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.     

The rationale for using a topical retinoid for inflammatory acne

Both comedogenesis and the development of inflammatory lesions in acne vulgaris appear to be related to genetic as well as immune processes. The key regulatory cytokine, interleukin-1alpha, has recently been documented as playing a major role in both the hypercornification and the orchestration of immune factors, ultimately resulting in noninflammatory and inflammatory lesions. Topical retinoids, such as tretinoin, and topical retinoid analogs, such as adapalene and tazarotene, help normalize the abnormal follicular keratinocyte desquamation - a key pathophysiologic factor in comedogenesis. This normalization also helps mitigate against the development of a propitious microenvironment for Propionibacterium acnes. Preclinical data suggest that topical retinoids and retinoid analogs may also have direct anti-inflammatory effects. A wealth of clinical data confirms that topical retinoids and retinoid analogs significantly reduce inflammatory lesions. Comparative clinical trials also demonstrate that adapalene has the best cutaneous tolerability profile of all these agents. Optimal therapy for inflammatory acne would involve the use of topical retinoids or retinoid analogs combined with oral or topical antibacterials.     

Acne in ethnic skin: special considerations for therapy

Acne vulgaris occurs in people of all ethnicities and races. Although the pathophysiology and treatment options are similar in all skin phototypes, darker-skinned patients have higher incidence rates of two sequelae of acne: postinflammatory hyperpigmentation and keloidal scarring. Postinflammatory hyperpigmentation may also be triggered by skin irritation. In choosing therapies for patients of color, therefore, clinicians must find a balance between aggressive early intervention to target inflammatory acne lesions, and gentle treatments to increase tolerability and avoid skin irritation. For most patients, a combination of topical retinoids, and topical or oral antibiotics with hydroquinone (as needed) to control hyperpigmentation will be successful. For patients with sensitive skin, topical agents in lower concentrations and cream vehicles are preferred. If tolerated, the retinoid strength can be titrated upward after four to six weeks. Ethnic patients also need to be counseled on use of noncomedogenic and nonirritating skin and hair-care products. Individualized care and close monitoring is required.     

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.

     

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.     

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.     

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 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.     

Topical tazarotene therapy for psoriasis,acne vulgaris,and photoaging

Psoriasis, acne vulgaris and photoaging are common conditions. Tazarotene is a pro-drug of tazarotenic acid, a receptor-selective retinoid, which has shown efficacy in the treatment of these disorders. In the treatment of acne vulgaris, it has greater comedolytic activity than the currently available topical retinoids. In psoriasis, tazarotene normalizes keratinocyte differentiation, reverses keratinocyte hyperproliferation and has better anti-inflammatory effects than any of the currently available topical retinoids. It is most commonly used as combination therapy with a topical corticosteroid or phototherapy in psoriasis, or with an antibiotic in acne.     

Current issues in antimicrobial therapy for the treatment of acne

This review summarizes current information regarding the use of antimicrobial agents for the treatment of patients with inflammatory acne. A number of drugs have been used effectively as topical or systemic therapy, often in combination with benzoyl peroxide or a retinoid. Propionibacterium acnes exhibits high in vitro sensitivity to a wide range of antimicrobials, including ampicillin, clindamycin, erythromycin, tetracycline, doxycycline, nadifloxacin, ofloxacin, minocycline, cephalexin, and gentamycin. However, not all of these drugs are equally effective in penetrating the lipid-filled microcomedo and reducing numbers of P. acnes in the skin. Antimicrobial therapy, particularly systemic treatment, may be complicated by the potential for drug–drug interactions. Historically, the potential for antimicrobials to reduce the effectiveness of oral contraceptives has been a concern in the treatment of acne. However, there is evidence to suggest that such an interaction does not take place in patients being treated with the antimicrobials most often used in dermatological practice. Antimicrobial therapy for acne has also been complicated by the emergence of antibiotic-resistant strains of P. acnes . Increasing P. acnes resistance can be combated by judicious use of retinoids in combination with antibiotics to reduce inflammation and infection, and employment of retinoids for maintenance therapy.     

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.     

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.     

Co-treatment with retinyl retinoate and a PPARα agonist reduces retinoid dermatitis

Background Retinoids have been used for the treatment of skin disorders such as acne, psoriasis, and photoaging. However, despite their beneficial effects, topical retinoids often cause severe local irritation called retinoid dermatitis. We previously developed a novel vitamin A derivative, retinyl retinoate, which induces less irritation and affords excellent tolerance. In this study, we examined whether co‐treatment with topical peroxisome proliferator‐activated receptor‐α (PPARα) agonists (e.g. WY14643) reduce retinoid dermatitis in hairless mouse skin. Methods The effect of concomitant treatment with a PPARα agonist on retinoid dermatitis in hairless mouse epidermis was evaluated by measuring transepidermal water loss, epidermal histology, and cytokine expression. Results Retinyl retinoate induced less severe retinoid dermatitis than retinoic acid. Topical application of a PPARα agonist improved the stratum corneum structure and function, reduced mRNA expression of interleukin (IL)‐1α, tumor necrosis factor‐α and IL‐8, and inhibited ear edema induced by retinoic acid or retinyl retinoate. Conclusions Our results indicate that PPARα agonists can potentially be used to improve retinoid dermatitis. We suggest that co‐treatment with retinyl retinoate and a PPARα agonist may reduce or prevent detrimental alterations in retinoid‐treated skin.     

