Efficacy and cutaneous safety of adapalene in black patients versus white patients with acne vulgaris

Acne vulgaris is the most common dermatologic disorder seen in American black patients (ie, African Americans and African Caribbeans, Fitzgerald skin types IV through VI). Despite its prevalence, there is a lack of data on the effects of treatments, such as the use of topical retinoids and retinoid analogs, in this patient population. Adapalene is a topical retinoid analog that has demonstrated efficacy in the reduction of noninflammatory and inflammatory lesions, along with excellent cutaneous tolerability. Most clinical studies of this agent have involved predominantly white patient populations. This meta-analysis of 5 randomized US and European studies was designed to evaluate the efficacy and safety of adapalene in black versus white patients. The percentage reduction in the number of inflammatory lesions was significantly greater among black patients compared with white patients (P=.012). The percentage reductions in total inflammatory and noninflammatory lesion counts were similar in the 2 groups (P>.3). There were significantly less erythema and scaling in black patients compared with white patients (P<.001 and P=.026 for worst scores for erythema and scaling, respectively). Although the incidence of dryness was similar in both groups, a smaller percentage of black than white patients had moderate or severe scores for dryness (7% vs 18%, respectively). In summary, adapalene appears to be a viable treatment for black patients with acne vulgaris.     

Developments in topical retinoid therapy for acne

Topical retinoic acid was introduced for acne treatment three decades ago. Since that time, researchers have discovered thousands of retinoids, originally defined as chemical analogs of vitamin A. After the identification of nuclear retinoid receptors in 1987, the definition of this class expanded to include molecules that bind to and activate such receptors. The receptor-selective retinoid agents, adapalene and tazarotene, were developed in the 1990s. Other innovations of the past decade include retinoid formulations and methods aimed at limiting retinoid absorption. Cutaneous irritation may be reduced without losing retinoid efficacy by inhibiting retinoid penetration into the deep epidermis and dermis. Examples include tretinoin in slow-release vehicles and the short-contact method of tazarotene gel therapy. Only trace amounts of adapalene are absorbed after topical application, perhaps explaining its relatively low irritancy. New formulations of existing agents, such as additional concentrations of tretinoin in microsphere gel and cream formulations of tazarotene, are now under investigation for acne. Current research focused on receptor selectivity holds the promise of yielding new retinoid molecules with improved benefits and safety.     

Topical Retinoids in Acne Vulgaris

Topical retinoids represent a mainstay of acne treatment because they expel mature comedones, reduce microcomedone formation, and exert anti-inflammatory effects. The first-generation retinoid tretinoin (all-trans retinoic acid) and the synthetic third-generation polyaromatics adapalene and tazarotene are approved for acne treatment by the US FDA, whereas topical tretinoin, isotretinoin (13-cis retinoic acid), and adapalene are accredited in Canada and Europe. Topical retinoids have a favorable safety profile distinct from the toxicity of their systemic counterparts. Local adverse effects, including erythema, dryness, itching, and stinging, occur frequently during the early treatment phase. Their impact varies with the vehicle formation, skin type, frequency and mode of application, use of moisturizers, and environmental factors such as sun exposure or temperature. The broad anti-acne activity and safety profile of topical retinoids justifies their use as first-line treatment in most types of non-inflammatory and inflammatory acne. They are also suitable as long-term medications, with no risk of inducing bacterial resistance, for maintenance of remission after cessation of initial combination therapy.     

An update of recent clinical trials examining adapalene and acne

Topical retinoids are a mainstay in the treatment of acne vulgaris. In the past these agents have been associated with irritant effects, however, newer generations of topical retinoids have emerged that have been designed to be less irritating. This paper focuses on the newer topical retinoid products, and specifically looks at adapalene and recent clinical studies that evaluate its efficacy and tolerability. Most of these studies evaluate adapalene in comparison with the new tretinoin formulations, which, like adapalene, have been designed to be less irritating than their predecessors. The various studies comparing the efficacy and tolerability of adapalene with the new formulations of tretinoin are described. A summary of the findings and their implications follows.     

