Unlocking Acne Treatment Potential with Retinoids

For years, retinoids, such as tretinoin have been an important step on the ladder to acne resolution. From severe to mild lesions, retinoids have proven to be effective regardless of the severity of the disease, with a quick-acting time but with certain unfriendly side effects.

Acne is a major challenge that compromises not only the skin but also self-esteem. Those with acne notice spots on their faces that make them feel somehow unattractive, depressed, or low self-perceived.

Therefore, we consider it essential to highlight and break down how retinoids work and why they have been positioned as the best treatment against this inflammatory condition in dermatology. Since many, although they know the wonderful results provided, do not know how they work and why they are so effective on acne-prone skin.

First things first: getting to know acne

Acne is a common chronic inflammatory skin disease, possibly more common than you might think. It affects 90% of teenagers, so anyone in their teens years had it at least once¹.

Although it is often perceived as a self-limited disease of adolescence, it still appears into adulthood, affecting at least 1% of men and 5% of women by their 40s. The symptoms are widely known because pimples rarely go unnoticed. Despite this, many still fail to identify the actual acne lesions, as other diseases can also lead to similar ones.

Acne is considered an inflammatory disease. However, the symptoms can be both inflammatory and non-inflammatory:

• Non-inflammatory acne: Open or closed comedones, including whiteheads and blackheads, respectively.
• Inflammatory acne: Includes papules, pustules, nodules, and cysts.

These lesions can appear anywhere but more frequently where a greater sebum production occurs, such as the face, neck, chest, or back ¹. As we said, some diseases tend to resemble acne, such as rosacea, keratosis pilaris, folliculitis or dermatitis. In these cases, the age, the onset and previous history make the difference in the diagnosis.

But what causes acne?

To understand how retinoids work, you must first know how acne arises. Acne, technically speaking, is the inflammation of the skin pilosebaceous unit. The unit where that characteristic facial oil is produced ².

Three important events mainly cause this inflammation:

· Increased skin cell regeneration cycle (i.e., increased desquamation and dead cells).

· Increased facial sebum production

· As a result of the above, the growth of a bacterium called Cutibacterium acnes (formerly Propionibacterium acnes).

Now, what makes these three events take place? Hormonal imbalance in favor of androgens. Not surprisingly, acne appears first and most often during puberty ¹. Androgens are "male" hormones, although they are not exclusive to the male gender.

Their main exponent is testosterone, but there are others, and a blood increase of them causes more sebum, more facial desquamation and greater unit obstruction ¹ Once the blockage occurs, the typical reddish pimple with pus on its surface appears ².

Retinoids

Vitamin A (retinol) and related compounds with either structural (retinol derivative) or functional (vitamin A activity) analogy are known as retinoids ³. Generally speaking, they are oil affinity molecules that easily reach the most superficial layer of the skin, the epidermis, where they provide beneficial effects through modulation functions.

There are many retinoids, ranging from natural to synthetic ones. Retinoic acid (tretinoin), its isomer isotretinoin, and several synthetic retinoids are used more for therapeutic purposes, while retinaldehyde, retinol and retinyl esters are used as cosmeceuticals ³.

This difference is based on both the chemical structure and the body's response to it. Thus, cosmeceutical retinoids focus more on improving the skin's appearance rather than treating acne lesions.

How retinoids work

Retinoids have a wide range of functions once they meet the body, which is why they have also been used in cancer therapy ⁴, regenerative medicine ⁵, and other medical fields. They work as cell growth regulators, immune system modulators, malignant cell growth inhibitors and alter cellular cohesiveness ⁶.

Surprisingly your body has receptors for almost all drugs. Once you apply or take a retinoid pill, it binds to specific receptors in the cell nucleus, decreasing pimple inflammation, normalizing skin desquamation, and regulating sebum production ⁶. The three main steps in the genesis of acne, remember?

Types of retinoids

The list is long and is made according to the source of each one, varying between natural and synthetic retinoids. So we will touch on them briefly.

Natural retinoids: not as effective as they may seem

Natural retinoids are in all living organisms, either as preformed vitamin A or as carotenoids, and are required for many biological processes, e.g., vision, cellular growth and reproduction ⁷.

They comprise retinyl esters, retinol and retinaldehyde. Although retinol is the most omnipotent compound, retinaldehyde is more potent because it requires only one step to reach the target site than retinol and retinyl esters, which require two and three steps. Despite this, natural retinoids are not routinely indicated in acne treatment, mainly because once the body receives them, it controls them ³.

Synthetic retinoids: the true mainstay in acne treatment

Synthetic retinoids, as their name indicates, are lab-made and chemically modified molecules of retinol to provide a therapeutic activity. They comprise retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin), 9-cis retinoic acid (alitretinoin), adapalene, tazarotene and bexarotene. Each with improvements in side effects, tolerability and effectiveness ³.

Proven efficacy of synthetic retinoids on acne

Now that you know that retinoids -in words- attack the three key steps in acne let's see if they are effective. Here we can get a little too dense with the clinical studies that show how they work in human skin. We will do this on a retinoid-by-retinoid basis.

