renal or hepatic impairment.Apremilast is an oral formulation of an intracellular phosphodiesterase 4 (PDE-4) inhibitor approved for psoriasis and psoriatic arthritis. Crisaborole is a topical formulation approved for mild-moderate AD. PDE-4 is a cytosolic enzyme that degrades cAMP to AMP within inflammatory cells including dendritic cells, T-cells, macrophages, monocytes, and keratinocytes.6,7 Increased cAMP leads to PKA activation, which phosphorylates transcription factors that prompt transcription of anti-inflammatory genes, including interleukin (IL)-10.7 This process also inhibits nuclear factor-?B (NF-?B), which decreases production of pro-inflammatory mediators TNF-α, interferon (IFN)-γ, and IL-23.7 Apremilast is metabolized through both CYP1A2 and non-CYP-mediated hydrolysis, to be cleared through urine and stool.7 Tofacitinib is an intracellular Janus kinase (JAK)-1 and JAK-3 inhibitor available in oral and topical formulations. JAKs are tyrosine kinases that bind to an activated intracytoplasmic cytokine receptor to activate STAT proteins. Activated STAT proteins undergo nuclear translocation to act as transcription factors that upregulate the expression of pro-inflammatory cytokines and growth factors. Tofacitinib inhibits intracellular signal transduction of IL-2, IL-4, IL-9, IL-15, and IL-21, together modulating various aspects of the immune response.6 Small molecules are less likely to interact with MHCII due to their size, making ADA formation unlikely. Therefore, in theory, small molecule inhibitors should not develop the same drug tolerance response. However, research investigating the long-term drug survival of small molecule inhibitors is warranted.Biologics and small molecules play an important role in the treatment of dermatologic diseases. It is important for dermatologists to recognize the similarities and differences between the two classes of drugs. Advantages of biologics include strong initial efficacy and proven safety profiles. Disadvantages include their subcutaneous or intravenous administration, storage requirements, and potential drug tolerance. Advantages of small molecules include their oral or topical formulation, and their lack of immunogenicity. Future head-to-head trials are needed to compare the efficacy and cost-value analyses of biologics to small molecules in treating dermatologic diseases. Additionally, as we move closer to an era of personalized