Topical Retinoids in Acne Vulgaris: A Systematic Review

Background

Topical retinoids are a first-line treatment for acne vulgaris.

Objective

This systematic review aims to evaluate the efficacy, safety, and tolerability of topical retinoids approved in the United States for the treatment of acne vulgaris.

Methods

A PubMed and Embase search was conducted using the search terms ‘adapalene,’ ‘tretinoin,’ ‘tazarotene,’ and ‘acne vulgaris.’ Selection of articles fit the following inclusion criteria: clinical trials evaluating both efficacy and safety/tolerability of topical retinoids approved in the United States for the treatment of acne vulgaris and published between January 1, 2008 and September 1, 2018. Exclusion criteria included clinical trials involving 20 subjects or fewer, subjects under 12 years of age, and topical retinoid combination therapies with moisturizers or aloe vera. Of 424 search results found, a total of 54 clinical trials were chosen based on selection criteria.

Results

Topical retinoids are superior to vehicle in improving Investigator Global Assessment and Investigator’s Static Global Assessment (24.1–28.8% and 13.3–17.3%, respectively; p < 0.001). A topical retinoid combined with benzoyl peroxide led to IGA improvement compared with vehicle (26.1–34.9% vs 7–11.8%; p < 0.001) at Week 12. Topical retinoid plus an oral antibiotic was superior to vehicle in reducing lesion counts (64–78.9% vs 41–56.8%, p < 0.001). There was no significant difference in efficacy between tretinoin and tazarotene. Tretinoin 0.05% resulted in 62% of patients experiencing AEs compared with adapalene 0.1% (19%) and adapalene 0.3% (40%). More patients receiving adapalene were tolerant of the AEs compared with tazarotene (55.4% vs 24.4%; p < 0.0012).

Conclusions

Topical retinoids are safe and efficacious for the treatment of acne vulgaris. They should be used in combination with benzoyl peroxide to optimize results in patients. The differences in efficacy of topical retinoids appears minor; therefore, the type of topical retinoid is not as important as choosing a particular strength of topical retinoid and combining it with an antimicrobial agent. Adapalene has a superior tolerability profile amongst topical retinoids.

     

The potential immunomodulatory effects of topical retinoids

New research has refined our understanding of the immunopathophysiology of acne. Various immune factors, including both innate and adaptive immune responses, have been implicated in the pathophysiology of inflammatory acne. Topical retinoids such as tretinoin, adapalene, and tazarotene, exhibit immunomodulatory effects that may help to explain their efficacy in the resolution of inflammatory lesions.     

Topical treatment in acne: current status and future aspects

During the last 20 years, the number of topical and systemic drugs for the treatment of acne vulgaris has been enriched. Topical drugs on the one hand have been newly discovered or further developments of already available agents such as in the group of retinoids or galenic formulation have improved efficacy or local tolerance. Topical retinoids are a mainstay in acne treatment since 1962. All-trans retinoic acid was the first and is still in use. Its irritative potential has led to the new galenics, i.e. incorporation in microsponges and in propolyomers, which increased the tolerability significantly. The isomer of tretinoin, isotretinoin, has the same clinical efficacy, but also a lower irritancy. A real breakthrough was adapalene, a retinoid-like agent, with a different retinoid receptor-binding profile, but in addition to the same clinical efficacy on inflammatory and non-inflammatory acne lesions compared to tretinoin, a better tolerability and, therefore, compliance. Unfortunately, over the past years topical retinoids have been less used in inflammatory acne than they should be, taking the the mechanisms of action into account. Topical antimicrobials, in particular topical antibiotics, should be used less often than in the past and only for short periods to avoid the development of resistances. It seems better to combine those agents with topical retinoids, with BPO or with azelaic acid to enhance the efficacy and slow down the development of resistance. BPO is still the gold standard for papular-pustular acne of mild-to-moderate type in concentrations of 2-5%. Azelaic acid is an alternative with efficacy on the comedo and is antibacterial without development of resistances. Finally, the physical removal by electrocautery or CO(2) laser of multiple densely packed closed comedones, macrocomedones and microcysts is necessary to enhance the efficacy of topical comedolytic agents and to speed up the therapeutic results. Photodynamic therapy has not yet been proven efficacious in controlled studies. Blue and red light can probably be used in association with local agents but enhancement of the irritative potential of topical and systemic agents has to be considered.     

