Atopic dermatitis (AD) is a chronic inflammatory systemic disease characterized by pruritus, erythema, and desquamation. It afflicts roughly 15–30% of children and 2–10% of adults across the globe, thereby constituting a prevalent condition with a significant potential to affect the well-being of afflicted individuals [1]. Conventional systemic therapy, typically encompassing immunosuppressants in conjunction with topical corticosteroids, is customarily employed to address moderate-to-severe AD, albeit it is marked by limited efficacy and undesirable side effects [2]. Thus, a pressing need exists for more efficacious treatments, including therapeutic options suitable for monotherapy [2]. In this context, the inhibition of the Janus kinase (JAK)-signal transducer and activation of transcription-mediated signaling pathways emerges as a promising therapeutic approach for managing moderate-to-severe AD, as substantiated by recent randomized, placebo-controlled trials [3, 4].

Upadacitinib, an orally administered JAK inhibitor demonstrating superior inhibitory potency for JAK1 compared to JAK2, JAK3, and tyrosine kinase 2, has obtained approval in over 50 countries for the management of moderate-to-severe AD [5]. Notably, one of the most frequently reported adverse events in the upadacitinib phase 3 trials, pertaining to the treatment of moderate-to-severe AD, was an acne-like eruption of uncertain etiology [3, 5]. During the 16-week period characterized by double-blind placebo control, the incidence of acne ranged from 7% to 13% with upadacitinib 15 mg, and from 14% to 17% with upadacitinib 30 mg, in comparison to the 2% incidence observed with placebo [6]. Altogether, acne manifested in 84 patients (9.8%) randomized to upadacitinib 15 mg, 131 patients (15.2%) randomized to upadacitinib 30 mg, and 19 patients (2.2%) randomized to placebo [6]. Notably, the majority of acne cases presented with mild-to-moderate severity (grade 1–2), with only one case reaching the classification of severe acne (grade 3) [6]. A noteworthy risk factor for the development of acne was a medical or family history of acne [6]. Furthermore, 40.5% and 46.6% of cases in the upadacitinib 15 mg and 30 mg groups, respectively, did not necessitate concomitant medication for management. Among those requiring intervention for acne, most patients received topical therapies, either as standalone treatments or in combination, which included antibiotics, benzoyl peroxide, or retinoids [6].

Recent theories have proposed that acne represents an mTORC1-driven disorder [7, 8]. Anti-acne therapy has been postulated to attenuate enhanced mTORC1 signaling in patients afflicted with acne [7, 8]. The mechanism of action of anti-acne agents has been linked to the modulation of mTORC1 signal transduction (Fig. 1). Androgens, by activating mTORC2, potentiate Akt-mediated activation of mTORC1 [7]. Collectively, it is conceivable that drug-induced modifications in various all-trans-retinoic acid (ATRA)-catabolizing P450 isoenzymes might influence FoxO-mediated mTORC1 signaling in acne, akin to the effects seen with P450-inducing drugs, including corticosteroids, neuropsychotherapeutic drugs, and antituberculosis drugs, which either exacerbate acne or induce acneiform skin eruptions [7].

Fig. 1.

Metabolism of retinol and its impact on mTORC1 signaling in keratinocytes and sebocytes. Implications of upadacitinib-mediated modulation of CYP3A4 in acne pathogenesis. ATRA stimulates FoxO expression, which inhibits mTORC1 and activates AMPK by raising sestrin 3, which in turns inhibits TSC1/TSC2 heterodimer and, thereby, inhibiting Rheb activity, which is required for mTORC1 activation. ATRA, all-trans-retinoic acid; RXR, retinoid X receptor; RAR, retinoic acid receptor; AMPK, adenosine monophosphate activated protein kinase; TSC, tuberous sclerosis complex; Rheb, Ras-homolog enriched in brain; mTORC1, mechanistic target of rapamycin complex 1. Adapted from Melnik [7].

Fig. 1.

