Topical anti-inflammatory treatments currently consist of topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Their effective use requires (Wollenberg et al., 2018):
Traditionally, these conventional therapies were used reactively, applied to lesional skin and then stopped or tapered once visible lesions had cleared. However, a shift towards proactive treatment has been recommended where, once lesions have cleared, twice weekly application of the topical anti-inflammatory is continued alongside liberal use of emollients. Good results have been observed with topical corticosteroids and TCI, although topical corticosteroids are typically prescribed for short periods and no data beyond 20 weeks is available indicating an ongoing need for more research and additional therapeutic options to complement conventional therapy (Wollenberg et al., 2018).
A variety of topical corticosteroids (TCS) are available for patients with atopic dermatitis with the appropriate treatment based on patient-related factors, such as severity, patient age, the area of the body is to be applied to, and the physiochemical properties of the drug (Kwatra & Mukhopadhyay, 2018; Wollenberg et al., 2018). Local adverse events can be a concern with the use of TCS, but systemic effects are typically restricted to prolonged use and/or the use of high potency options (Kwatra & Mukhopadhyay, 2018).
Many divide the available TCS into four classes not taking into account the type of formulation: mild, moderate, strong and very strong preparations (Thomsen, 2014). However, the World Health Organization divides TCS into seven classes/groups based on potency, concentration and vehicle, meaning the same drug can be placed into different classes. These seven classes are then placed into four groups with group I being ultrahigh potency and group IV low potency (Kwatra & Mukhopadhyay, 2018).
Table 6: Classification of topical corticosteroids by potency (Thomsen, 2014).
When choosing a TCS (Wollenberg et al., 2018):
Corticosteroids have anti-proliferative, immunosuppressive, anti-inflammatory and vasoconstrictor actions. These effects can be divided into ‘genomic’ and ‘non-genomic’ mechanisms (Kwatra & Mukhopadhyay, 2018).
The genomic mechanism of action involves corticosteroid binding to the nuclear glucocorticoid receptor resulting in changes to protein transcription. This process has been shown to induce transcription of anti-inflammatory proteins and have a broad range of effects on the cells of the immune system (Kwatra & Mukhopadhyay, 2018).
Table 7: Corticosteroid effects on immune cells (Kwatra & Mukhopadhyay, 2018).
While significant progress has been made in our understanding of the genomic effects topical corticosteroids has, less is known about the non-genomic mechanisms of action. However, it has been proposed that corticosteroid interactions at the plasma- and mitochondrial membranes could alter their physicochemical properties and activities of membrane-associated proteins (Kwatra & Mukhopadhyay, 2018).
Two topical calcineurin inhibitors have been approved for the management of atopic dermatitis; tacrolimus ointment for moderate-to-severe disease and pimecrolimus cream for mild or moderate disease. While tacrolimus is comparable to a moderate to strong topical corticosteroids, pimecrolimus has a similar potency to a mild topical corticosteroid (Thomsen, 2014). Importantly, topical calcineurin inhibitors are not associated with thinning of the skin as seen with topical corticosteroids allowing them to be used for longer periods of time. Long-term safety data has been published for each topical calcineurin inhibitor. A 4-year follow-up of patients using continuous or intermittent tacrolimus revealed a safety profile that was consistent with shorter periods of use indicating that long-term use gave no additional reason for concern (Reitamo et al., 2008). Meanwhile, a 5-year follow-up of patients receiving topical corticosteroids with pimecrolimus or topical corticosteroid alone showed a similar profile and frequency of adverse events between the two groups while the addition of pimecrolimus was found to be steroid sparing (Sigurgeirsson et al., 2015). However, some concerns have been raised with a commentary article highlighting that patients receiving pimecrolimus saw a higher incidence of bronchitis, infected eczema, impetigo and nasopharyngitis (Weidinger et al., 2017).
Calcineurin inhibitors are effective immunosuppressants; oral tacrolimus is a widely used therapy for the prevention of transplant rejection. The topical calcineurin inhibitors function by suppressing the synthesis of pro-inflammatory cytokines in the skin. Both pimecrolimus and tacrolimus block the synthesis and release of IL-2, IL-3, IL-4, IL-5, interferon γ (IFNγ), and tumour necrosis factor α (TNFα) from T cells and Mast cells. However, tacrolimus also inhibits eosinophil and basophil activity, while blocking Langerhans cell function and promoting their apoptosis (Gutfreund et al., 2013).