Cutaneous Tolerability to Tretinoin Shows Little Variation With Fitzpatrick Skin Type

June 2014 | Volume 13 | Issue 6 | Original Article | 706 | Copyright © June 2014

Guy F. Webster MD PhD

The Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA

Determinants of skin irritability are poorly understood. This study aims to assess differences in cutaneous safety/irritation based on Fitzpatrick skin type among patients with acne treated with tretinoin gel microsphere (TGM).
This was a phase 4, 12-week, prospective, nonrandomized, open-label, multicenter study. Approximately 500 patients with mild to moderate acne were treated with TGM 0.04% or 0.1% and assessed for cutaneous irritation at baseline and weeks 3, 6, and 12.
In this post hoc analysis of patients with Fitzpatrick skin type I-III vs Fitzpatrick skin type IV-VI, there was a general trend toward initial worsening of cutaneous adverse events (AEs) by week 3 across all variables and groups. This was followed by a trend toward improvement and resolution of skin-related AEs from week 3 to week 12 regardless of Fitzpatrick skin type, with a few exceptions. Erythema was the only cutaneous AE that consistently decreased among patients with darker skin. Results from a subsequent 3-group analysis (Fitzpatrick I-II vs Fitzpatrick III-IV vs Fitzpatrick V-VI) generally mirrored those from the 2-group study.
Study limitations include patient nonadherence, lack of a placebo arm, and lack of data regarding the impact of concurrent medications on outcomes. There was no correlation between irritation and Fitzpatrick skin type.
ABBREVIATIONS USED: adverse event (AE), analysis of variance (ANOVA), benzoyl peroxide (BP), case report form (CRF), modified Global Acne Grading Score (mGAGS), tretinoin gel microsphere (TGM)

J Drugs Dermatol. 2014;13(6):706-711.


Acne vulgaris is one of the most common conditions encountered in dermatology and affects individuals across all racial and ethnic groups.1 However, there is little known regarding variation in response to treatment in different skin types. Determinants of skin irritability are poorly understood as well. It has been assumed by many that lighter skin is more irritable for reasons not founded in data; and indeed there are scant data to consider. Previous studies have reported either no differences between lighter and darker skin types or less cutaneous irritation associated with acne treatments in darker skin.2,3 A meta-analysis of clinical trials of adapalene gel 0.1% use in 46 Black and 609 Caucasian patients found that Black patients had a reduced incidence of erythema and scaling compared to lighter skin types.3 A second meta-analysis of 909 patients across 3 clinical trials found that adapalene 0.1%/benzoyl peroxide (BP) 2.5% was not associated with any differences in irritation between lighter (Fitzpatrick I-III) and darker (Fitzpatrick IV-VI) skin types.2 A study of clindamycin phosphate 1.2%/BP 2.5% found that cutaneous irritation was comparable between darker and lighter Fitzpatrick skin types. However, erythema was worse in patients with Fitzpatrick skin types I-III, as patients with darker skin (Fitzpatrick IV-VI) were rated as having “none” more often, possibly due to difficulty observing erythema in darker skin.4
Topical tretinoin (all-trans retinoic acid) is a common treatment for acne vulgaris and is often recommended as maintenance therapy for acne, particularly because it reduces comedo formation without inducing bacterial resistance.5,6 Topical tretinoin is associated with the potential for skin irritation, particularly during the first 1 to 2 weeks of treatment.7,8 However, newer formulations such as TGM have been designed with controlled-release mechanisms intended to reduce irritation potential. TGM 0.1% and 0.04% are encapsulated in a microsphere delivery system and suspended in an aqueous gel with the intention of reducing irritation. This formulation uses patented methyl methacrylate/glycol dimethacrylate cross-polymer porous microspheres (Microsponge® System), which allow for slower delivery of active ingredients to the skin.9,10 TGM 0.04% and 0.1% have been shown to reduce inflammatory and noninflammatory lesions, with cutaneous adverse events (AEs) occurring in the early phase of treatment. In patients with mild to moderate acne, skin-related AEs in a 12-week trial included burning (2.6% and 7.7% for 0.04% and 0.1%, respectively) and irritation (6.4% and 3.8%, respectively). Fewer patients in the 0.04% group experienced dryness during the early phase of treatment.11 In a phase 4, 12-week, prospective, nonrandomized, open-label, multicenter community-based study of TGM (0.04% or 0.1%), cutaneous irritation variables (erythema, dry-