Metabolism of retinol and its impact on mTORC1 signaling in keratinocytes and sebocytes. Implications of upadacitinib-mediated modulation of CYP3A4 in acne pathogenesis. ATRA stimulates FoxO expression, which inhibits mTORC1 and activates AMPK by raising sestrin 3, which in turns inhibits TSC1/TSC2 heterodimer and, thereby, inhibiting Rheb activity, which is required for mTORC1 activation. ATRA, all-trans-retinoic acid; RXR, retinoid X receptor; RAR, retinoic acid receptor; AMPK, adenosine monophosphate activated protein kinase; TSC, tuberous sclerosis complex; Rheb, Ras-homolog enriched in brain; mTORC1, mechanistic target of rapamycin complex 1. Adapted from Melnik [7].

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The underlying etiology of upadacitinib-associated acne in AD patients remains obscure. Acne has been documented in trials evaluating other systemic JAK inhibitors for the treatment of moderate-to-severe AD [3, 5]. Acne occurred in 1.3–2.9% and 5.8–6.6% of patients receiving abrocitinib at daily doses of 100 mg and 200 mg (as compared to 0% in the placebo group) [4]. In addition, acne manifested in only 4% of patients receiving 4 mg of baricitinib for AD treatment. It is worth noting that upadacitinib acts as a CYP3A4 inducer, distinguishing it from abrocitinib and baricitinib. Mohamed et al. [9] demonstrated that the administration of multiple doses of upadacitinib led to a 26% decrease in plasma exposures of midazolam, a sensitive CYP3A substrate, reflecting its impact on CYP3A activity. Abrocitinib is primarily metabolized by CYP2C19 and CYP2C9, while baricitinib is primarily excreted through renal filtration, exerting no clinical influence on CYP3A4 activity or induction [10].

Consequently, the upregulation of CYP3A4 activity upon upadacitinib administration may culminate in reduced levels of ATRA signaling in acroinfundibular keratinocytes and sebocytes. The increased ATRA degradation may, thus, constitute an additional route for ATRA-FoxO1-mediated effects on mTORC1 in acne and, in susceptible individuals, contribute to the incidence of acne within the AD population treated with upadacitinib. While this implies a potential connection between the JAK pathway and acne, it does not fully elucidate the cause of treatment-induced acne observed with JAK inhibition, whether topically or systemically. Clinically, patients exhibit signs indicative of acneiform eruptions alongside classic acne (Fig. 2, 3) [11]. In their retrospective analysis, Avallone et al. [12] reported a 16% incidence rate of these conditions in patients treated with upadacitinib. Of this group, 89.5% developed new-onset acne, with 93.8% categorized as mild to moderate. Regarding management, a minority of 31% required intervention, predominantly with topical agents. Upadacitinib discontinuation was necessary for only 6.3% of the cases. Further research is warranted to unravel the mechanisms underlying the emergence of acne in patients treated with upadacitinib, particularly those with AD.

Fig. 2.

A 24-year-old female patient is undergoing 15 mg upadacitinib therapy for a moderate acneiform eruption. Observe the widespread distribution and uniform appearance of the lesions.

Fig. 2.

A 24-year-old female patient is undergoing 15 mg upadacitinib therapy for a moderate acneiform eruption. Observe the widespread distribution and uniform appearance of the lesions.

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Fig. 3.

A 29-year-old male patient presented with an acneiform eruption while on 15 mg of upadacitinib, characterized by the monomorphic nature of the lesions and a clear central area on the back.

Fig. 3.

A 29-year-old male patient presented with an acneiform eruption while on 15 mg of upadacitinib, characterized by the monomorphic nature of the lesions and a clear central area on the back.

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The authors have no conflicts of interest to declare.

There was no funding.

Guilherme Muzy: approval of the final version of the manuscript, critical literature review; data collection, analysis, and interpretation; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic management of studied cases; manuscript critical review; preparation and writing of the manuscript; statistical analysis; and study conception and planning.

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