What are the effects of retinoids on acne?

Acne: What are the biological mechanisms involved?

Far from being a mere aesthetic concern, acne is a skin disease that affects the sebaceous glands, the organs responsible for sebum production. It is often associated with teenagers, but it can persist or appear in adulthood. Its development relies on the interaction of several biological mechanisms, including hormonal, immune, microbial, and keratinocyte processes, which self-perpetuate and exacerbate the dermatosis.

Hyperseborrhoea : As a component of the hydrolipidic film present on the skin's surface, sebum is an important element that protects the skin. However, when it is produced in excess under the influence of androgens, as can be the case during adolescence or following hormonal changes, it can clog the skin's pores. In response to this blockage, a plug forms, creating a spot. Moreover, this overproduction of sebum creates an environment conducive to bacterial proliferation.
Hyperkeratinisation : The inside of the pilosebaceous canal is lined with keratinocytes which, under normal circumstances, desquamate regularly. However, in acne-prone skin, the keratinocytes no longer desquamate properly, accumulate and block the orifices of the hair follicles. This phenomenon is notably due to a disruption of the retinoic acid receptors and an abnormal response to androgens.
An overgrowth of Cutibacterium acnes : C. acnes is an anaerobic bacterium naturally present on the skin. However, in acne-prone skin, it is present in excess. By feeding on sebum, this bacterium breaks down triglycerides into irritating free fatty acids and releases pro-inflammatory mediators. This immune activation contributes to local inflammation.
An exaggerated inflammatory response : Inflammatory lesions of acne, such as papules, pustules or nodules, result from an exaggerated immune response to the presence of C. acnes. This bacterium activates Toll-like receptors (TLR-2) on the surface of keratinocytes and macrophages, leading to the release of pro-inflammatory cytokines (IL-1β, TNF-α). A marked local inflammation then sets in.

Topical retinoids, a first line of defence against acne.

Topical retinoids are the first line of treatment for acne, and for good reason, they target several key factors in acne pathophysiology, including hyperkeratinisation and inflammation. These vitamin A derivatives work by activating the nuclear RAR receptors present in keratinocytes, which alters the expression of many genes involved in cell differentiation, epidermal proliferation, and inflammation. Indeed, retinoids are particularly known for their ability to normalise epidermal renewal, which helps to counteract acne hyperkeratinisation. At the same time, retinoids exert a direct anti-inflammatory action. They reduce the production of interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) and inhibit the infiltration of neutrophils into the dermis. This dual effect — keratolytic and anti-inflammatory — explains their effectiveness on inflammatory lesions such as papules or pustules, in addition to retentional lesions, like comedones.

A retrospective study conducted blindly by five investigators compared the effectiveness of several topical retinoids in the treatment of inflammatory acne. The researchers evaluated photos of 577 patients who underwent a 12 to 15 week treatment with one of the following products: tazarotene 0.1%, adapalene 0.1%, tretinoin 0.1% microsponge, tretinoin 0.025% in gel or a placebo. The results show that all four retinoids led to a significant improvement in inflammatory acne compared to the placebo. The overall analysis of the treatment response confirmed an improvement in 36% of patients under tazarotene, 34% under adapalene, 31% under tretinoin microsponge and 28% under tretinoin in gel, versus 17% for the placebo.

Efficacité clinique de la monothérapie par rétinoïde topique sur des lésions inflammatoires après 12 ou 15 semaines de traitement. — Clinical efficacy of topical retinoid monotherapy on inflammatory lesions after 12 or 15 weeks of treatment.
Source: LEYDEN J. J. et al. Topical Retinoids in Inflammatory Acne: A Retrospective, Investigator-Blinded, Vehicle-Controlled, Photographic Assessment. Clinical Therapeutics (2004).