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.     

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.     

Pharmacologic modulation of sebaceous gland activity: mechanisms and clinical applications

Acne vulgaris is a common skin condition seen by physicians. It primarily affects adolescents, but can continue into adulthood. A key factor in the pathogenesis of acne is sebum production. Typical therapy includes combinations of topical retinoids and antimicrobials for mild acne, with the addition of oral antibiotics for moderate to severe disease. In the most recalcitrant cases or for nodulocystic acne, oral retinoids are indicated. In women who fail to respond to conventional treatment, hormonal therapy is often used adjunctively. Only isotretinoin and hormonal therapy improve acne via their action on the sebaceous glands. This article focuses on the mechanisms by which these treatment modalities act on the sebaceous glands and their clinical use in the practice of medicine.     

Receptor-Selective Retinoids for Psoriasis

Topical and oral retinoids have been successfully used in antipsoriatic therapy over the last 50 years. Development of more selective agents has led to an improved efficacy and safety profile. The first topical receptor-selective retinoid to be approved for the treatment of plaque psoriasis is tazarotene. Topical tazarotene displays an onset of action and efficacy similar to those of other established antipsoriatic agents. Common adverse events of this agent such as pruritus, burning, local skin irritation, and erythema are limited to the skin and generally mild or moderate in severity. Although effective as monotherapy, evidence is accumulating that combining topical tazarotene with other established antipsoriatic therapies results in enhanced efficacy and reduced adverse events. In particular, concomitant use of topical tazarotene with a mid-potency or high-potency corticosteroid in the treatment of psoriatic plaques enhances efficacy and reduces the risk of corticosteroid-induced skin atrophy. Combination of phototherapy with tazarotene accelerates the clinical response and diminishes the cumulative UVB or psoralen plus UVA (PUVA) exposure load. Recently, an oral form of tazarotene has been developed. The results of completed phase III clinical trials of this agent indicate a beneficial effect in moderate to severe plaque psoriasis. Adverse events are generally of mild severity, and most of those observed, such as cheilitis and dry skin, are typical of hypervitaminosis A. Of note, oral tazarotene appears not to be associated with other adverse events that are typical of oral retinoids, including hypertriglyceridemia and hypercholesterolemia. However, since head-to-head trials with acitretin (the only retinoid currently approved for systemic therapy) have not been conducted, it is unclear whether tazarotene is any safer or more effective than acitretin. Moreover, the major drawback of oral tazarotene is teratogenicity, which may limit its use in female patients. Further studies evaluating long-term clinical outcomes with oral tazarotene and its use in combination therapies are awaited.     

Retinoid therapy: compatible skin care.

Topically applied tretinoin (a retinoid) has been used for over 25 years to treat acne and disorders of keratinization. Now, tretinoin emollient cream, 0.05% (Renova(R)), may be prescribed for the treatment of photodamaged and chronologically aged skin, in conjunction with appropriate skin care and sun protection routines. Mild to moderate cutaneous side effects to topical tretinoin, such as xerosis, peeling, erythema and subjective irritation, are experienced by a majority of patients undergoing retinoid therapy. Results of clinical compatibility testing show that concomitant use of effective moisturizers, mild cleansers and daily sunscreens greatly enhance skin tolerance and patient comfort. A frequently prescribed regimen for topical treatment of photodamaged skin includes a combination of tretinoin and glycolic acid. While many clinicians report the use of both these agents for the management of their patients, little information exists in the literature about their compatibility in concomitant use. The results of a double-blind clinical study demonstrate that daytime usage of one of two 8% glycolic acid lotions in addition to nightly applications of Renova was well tolerated as part of a comprehensive skin care and sun protection program.     

Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor‐γ agonist trifarotene

Acne is a chronic inflammatory skin disease, linked to changes in hormone levels. It mainly affects adolescents and young adults, and may lead to permanent scarring. 1.5 billion people aged between 15 and 45 suffer from some form of acne – mild, moderate or severe. Retinoic acid is one type of treatment for acne, and there are several different types, which are applied directly to the skin (topically). Trifarotene is a new type of retinoic acid which is able to act against only one particular retinoic acid receptor, and this study looked at whether it might be suitable for use in acne and other skin diseases, and potentially have an improved efficacy and safety profile compared with less selective retinoids (i.e. ones that target more than one retinoic acid receptor). Looking at the biological pathways of the drug, the authors suggest that it should be very effective in acne. Furthermore, trifarotene is expected to be rapidly eliminated in the blood stream, thereby potentially leading to fewer side effects and making it particularly useful for the treatment of large skin surface areas, such as the back and chest of acne patients. Based on these favourable characteristics of trifarotene, it is worth now investigating the clinical efficacy of this retinoid.