An innovative treatment option for acne vulgaris – combining clindamycin (1%) and tretinoin (0.025%),  – was launched in South Africa in November, by Viatris. This new gel combination formulation is indicated for patients ≥12-years with moderate acne vulgaris when papules and pustules are present. 

An innovative treatment option for acne vulgaris - combining clindamycin (1%) and tretinoin (0.025%), - was launched in South Africa in November.

Current clinical management of acne in South Africa Dr Willie Visser, Head of Dermatology at the University of Stellenbosch, Tygerberg Academic Hospital (Western Cape)

Acne vulgaris is a common, sebaceous skin condition caused by the blocking of hair follicles. Due to hormonal influences, the sebaceous gland enlarges and more sebaceous fluid is produced, which accumulates in a blocked pore, causing a waxing, solidified sebum.1

This environment is conducive to the proliferation of bacteria, which may lead to the formation of an open or closed comedone. If the comedones rupture and disperse the bacteria into the skin tissue – as opposed to on the skin’s surface – the body responds with inflammation to fight the bacteria. This inflamed lesion forms a papule, which can result in permanent scarring if not treated early and effectively.1

Numerous studies have shown that acne negatively impacts the psychological well-being and quality of life of patients, which may result in depression, anxiety, and social isolation.1

A misnomer is that acne only affects teenagers. However, a significant number of patients either continue to experience acne or develop new-onset acne after the teenaged years.1

Close to 100% of teenagers develop acne at some point.12 However, a study by Collier et al assessed the prevalence of acne in different age groups. They found in the age group, 20 to 29 years, the prevalence of acne was 50.9% in women versus 42.5% in men. In those between 30 to 39 years, the prevalence was 35.2% in women and 20.1% in men complained of acne. In the group 40 to 49 years, the prevalence was 26.3% in women versus 12% in men and in those 50 years and older, the prevalence was 15.3% in women and 7.3% in men.2

The authors concluded that acne continues to be a common skin problem past the teenaged years, with women being affected at higher rates than men in all age groups.2,12

What causes acne?

Patients should be viewed holistically and factors that may cause acne should be discussed at their first visit. Examples include:1

  • Nutrition: Skim milk, assimilated saccharides, nibbling, and nutritional supplements containing whey protein/leucine. Dr Visser did point out that the role of nutrition as a cause of acne is controversial
  • Medication: Contraceptives (type of progestin used) and the use of anabolic steroids or testosterone
  • Occupational: Cosmetics and mechanical factors
  • Pollution: Air and industrial pollutants, tobacco, and cannabis use
  • Climate: Heat, humidity, ultraviolet radiation
  • Psychological: Stress
  • Smoking status.

Factors that guide treatment

Dr Visser explained that different treatment modalities are recommended based on:1

  • Lesion/acne type: blackheads, pimples, cysts, scarring. The type of lesion should guide the approach to acne management. The overall aim of treatment is to prevent permanent scarring
  • The grade of acne: mild, moderate, or severe

The grade of acne determines whether or not treatment should be intensified. About 75% of patients have mild to moderate acne and can be managed in general practice. The remaining 25% develop severe disease and must be managed by a dermatologist

  • Mild (grade 1): there are two types of comedones: open and closed. Open comedones are due to plugging of the pilosebaceous orifice by sebum on the skin surface. Closed comedones are due to keratin and sebum plugging the pilosebaceous orifice below the skin surface. Treatment includes topical therapies
  • Moderate (grade 2): inflammatory papules present as a small papule with erythema. Treatment with topical (combination products) and/or systemic therapies is recommended
  • Moderate (grade 3): pustules/pimples are present. Treatment with topical (combination products) and/or systemic therapies is recommended
  • Severe (grade 4): many pustules coalesce to form nodules and cysts. Treatment with systemic retinoids is recommended.

Topical therapies

Topical retinoids should be used in almost all acne patients, stressed Dr Visser. Topical therapies include retinoids, benzoyl peroxide, topical antibiotics, azelaic acid, combinations of clindamycin plus retinoids or benzoyl peroxide and retinoids. He cautioned that antibiotic use could lead to resistant Cutibacterium acnes, especially when using erythromycin, which may lead to resistance to all tetracyclines.

Staphylococcus. epidermidis is also a concern. The plasmids may transfer this into resistance to Staphylococcus aureus – a situation you want to avoid if you are treating patients with acne.1

He added that ‘spot treatment’ is ineffective. Topical preparations should be applied daily over the entire area affected and treatment should be continued even after clearance.1

Systemic therapies

Systemic therapies include antibiotics, hormonal therapy (eg the pill and anti-androgens for use only in females) is a safe option, retinoids and dapsone. Systemic antibiotics are anti-inflammatory and -bacterial.1

Systemic antibiotics and hormonal therapies have a delayed onset of action and take between three and four months for improvements to become visible. Dr Visser recommended starting female patients on hormonal therapy early in the onset of the condition. He noted that not all contraceptives are effective, adding that depo provera, nuristerate, and triphasil are not skin-friendly and should not be used in patients with acne.1

Systemic antibiotics should be used in combination with topical products to reduce the risk of resistance development. There is no rationale for using it as monotherapy, Dr Visser pointed out.1

Systemic retinoids should be used when cysts and nodules are present if other therapies have failed after three to four months of use and when prevention of scarring is the objective. In addition, systemic retinoids can be used if the patient presents with gram-negative folliculitis after prolonged antibiotic use. Systemic retinoids are associated with side-effects such as dry lips (100%), dry nose (66%), dry skin (50%), dry eyes (40%) and acne worsening (35%).1