Topical tretinoin or adapalene in acne vulgaris: an overview

Retinoids target several pathoetiologic events of acne vulgaris. The undisputed efficacy of tretinoin, and yet its underutilization, due to apprehension of retinoid dermatitis, triggered a search for newer, well-tolerated retinoids. The discovery of nuclear retinoic acid receptors has provided clues to a rational design of synthetic, receptor-selective retinoic acid agonists. Adapalene is an addition to the arsenal of topical retinoids. It possesses the biological properties of tretinoin, but has a distinct physiochemical profile, including high lipophilicity and increased chemical and photostability. It exhibits selective affinity for nuclear retinoic acid receptors and does not bind to cytosolic retinoic acid binding proteins. It exemplifies the formulation of a novel retinoid with specific pharmacologic profile and clinical objectives. Accordingly, numerous clinical trials have compared adapalene and tretinoin in the management of acne vulgaris and concluded that tretinoin 0.05% gel exhibits a greater anti-acne efficacy than adapalene 0.1% gel, but has higher skin irritation potential. This article reviews the pharmacology of adapalene, including its retinoid receptor binding profile, antiproliferative effects, cell differentiation modulation, comedolytic and anti-inflammatory activity, and specifically focuses on the comparison of the efficacy and irritation profile of adapalene and tretinoin.     

Efficacy of combined topical treatment of acne vulgaris with adapalene and nadifloxacin: a randomized study

Topical retinoid and antibiotic combination therapy is an integral part of acne treatment and is considered the appropriate first-line therapy according to the Japanese guideline for moderate and severe acne. In this combination, clindamycin or doxycycline are mostly used as antibiotics, but there have been no reports on the effectiveness of nadifloxacin, a widely used antibiotic in Japan and European countries for acne, in combination with topical retinoid. To confirm the efficacy and safety of adapalene gel and nadifloxacin cream in the treatment of Japanese patients with acne vulgaris, a total of 50 patients were randomized to the two groups, the combination therapy and the adapalene monotherapy, and each therapy was tested for 8 weeks. The percentage reduction in the number of inflammatory acne lesions was evaluated and the safety was monitored through adverse events. The combination of adapalene gel and nadifloxacin cream produced a significantly higher reduction in the inflammatory lesions at 2 weeks (P = 0.047) and at 8 weeks (P = 0.011) after the starting than did adapalene gel monotherapy. The combination did not elevate the side effects of erythema and scale scores, but rather significantly depressed erythema at 1 week. This study showed the efficacy and safety of the combination therapy of nadifloxacin cream with adapalene gel for the inflammatory acne.     

The integral role of topical and oral retinoids in the early treatment of acne

This article will review the rationale for early use of topical retinoids alone or in combination with topical antimicrobials in light of the pathogenesis of microcomedones and later lesions. Knowledge of the pathogenic processes in acne vulgaris has risen dramatically over the last three decades. It is now widely accepted that acne is the result of four distinct processes: increased proliferation, cornification, and shedding of follicular epithelium; increased sebum production; colonization of the follicle with Propionibacterium acnes ; and induction of inflammatory responses by bacterial antigens and cell signals. Clinical focus of disease management has shifted toward earlier treatment targeting these fundamental processes. Elimination of microcomedones, the precursor to all subsequent lesions, would optimize acne therapy by preventing the later inflammatory stages of disease. With the exception of oral isotretinoin, no single first-line agent addresses all pathogenic mechanisms. Topical retinoids have comedolytic and in some cases anti-inflammatory effects, but have no direct impact on P. acnes . Thus treatment with a combination of topical retinoid and topical antimicrobial is warranted. The former can also enhance penetration of the latter by increasing microcomedonal extrusion. In selecting a combination, one must consider efficacy, cost, and likelihood of compliance. Once thought to be effective primarily for treating comedones, topical retinoids have also been demonstrated to be effective in reducing inflammatory lesions. The activity of a topical retinoid combined with an antimicrobial agent has been shown to clear more lesions and to clear them more rapidly than antimicrobial therapy alone. Topical retinoids are also used effectively to maintain remissions.     

