There has been a long‐standing dermatology‐driven interest in vitamin A (retinol) and its derivatives (retinoids) (see Fig. 1). In 1925, Wolbach and Howe were one of the first to report that vitamin A deficiency induces abnormal epithelial keratinization in rats.1 Not much later, in 1933, nutritional vitamin A deficiency in humans was linked to the development of phrynoderma (‘toad skin’) with follicular hyperkeratosis, hyperpigmentation and xerosis cutis.2 These observations fuelled clinical interest in vitamin A as a potential pharmacological treatment for keratinization skin diseases, but initial studies from the 1940s and early 1950s in patients with ichthyosis, pityriasis rubra pilaris and Darier disease showed that the dose levels of oral vitamin A required for sufficient therapeutic responses caused unacceptable toxicity.3, 4 Aiming for an improved safety profile, chemical compounds with structural or functional similarities to vitamin A (i.e. the retinoids) were synthesized by the ground‐breaking works of Bollag, among others.5 Two of the first synthetic retinoids developed were all‐trans‐retinoic acid (ATRA, also known as tretinoin) and 13‐cis‐retinoic acid (better known as isotretinoin) back in 1946 and 1955, respectively.6, 7 Pioneering studies by Stuettgen and Kligman et al., among others in the 1960s, established topical tretinoin as a dermatological treatment.8-10 However, further drug development was delayed by concerns for retinoids’ teratogenicity potential in the wake of the thalidomide tragedy.11 The next breakthrough did not come until 1982 when oral isotretinoin received U.S. market approval for severe acne.12

Figure 1 Open in figure viewer PowerPoint Historical development of retinoids as a class of drugs in dermatology. FDA, U.S. Food and Drug Administration.

Ever since, retinoids have remained a major class of dermatological treatment. Both topical and oral retinoid formulations have been in use across a wide range of inflammatory, (pre‐)malignant and keratinization skin diseases – these include, among others, acne, psoriasis, cutaneous lymphoma, ichthyosis and photoageing.10, 12 The increasing clinical applications of retinoids have been paralleled with intensive skin biology research, showing that the pleotropic cellular effects of retinoids are mediated by two types of nuclear receptors: the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), both of which are present in three isoforms (α, β and γ) (see Fig. 2).13

Figure 2 Open in figure viewer PowerPoint Mode of action of retinoids. R, retinoid; RA, retinoic acid; RAR, retinoic acid receptor; RARE, retinoic acid response element; RXR, retinoid X receptor.

Even though more than 2000 retinoid compounds have been developed, a limited number is currently in clinical use.10 Three generations of retinoids are distinguished: first, the nonaromatic retinoids, including tretinoin, isotretinoin and alitretinoin; second, the mono‐aromatic retinoids, which include acitretin and the no longer widely available etretinate; and third, the poly‐aromatic retinoids bexarotene, tazarotene and adapalene.12

In this issue of the BJD, Aubert and colleagues describe preclinical pharmacological evaluations of trifarotene, a novel first‐in‐class fourth‐generation topical retinoid.14 By using multiple in vitro and in vivo assays, the authors demonstrate robust and favourable metabolic and pharmacokinetic properties of trifarotene. Moreover, in multiple mouse models trifarotene exhibited superior comedolytic, anti‐inflammatory and depigmenting activity compared with other topical retinoids. Gene expression profiling in skin samples of patients with acne treated with trifarotene 0.005% cream was helpful to establish further clinical relevance. As opposed to other topical retinoid agents, trifarotene is a potent and selective RAR‐γ agonist and this may avoid RAR‐β‐mediated skin irritation. Consequently, it is hoped that this might translate to a better tolerability, as ‘retinoid dermatitis’ is a well‐known and potential treatment‐limiting side‐effect of topical retinoids.15

In conclusion, well over 50 years since the introduction of the first topical retinoid, the class of retinoids is now expanded with a fourth‐generation topical compound. Trifarotene shows favourable preliminary pharmacokinetics and pharmacodynamics supporting its continuous development. With a potential market in sight – among others, acne (high numbers), keratinization disorders (chronic need) and photoageing (cosmetic demands) – the arrival of a topical retinoid with an improved tolerability profile is much awaited.