In Lithuania, a new treatment for acne – tretinoin and clindamycin gel (Treclinac)

Common acne, or acne vulgaris, is a chronic inflammatory skin disease of the pilosebaceous unit, consisting of a sebaceous gland and hair follicle (1, 2). The term acne was first used in the 6th century by the physician Aetius Amidenus, who served Emperor Justinian. Later, the concept was translated from Greek to Latin, leading to misunderstandings about the true origin of the word. There was a debate whether the term acne originated from the Greek word acme, meaning peak, or if the origin of the term acne was simply original. This word fell out of use until the 1800s when it was reintroduced in medical dictionaries (3).

Acne Epidemiology

Acne (common acne) is a disease affecting people of all races and ethnic groups (4, 5). This disease affects patients of all age groups (3), most commonly adolescents (85% in the 12–24 age group) (4, 6). The prevalence indicators are similar among patients with light skin phototypes (Fitzpatrick types I–III) and those with darker skin (Fitzpatrick types IV–VI) (5).

Acne Etiopathogenesis

Acne is caused by many factors (3, 4). A significant genetic predisposition is important in its onset, but little is known about the exact inheritance mechanisms (2, 4, 7). The susceptibility to acne and the severity of the disease among identical twins are highly correlated (3). It has been found that cytochrome P450 1A1 and steroid 21-hydroxylase genes are involved (4). There are four main etiopathogenetic factors that interact in the formation of acne lesions (1–4, 6, 7): 1. Hyperplasia of sebaceous glands and increased sebum production in the sebaceous gland. It is known that the number and activity of sebaceous glands are hereditary. Patients with seborrhea and acne have many more lobules in the sebaceous gland compared to non-affected individuals. Neuropeptidases, melanocyte-stimulating hormones, insulin-like growth factor 1R, corticotropin-releasing hormone R1, dipeptidyl peptidase IV, and neprilysin N are involved in regulating the activity of sebaceous glands. Their activity also depends on stimulation by sex hormones. 2. Altered hormone balance. At the onset of puberty, there is an increase in androgens in male patients and a strengthening of the androgenic properties of progesterone and other hormones in female patients. Many girls and women with acne have higher androgen concentrations in their blood serum, but it does not exceed the upper limit of normal concentration. 3. Altered keratinization process. There is an increased production of korneocytes in the pilosebaceous unit, increased adhesion, they accumulate in the follicular ducts. The formation of a microcomedone in the keratinized upper part of the follicle is one of the first stages of acne development. As the comedone expands, the content of keratinocytes and sebum in the follicular ducts is increasingly compressed. With increasing tensile forces, the comedone wall ruptures, immunogenic keratin and sebum are released, initiating an inflammatory reaction. T helper cells, foreign body giant cells, neutrophils promote the formation of inflammatory papules, nodules, cysts, and with neutrophils predominating, purulent pustules form. 4) Follicular colonization by P. acnes bacteria. It initiates the skin's immune system through Toll-like receptors, as well as releases pro-inflammatory mediators (IL-1α, IL-8, and TNF-α). It has been observed that the quantity of this microorganism does not correlate with the severity of the disease itself. Understanding the etiopathogenesis is important as it explains the possible different forms of acne that require different treatment approaches.

Acne Clinic

It is a polymorphic disease, so the clinical picture can vary greatly: from mild comedonal to fulminant forms with systemic symptoms (3, 4). The face is most commonly affected (99% of cases), less frequently the back (60% of cases), and chest skin (15% of cases) (4).

Comedonal acne

Comedones are non-inflammatory acne elements. These are small papules of approximately 1 mm in diameter (3). They are classified as open (blackheads) and closed (whiteheads) comedones (3, 4). In childhood, comedones most commonly form in the central part of the face. Closed comedones do not have visibly open follicular pores and are less noticeable (3, 4, 6).

Papulopustular acne

Patients typically present with a combination of non-inflammatory and inflammatory rash elements. Inflammatory rash elements form from microcomedones or clinically visible non-inflammatory elements. They can be superficial and deep. Superficial inflammatory rash elements consist of papules and pustules (5 mm or smaller in diameter). In more severe cases of the disease, they can develop into deep pustules and nodules (4, 6).

Nodular and conglobate acne

Nodular form is most common in adult women. It is characterized by small, firm, palpable, painful nodules up to 5 mm in diameter, medium-sized nodules of 5–10 mm in diameter, and large nodules larger than 10 mm in diameter (3, 4). They can rupture deeply and widely, forming sinuses. Conglobate acne is a rare severe form of acne with systemic symptoms. The disease begins in the patient's 20–30 years of age. It is characterized by multiple grouped comedones, among which are inflamed papules, painful suppurating and merging nodules that form scars. Lesions appear on the trunk, limbs, and can spread to the buttocks (4, 6).

Other variants of acne

There are several rarer and unusual variants of acne or acne complications: fulminant acne (one of the most severe forms with systemic symptoms), gram-negative folliculitis, mechanical acne, occupational acne due to oil/tar, carbohydrate effects, neonatal (beginning at 2 weeks of age) and infant acne (beginning at 3–6 months of age), persistent acne, acne associated with genetic and iatrogenic endocrinopathies, drug-induced acne when taking anabolic steroids, corticosteroids, B-group vitamins, epidermal growth factors, and other drugs (3, 4, 6).