Tretinoin

Let's start with the first of all. Tretinoin is a topical retinoid widely used in acne. Its proven clinical efficacy dates back to 98s, where adapalene (another retinoid) was compared with 0.025% tretinoin in acne-prone skin, showing that a daily application of tretinoin before bedtime for 12 weeks reduced the number of pimples by 52% ⁸. Other similar studies observed similar results ⁹ ¹⁰ ¹¹.

According to a second trial, 0.025% tretinoin is also highly effective in mild, moderate, or severe acne in single therapy (monotherapy), reducing inflammation and scarring based on clinical photographic evidence after a 12-week treatment regimen ¹².

Recent studies focus on improving vehicles, where new formulations such as nanoemulsions ¹³, 0.04% microsphere gel ¹⁴, a new 0.05% lotion ¹⁵, or in combination with other ingredients such essential oils ¹⁶ maintain effectiveness even in the first tests.

Isotretinoin

Among natural and synthetic retinoids, only oral isotretinoin significantly stops sebum production and considerably improves acne because its target is the sebocyte itself, stopping its proliferation and activity and finally preventing sebum production ¹⁷, ¹8. Tretinoin and alitretinoin do not have this action, and thanks to this, isotretinoin is considered state-of-the-art for acne.

Isotretinoin is taken in pill form, and 20 mg oral isotretinoin is effective in both daily and alternate-day therapy against moderate and severe acne after a 24-week treatment regimen, with a slight but significant difference in favor of the daily regimen ¹⁹. Another trial comparing conventional (daily) with intermittent (first ten days of each month) therapy showed similar results ²⁰.

In low-dose therapy, isotretinoin decreased both the number of inflammatory lesions (pimples) and the number of non-inflammatory lesions (blackheads/comedones). The latter is thanks to its ability to reduce the greasy face ²¹ ²².

Alitretinoin

Although an oral synthetic retinoid, alitretinoin is rarely or never used in acne since it does not suppress sebocytes, and therefore it is considered useless when isotretinoin is available ⁶. It is used in other inflammatory diseases such as chronic hand eczema (CHE), cutaneous Kaposi's sarcoma, signs of photoageing, and lichen planus ⁶.

Adapalene

Adapalene is a third-generation synthetic retinoid known for its good results, few side effects, and undetectable levels in blood plasma. As well as the next ones, new synthetic retinoids are intended to improve tolerability while maintaining similar efficacy compared to topical tretinoin, and clinical trials confirm so ⁶.

Adapalene has a similar biological activity to tretinoin but by different pharmacological pathways and is therefore considered better tolerated, the reason why patients and dermatologists prefer it over conventional retinoids ²³.

The 0.1% adapalene gel is somehow equally effective to 0.05% tretinoin gel in reducing inflammatory lesions in a 10-week treatment regimen. However, it produces less scaling, irritation and stinging compared to tretinoin ²⁴.

Adapalene is even more effective when the dose is increased (0.3%), although 0.05% tretinoin is still slightly more effective in reducing the number of face pimples ²⁵ ²⁶. Recent trials focus on new directions and use in post-acne scarring ²⁷.

Tazarotene

Like adapalene, tazarotene is a third-generation retinoid initially intended for psoriasis and is now used in acne. Due to its rapid metabolism, its blood concentrations are very low, almost indetectable ⁶.

Patients with mild-to-moderate acne applied either the tazarotene 0.1% gel or the tretinoin 0.025% gel once daily for up to 12 weeks. The tazarotene achieved a 24% greater reduction in the open comedon count (whiteheads) than tretinoin shown by photographs ²⁸.

It also achieved a greater reduction in papule count and a more rapid reduction in pustule count than tretinoin. Both drugs were equally good in reducing the closed comedon count (blackheads) ²⁸.

Then another study compared the effectiveness of 0.1% tazarotene gel versus 0.1% tretinoin microsponge showing that daily application of tazarotene significantly reduced the number of pimples after a 12-week therapeutic regimen ²⁹.

One study compared the effectiveness of adapalene and tazarotene, both being third-generation retinoids. The daily application of 0.1% tazarotene gel vs. 0.1% adapalene gel showed that tazarotene had an overall higher efficacy (78%) in the treatment vs. adapalene (52%) ³⁰. Results that were later supported by another similar trial ³¹.

Bexarotene

Because it only binds to a specific receptor, the X receptor, bexarotene, has greater cell growth and proliferation activity than an antimicrobial and sebum regulator. It is not used in dermatology against acne but as a treatment for cutaneous T-cell lymphoma (CTCL), some hand dermatitis and plaque psoriasis ³².

Conclusion

Retinoids, both topical and taken, are highly effective acne medications proven by science and human trials, where isotretinoin is considered the only drug capable of achieving permanent acne healing in some cases.

Acne is a challenging disease for both the physician and the patient. Many patients give up treatment because they do not see immediate results, while others do so because they cannot tolerate the side effects.

Like any medication, retinoids are not side-effect-free, so you should use them under strict dermatological prescription and after an informative talk about the possible implications of their use.

Also, they are usually combined with other medications or facial care tailored on side effects, such as gentle cleansers, moisturizers and soothers.