Topical retinoids in the treatment of acne vulgaris

Topical retinoids are highly effective in the treatment of both comedonal and inflammatory lesions of acne and are a vital part of almost any acne regimen. A better understanding of the structure and function of this class of medications has led to better outcomes in treatments of patients with acne. In this article, the structure and function of retinoids is first reviewed. Then, the clinical effectiveness and tolerability of each of the available topical retinoid formulations is summarized.     

Effect of sequential application of topical adapalene and clindamycin phosphate in the treatment of Japanese patients with acne vulgaris

The efficacy of combined therapy with a retinoid and antibiotic for Japanese patients with acne vulgaris remains to be established. Further, maintenance strategies limiting the use of topical retinoids must be identified. The objectives of this study are to determine the efficacy of sequential application of topical adapalene and clindamycin phosphate and to assess the impact of this regimen on patients' quality of life. Sixty-six patients were recruited. The regimen comprised two phases. For the 4-week initial treatment, 1% clindamycin phosphate gel was applied twice daily and 0.1% adapalene gel, once. In the 4-week maintenance phase, patients were randomly assigned to the OD group (adapalene applied once daily) or the TW group (adapalene applied once daily on 2 days per week). The acne severity score, lesion counts, microcomedone count, and sebum amount were measured. Quality of life (QOL) was assessed using Skindex-16. All parameters improved significantly by week 4 of initial treatment. No statistically significant differences were found in the improvement of clinical findings between the groups. All QOL scores improved significantly and did not significantly differ between the groups. Our regimen may enable clinical control of acne in Japanese patients and improve their QOL. For limiting retinoid use, weekly application of adapalene during maintenance is suitable.     

Adapalene gel 0.1% is effective and safe for Japanese patients with acne vulgaris: a randomized, multicenter, investigator-blinded, controlled study

BACKGROUND: Topical retinoids, such as adapalene, are an integral part of acne therapy in most regions and are considered appropriate first-line therapy by international guidelines for all cases of acne with the exception of the most severe. However, there are currently no topical retinoids available for the treatment of acne vulgaris in Japan. OBJECTIVE: To confirm efficacy and safety of adapalene gel 0.1% versus the corresponding gel vehicle in the treatment of Japanese patients with acne vulgaris for up to 12 weeks. METHODS: A total of 200 patients were randomized to receive adapalene gel 0.1%, or vehicle once-daily for 12 weeks. Percent reduction in lesion counts (total, inflammatory, and non-inflammatory) and subject satisfaction were evaluated. Safety was monitored through adverse events and laboratory tests. RESULTS: Adapalene gel 0.1% produced significantly better reductions in total (P<0.0001), inflammatory (P=0.0010), and non-inflammatory lesions (P<0.0001) at endpoint (week 12, last observation carried forward) than gel vehicle, with a higher overall subject satisfaction. The primary efficacy variable, the median percent reduction of total lesion counts at endpoint, was significantly greater with adapalene gel 0.1% (63.2%) compared to that with the vehicle (36.9%) in the ITT population (P<0.0001). Significantly greater results were observed as early as week 1. Adapalene was well tolerated, with adverse events that were mostly mild-to-moderate and transient in nature. CONCLUSIONS: Adapalene gel 0.1% was effective in the treatment of acne vulgaris in Japanese patients. Adapalene was safe and well tolerated, consistent with the good tolerability profile demonstrated in other patient populations.     

Spotlight on Adapalene in Acne Vulgaris

Adapalene (Differin) is a retinoid agent indicated for the topical treatment of acne vulgaris. In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favorable tolerability profile compared with other retinoids. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris.     