Differential diagnosis of acne

The differential diagnosis of acne is broad. During the neonatal period, it should be differentiated from sebaceous gland hyperplasia, erythema toxicum, and candidiasis. Comedonal acne is distinguished from other follicular occlusion diseases due to occupational factors, sebaceous gland hyperplasia, Winers' pores, Favre-Racouchot syndrome, naevus comedonicus. Folliculitis, pseudofolliculitis, rosacea, perioral dermatitis, trichoepithelioma, trichodiskoma, fibrofolliculoma steatocystoma are differentiated from papulopustular, nodular forms of acne (3).

Prognostic Factors of Disease Severity

When treating acne, many factors related to a more severe course should be considered: family history of acne, inflammatory process, persistent or late-onset disease, hyperseborrhea, androgenic factors, acne in the waist area, and/or psychological consequences. Previous infantile acne is also correlated with recurring acne in adolescence. Early and strong seborrhea, early onset with menstruation also allows the physician to predict a more severe course of the disease.

Scarring usually develops in the place of former deep inflammatory rash elements in patients prone to scarring. Scars can form by increasing collagen (hypertrophic and keloid scars) or by losing collagen (4). Scarring in adolescents in the facial area is observed in up to 20% of cases (2).

After acne regression, inflammatory hyperpigmentation or erythema may remain, which can disappear after a few months or remain as permanent changes (3).

In general, determining an accurate prognosis of the disease by just examining the patient is very difficult or even impossible (6).

Principles of Acne Treatment

A careful history and examination of the patient help in selecting appropriate treatment. It is important to find out what

prescription and non-prescription remedies the patient has used so far and is currently using (3).

Combination therapy is prescribed for acne treatment, which includes several pathogenetic mechanisms: benzoyl peroxide, local and systemic retinoids, local and systemic antibiotics, anti-androgens, and other measures (1, 2, 4, 6, 8–10).

The treatment plan is determined based on the severity of the disease (6), therefore the treatment of comedonal, papulopustular, nodular/conglobate acne varies.

Since comedonal acne is mild to moderate, topical treatment is recommended for this form (4). Topical retinoids adapalene, tretinoin are considered the best preparations for treating comedonal acne (4, 6), as they inhibit the growth of P. acnes, inflammatory reactions, have a keratolytic effect, thus normalizing desquamation, protecting against follicular occlusion (2–4, 7, 9, 11). At the beginning of treatment, they may cause a slight worsening of acne. Retinoids cause mild photosensitivity, so they are recommended for evening use. Benzoyl peroxide or azelaic acid can be used for treating comedonal acne (6). Benzoyl peroxide acts on P. acnes and does not induce resistance, also showing anti-inflammatory, keratolytic effects (2, 3, 7). Azelaic acid acts as a comedolytic, also suppressing P. acnes. It is also suitable for treating inflammatory hyperpigmentation. Chemical peels of low concentration on facial skin (exfoliation) with α-hydroxy acids (including glycolic acid), salicylic acid, trichloroacetic acid are suitable for this type of acne (3). Data on treating comedonal acne with lasers or other light sources are insufficient (4).

In treating mild to moderate papulopustular forms of the disease, good results are achieved by combining drugs with different mechanisms of action - antibiotics (which reduce colonization of P. acnes) with retinoids (4, 8, 10, 12–15) or with benzoyl peroxide (4, 8). In terms of local monotherapy, erythromycin is available in Lithuania. Systemic antibiotics used to treat acne in Lithuania include doxycycline. It is prescribed at 50–100 mg/day for 2–3 months (3–4). Erythromycin or other macrolides may be used as an alternative (4). For adult women with acne

Exacerbation before menstruation can be supplemented with systemic antiandrogens or a combination of estrogen-progestin (2, 6). Hormonal treatment can be effective regardless of whether serum androgen levels are elevated

Spironolactone is prescribed at 50–100 mg/day or estrogen and progestin combinations. The effect is observed after approximately 3 months (3). In severe cases, immediate treatment with systemic isotretinoin is recommended (4, 6). Isotretinoin acts as a sebostatic agent, suppresses the formation of comedones, has an immunomodulatory effect, but is teratogenic, can cause bone and muscle pain, especially in athletes, and when combined with tetracyclines, it can promote the formation of brain pseudotumors (2–3, 6). Prescribed at 0.5–1.0 mg/kg for 3–6 months (3–4, 6). Data on effective treatment of inflammatory papulopustular acne with lasers and other light sources is also insufficient (4).

For nodular/conglobate acne, the most effective treatment is systemic isotretinoin at 0.5–4–1.0 mg/kg for 3–6 months (4, 6). Its effectiveness is higher than treating with systemic antibiotics combined with topical preparations (4).

Treclinac – a novelty in acne treatment in Lithuania

This year, a new combined 1% clindamycin and 0.025% tretinoin preparation (Treclinac) has entered the Lithuanian market, intended for the treatment of comedonal and papulopustular acne.