Today, in dermatology, three retinoids stand out: tretinoin, adapalene, and tazarotene. Tretinoin, or all-trans retinoic acid, is available in concentrations ranging from 0.01% to 0.1%. It is highly effective but is often deemed too irritating for sensitive skin. Adapalene, a third-generation retinoid, is more selective for RAR-β and RAR-γ receptors, which gives it better tolerance. It is offered in concentrations ranging from 0.1% to 0.3%. Finally, tazarotene, more potent and more irritating, is generally reserved for adults, with concentrations of 0.05 to 0.1%.

It's worth noting that topical retinoids often cause local irritations at the start of treatment. These are usually temporary, as the skin adjusts to the molecule. However, in cases of severe, persistent irritation, it's advisable to consult a dermatologist. Topical retinoids are also associated with a rebound effect, or purging, a term referring to the sudden appearance of spots. Although it can be discouraging, this phenomenon is normal and indicates the effectiveness of the treatment. For your information, a purge typically lasts one to two months, while a treatment cycle usually lasts three months. To maintain the results achieved with topical retinoids, it's often necessary to continue using them beyond the treatment period, about two to three times a week.

Even though the risks are less pronounced than with oral retinoids, the use of topical retinoids is still contraindicated for pregnant women, breastfeeding women, or those planning a pregnancy.

Oral retinoids, in cases of severe or persistent acne.

When acne becomes severe, nodular, or resistant to topical treatments, despite good adherence, oral retinoids, specifically isotretinoin, represent the most effective option currently available. Their effectiveness is based on their ability to act on all mechanisms related to acne. In addition to normalising cell renewal and having an anti-inflammatory action, isotretinoin has a sebostatic effect not found in topical retinoids. Indeed, this molecule inhibits the activity of the sebaceous glands, thus reducing sebum production. Furthermore, some studies have shown that it is capable of causing them to atrophy, a property particularly interesting for preventing acne relapse in oily skin.

Isotretinoin also exerts an indirect antibacterial effect by altering the follicular environment. Indeed, by inhibiting the proliferation of sebocytes and inducing their dedifferentiation into keratinocytes, it significantly reduces sebum production, which is the main nutritional substrate of C. acnes. This reduction in sebum limits the colonisation of the hair canal by the bacteria, although the molecule does not have a bactericidal or bacteriostatic action. Moreover, unlike oral antibiotics frequently used in acne, isotretinoin does not lead to bacterial resistance.

A systematic review analysed data from 11 randomised clinical trials on the efficacy of isotretinoin in the treatment of acne, involving a total of 760 patients. The participants most often had moderate to severe acne. Across all studies, isotretinoin proved more effective than control treatments (placebo, oral antibiotics or others), with a significant and clinically relevant reduction in the number of acne lesions. However, this benefit is accompanied by an increased risk of adverse effects: their frequency was twice as high in the isotretinoin groups (751 events) than in the control groups (388 events). The majority of reported effects were skin-related and linked to dryness (xerosis, cheilitis), but some more severe cases led to treatment discontinuation, particularly following an elevation of liver enzymes.

Isotretinoin is prescribed at doses ranging from 0.5 to 1 mg/kg/day, with a cumulative target around 120 to 150 mg/kg, achievable after several months of treatment. To limit the purge and side effects associated with isotretinoin, it is possible to start with a low dosage (0.2 mg/kg/day) and gradually increase it. Reaching the cumulative dose maximises the chances of long-term remission. An insufficient cumulative dose is indeed associated with an increased risk of relapse after stopping treatment. In this case, a new course of treatment may be considered.

While isotretinoin is currently the most effective solution for combating acne, it is far from free of side effects, as mentioned earlier. The most common is xerosis, affecting the skin and mucous membranes: dry lips, ocular, nasal or skin dryness are almost systematic. Joint and muscle pains also occur quite frequently, as does an increase in cholesterol levels and transaminases, liver enzymes, that is, present in the liver. Blood tests are thus prescribed every three months to monitor these parameters. That said, one of the most significant risks of isotretinoin is its high teratogenic potential : a pregnancy under isotretinoin exposes to a major malformation risk (up to 35% according to a FELDMAN study), which requires rigorous contraception throughout the duration of the treatment and one month after stopping, as well as a monthly blood test to verify the absence of pregnancy.