Retinoid Therapy for Acne

Retinoids play a vital role in the treatment of acne because they act on the primary lesion, the microcomedo. They are synthetic derivatives of vitamin A (retinol), and are selected for their effectiveness. Several compounds are used for acne, either in topical or systemic form.We describe and compare the different topical retinoids, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), adapalene (derived from naphthoic acid), and tazarotene (acetylenic retinoid). They act mainly as comedolytics, but anti-inflammatory actions have also been discovered recently. The retinoids have great beneficial effects, but also some adverse effects, the main one being teratogenicity. It is preferable not to use them in topical form for pregnant women, although a pregnancy test is only compulsory for tazarotene. Only isotretinoin is used in systemic form. It acts on all the factors of acne and offers long remissions, and sometimes complete cures. Precautions must be taken for women of childbearing age due to its teratogenicity. It is also important to be aware of its other adverse effects, explain them to the patient and, if possible, deal with them in advance.     

Effects of topical retinoid therapy on acne lesions: a psychometric assessment

Topical retinoids are believed to increase inflammatory lesions within the first few weeks of treatment. We evaluated data from several clinical trials for evidence of a signal for retinoid aggravation of inflammatory lesions using a psychometric method and the proportion of participants who demonstrated varying degrees of increased lesion counts. We first determined the validity of a psychometric method based on Stevens' power law called the visual logarithmic scale (VLS) used to evaluate the perceived changes in inflammatory lesions. There was concurrence between the VLS model and the dermatologists' visual assessment of a flare in 80.0% (32/40) of participants (P=.0258). A subsequent analysis was performed using data from clinical trials to assess the occurrence of flares using the VLS model or percentage-based definitions (5%, 10%, or 20% increase) following the first week of treatment with various adapalene gel formulations. In this analysis, no evidence of worsening or a flare was seen by either the VLS model or percentage-based definitions. The VLS model is valid for assessing the changes in acne severity. Topical retinoid treatment was not associated with a flare as measured by either the VLS model or the proportion of participants who showed an increase in inflammatory lesions.     

Topical adapalene gel 0.1% vs. isotretinoin gel 0.05% in the treatment of acne vulgaris: a randomized open-label clinical trial

BACKGROUND: Topical application of isotretinoin and adapalene has proved effective in treating acne vulgaris. Both drugs demonstrate therapeutic advantages and less irritancy over tretinoin, the most widely used treatment for acne. They both act as retinoid agonists, but differ in their affinity profile for nuclear and cytosolic retinoic acid receptors. OBJECTIVE: To compare the efficacy and tolerability of adapalene gel 0.1% and isotretinoin gel 0.05% in the treatment of acne vulgaris of the face, in a randomized open-label clinical trial. METHODS: Eighty patients were enrolled and were instructed to apply adapalene gel 0.1% or isotretinoin gel 0.05% once daily over a 12-week treatment period. Efficacy determination included noninflammatory and inflammatory lesion counts by the investigator and global evaluation of improvement. Cutaneous tolerance was assessed by determining erythema, scaling and burning with pruritus. RESULTS: Adapalene and isotretinoin gels were highly effective in treating facial acne. Adapalene gel produced greater reductions in noninflammatory and inflammatory lesion counts than did isotretinoin gel, but differences between treatments were not statistically significant. Adapalene gel was significantly better tolerated than isotretinoin gel during the whole treatment period. CONCLUSIONS: The two gels studied demonstrated comparable efficacy. When adapalene and isotretinoin were compared, significantly lower skin irritation was noted with adapalene, indicating that adapalene may begin a new era of treatment with low-irritant retinoids.     