Clindamycin exhibits in vitro activity against Propionibacterium acnes, anti-inflammatory effects on common acne lesions. Topically used tretinoin has comedolytic and anti-inflammatory effects. Tretinoin reduces the cohesion of follicular epithelial cells, thereby reducing the formation of microcomedones. In addition, tretinoin stimulates mitotic activity and increases the turnover of follicular epithelial cells, thus promoting the extrusion of comedones. Tretinoin alleviates inflammation by inhibiting transmembrane recognition receptors (toll-like receptors).

Treclinac preparation has unique properties – it uses two forms of tretinoin: soluble tretinoin ensures rapid action, while the crystalline suspension form of tretinoin dissolves slowly and ensures long-term penetration into the hair follicle. This results in good tolerability of the preparation. Additionally, tretinoin particles are very small and penetrate the hair follicle better, which affects the effectiveness of the preparation.

When treating with the combination of clindamycin and tretinoin (Treclinac), not only are the individual effects of both active substances combined, but there is also an additional synergistic effect (16, 17). This combination acts anti-inflammatory, antibacterially, comedolytically, and anti-comedogenically (7). When these substances are used together, tretinoin enhances the penetration of clindamycin, thereby reducing the risk of antibiotic resistance, increasing the spectrum of antibacterial activity in treating residual acne lesions (8, 9, 11, 16). Treatment with this combination of active substances targets many pathogenic factors: abnormal follicular keratinization, P. acnes proliferation, inflammation, and increased sebum production (16). The drug reduces both non-inflammatory and inflammatory acne lesions, is well tolerated (14, 17, 18). The drug slowly penetrates the skin, its concentration in the skin increases very gradually, reducing the likelihood of skin irritation reactions (19). There is no data suggesting that the drug causes exacerbations (17). It has also been observed that patients adhere better to the treatment regimen when treated with a combined drug that only needs to be taken once a day, compared to treating them with several separate preparations (7–8, 12, 17). Importantly, Treclinac does not contain alcohol and has a gel consistency, therefore it does not clog pores (19).

Before prescribing this medication, it is important to assess the patient's current treatment, any additional measures being taken, as well as evaluate certain social circumstances. This combination drug should not be prescribed or taken by women planning to conceive, pregnant or breastfeeding women; it should be used with caution by patients with atopic dermatitis and other facial dermatoses, as well as by individuals working in sunlight (16).

Treclinac effectiveness in treating acne:  research results

Studies show that a 1% clindamycin and 0.025% tretinoin gel (Treclinac) is more effective in treating mild to moderate acne compared to clindamycin gel, tretinoin gel, or placebos. A joint data analysis of phase III clinical trials (involving more than 2,200 patients) showed that treatment with clindamycin/tretinoin gel was successful for a larger proportion of patients compared to clindamycin gel, tretinoin gel, or a placebo gel (p<0.0001). The overall average number of lesions decreased by 49%, 38%, 40%, and 23% respectively (20).

Another phase III trial showed that a 1% clindamycin and 0.025% tretinoin gel (Treclinac), administered once daily, was at least as effective as a 1% clindamycin lotion administered twice daily in treating 209 patients with mild to moderate acne. After 12 weeks of treatment, the absolute reduction in inflamed lesions in the Treclinac group was 44%, compared to 31% in the clindamycin lotion group (21).

An analysis of 6 active control parallel trials (n=680) showed that in treating mild to moderate acne, clindamycin/tretinoin gel (Treclinac) significantly reduced the number of lesions (both total and inflamed) after 4 weeks compared to tretinoin or clindamycin gel alone, and after 12 weeks, it also reduced non-inflamed lesions (22).

According to the study data by L. Krochmalo and colleagues, similar results were obtained in treating 1,136 patients with mild to moderate acne over a 12-week period. 87% of patients completed the 12-week treatment course. Clindamycin/tretinoin gel was the most effective among all compared treatment options in reducing the total, inflamed, and non-inflamed skin lesions (23).

Maintenance therapy and other treatment recommendations

It has been proven that discontinuation of retinoid therapy leads to an immediate increase in simple acne. The goal of maintenance therapy is to reduce the recurrence of visible lesions. It is recommended to use the topical retinoid adapalene or, alternatively, azelaic acid preparation. Maintenance therapy may last for months or even years depending on the patient.

It is important to inform the patient that acne is a chronic, often exacerbating condition, and to explain its pathophysiology. This helps patients cooperate better and adhere to the prescribed treatment regimen (4). It is necessary to discuss with the patient that maintaining skin cleanliness is not the most important factor in treating acne, so there is no need to buy and use expensive cleansers. Gentle washing twice daily is completely sufficient (6).

There is no perfect acne treatment overall, but episodes of breakouts can be reduced for almost every patient (2).

Conclusion

The importance of acne treatment is undeniable, as this condition worsens the quality of life for patients, is associated with lower self-esteem, and social isolation. In order to achieve good long-term treatment results, the treatment must be well tolerated, convenient, and compatible with the patient's lifestyle.

Edita Naruševičiūtė-Skripkienė Vilnius University Hospital Santaros Clinics, Department of Dermatovenereology