Topical retinoids in acne – an evidence‐based overview

Topical retinoids are important tools in the management of acne because they act against comedones and microcomedones and have direct anti‐inflammatory effects. The substances approved for acne treatment comprise tretinoin (all‐trans‐retinoic acid),isotretinoin (13‐cis retinoic acid) as well as the synthetic third‐generation polyaromatic retinoids adapalene and tazarotene,the latter being approved for acne treatment in the US only.Retinaldehyde is used in cosmetic preparations against acne. All topical retinoids are effective as single agents in mild to moderate acne but differ in efficacy and tolerability. Tazarotene 0.1% is more effective than tretinoin 0.025% or 0.1% microsphere gel or adapalene 0.1% gel or cream (EBM‐level 2c). Adapalene 0.1% is equally effective to tretinoin 0.025% or tretinoin microsphere 0.1% gel or tretinoin 0.05% cream or isotretinoin 0.05% gel (EBM‐level 2c). Adapalene 0.1% gel is significantly better tolerated than tazarotene 0.1% gel, tretinoin 0.025% and tretinoin 0.05% gel, tretinoin 0.05% cream,tretinoin microsphere 0.1% gel or isotretinoin 0.05% gel (EBM‐level 2c).The safety profile of topical retinoids differs from their systemic counterparts and is related mainly to local adverse effects, such as erythema, dry‐ness,itching and stinging.The currently available evidence justifies the use of topical retinoids in most types of acne and during maintenance treatment.     

In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inflammatory lesions

The anti-inflammatory mechanisms of adapalene, a synthetic retinoid used for the treatment of acne patients, are partially understood. They seem particularly related to the modulation of the non-specific immunity. Recent studies have shown that Toll-like receptor (TLR)-2 expression, a receptor of the innate immune system, was increased in acne lesions and could play an essential role in acne-linked inflammation. The aim of our study was to investigate the new mechanisms of the anti-inflammatory activity of adapalene in vitro, and more specifically the modulatory effect of adapalene on the expression of TLR-2, CD1d, a cell surface glycoprotein that plays a role as antigen-presenting molecules and is responsible for the development of cutaneous inflammation, and also on the expression and the secretion of the anti-inflammatory interleukin (IL)-10 cytokine. Both explants of normal human skin and explants of acne patients were incubated with adapalene (10(-7) or 10(-6) M) or the control medium for 24 h. Evaluation of epidermal expression by immunohistochemistry showed a decreased expression of TLR-2 and IL-10 in explants of normal skin and explants of acne with adapalene. On the contrary, adapalene increased CD1d expression in explants of acne patients. Thus, adapalene can modulate the epidermal immune system by increasing the CD1d expression and by decreasing the IL-10 expression by keratinocytes. Moreover, these modulations could increase the interactions between dendritic cells and T lymphocytes and could strengthen the antimicrobial activity against Propionibacterium acnes. The decreased expression of TLR-2 by the keratinocytes can contribute to explain the anti-inflammatory activity of adapalene observed in clinical practice.     

South‐East Asia study alliance guidelines on the management of acne vulgaris in South‐East Asian patients

The management of acne in South‐East Asia is unique, as Asian skin and local variables require a clinical approach unlike that utilized in other parts of the world. There are different treatment guidelines per country in the region, and a group of leading dermatologists from these countries convened to review these guidelines, discuss current practices and recent advances, and formulate consensus guidelines to harmonize the management of acne vulgaris in the region. Emphasis has been placed on formulating recommendations to impede the development of antibiotic resistance in Propionibacterium acnes. The group adopted the Acne Consensus Conference system for grading acne severity. The group recommends that patients may be treated with topical medications including retinoids, benzoyl peroxide (BPO), salicylic acid, a combination of retinoid and BPO, or a combination of retinoids and BPO with or without antibiotics for mild acne; topical retinoid with topical BPO and a oral antibiotic for moderate acne; and oral isotretinoin if the patient fails first‐line treatment (a 6‐ or 8‐week trial of combined oral antibiotics and topical retinoids with BPO) for severe acne. Maintenance acne treatment using topical retinoids with or without BPO is recommended. To prevent the development of antibiotic resistance, topical antibiotics should not be used as monotherapy or used simultaneously with oral antibiotics. Skin care, comprised of cleansing, moisturizing and sun protection, is likewise recommended. Patient education and good communication is recommended to improve adherence, and advice should be given about the characteristics of the skin care products patients should use.