The relationship between isotretinoin treatment for acne and depression is controversial. A meta-analysis did not show a positive association between isotretinoin use and depression. In fact, it showed that depression declined after use, said Dr Visser.1

However, he cautioned, individual susceptibility to depression during isotretinoin use cannot be ruled out and patients should be made aware of this risk.1

Other factors: age, sex, pregnancy, and other comorbidities such as atopic dermatitis. Topical retinoids are not recommended in pregnant patients as it may cause foetal abnormalities.1

Maintenance therapy

Maintenance therapy is required for six months to a year after resolution of acne. In the majority of cases, acne only resolves at around the age of 25. Topical retinoids or azelaic acid are recommended for maintenance therapy. Topical retinoids are preferred because azelaic acid has been associated with skin irritation. In patients who present with inflamed papules, combination therapy is recommended. Combined contraceptives work well for maintenance in female patients.1

Acne should be viewed as a chronic condition. Therefore, it is extremely important to educate your patients about basic skin care as well as sun protection, he concluded.1

Introducing Treclin, a unique formulation

Prof Harald Gollnick, Department of Dermatology and Venereology, Medical Faculty Otto-von-Guericke-University (Germany)

Guidelines promote the combined use of treatments with different modes of action in order to modulate two or more acne aetiological factors simultaneously, resulting in faster onset of action and/or greater efficacy.3

The current best practice is to use topical retinoids at the onset of therapy even in patients presenting with predominantly inflammatory acne. In these patients, topical or oral antibiotics or -microbials should be added to provide a significantly greater and more rapid effect.4

An effective strategy is to initiate topical retinoid therapy at the same time as oral or topical antibiotics or -microbials and continue until reasonable clearance of inflammatory lesions occurs.4

Benefits of combination therapy

According to Prof Gollnick, combination therapy is effective because it targets more than one pathogenic factor simultaneously. Combinations that treat bacterial colonisation have anti-inflammatory effects and control comedogenesis (eg an antibiotic-retinoid combination). Using these combinations is more rational and effective, he stressed.1

Combination therapy with a topical retinoid and an antibiotic can normalise follicular epithelial desquamation and reduce bacterial proliferation. The new retinoids have an additional anti-inflammatory action along with their effect on the preclinical microcomedo and, co-administered with a topical or an oral antibiotic, are a rational initial therapy for all but the most severe forms of acne.5

An innovate formulation for acne

Clindamycin (1%) and tretinoin (0.025%) (Clin-RA) is an aqueous gel formulation containing solubilised clindamycin phosphate 1% and a stable combination of both solubilised and crystalline tretinoin 0.025%. Treclin has been evaluated in three pivotal phase III studies, among other studies including a 52-week trial.8,9

Dréno et al evaluated the efficacy and safety of Clin-RA in three 12-week randomised studies. The objective of these studies was to pool the data in order to evaluate the efficacy and safety of Clin-RA in all participants as well as subgroups (adolescents) and acne severity.9

The studies recruited 4550 patients, who were randomised to Clin-RA, clindamycin, tretinoin and vehicle. The researchers evaluated Evaluations included percentage change in lesions, treatment success rate, proportions of patients with ≥50% or ≥80% continuous reduction in lesions, adverse events, and cutaneous tolerability.9

Inflammatory, non-inflammatory and total lesions were reduced in the overall study group, as well as significantly higher success rates with Clin-RA compared with clindamycin, tretinoin and vehicle alone.9

In the adolescent group (n=2915), reduction in all types of lesions was also significantly greater with Clin-RA versus comparators. In patients with mild/moderate acne (n=3662 patients) similar results were reported and in those with severe acne (n=880), the percentage reduction in all lesion types was significantly greater with Clin-RA versus vehicle. At 12 weeks, a greater proportion of patients treated with Clin-RA had a ≥50% or ≥80% continuous reduction in all types of lesions compared with clindamycin, tretinoin and vehicle.9

In the active and vehicle groups, adverse event (AE) frequencies were similar and mean tolerability scores over time were <1 (mild) were similar in all groups. The team concluded that Clin-RA is safe, has superior efficacy to its component monotherapies and should be considered as one of the first-line therapies for mild-to-moderate facial acne.9

Another advantage of Clin-RA is that it is not associated with acne flaring or an increase in clindamycin-resistant Cutibacterium acnes (formerly Propionibacterium acnes) counts. Clin-RA is considered as effective as an adapalene 0.1%/benzoyl peroxide 2.5% fixed-dose formulation but has a more favourable tolerability profile.10

Clin-RA may be more effective than clindamycin 1%/benzoyl peroxide 5% at treating non-inflammatory acne lesions since the latter does not contain a retinoid to target comedones. Clin-RA is also easy for patients to manage and apply and has the advantage of not containing benzoyl peroxide, which can bleach hair and fabrics. Taken together, the profile of Clin-RA suggests Clin-RA to be a first-line treatment for patients with facial acne.10

Speed is of the essence when dealing with acne patients in general and teenagers in particular, said Prof Gollnick. Teens have zero tolerance for delayed gratification.6

The onset of action of Clin-RA is rapid, occurring within two weeks of treatment initiation. As shown by Dréno et al, a greater proportion of Clin-RA treated patients had a ≥50% or ≥80% continuous reduction in all types of lesions at week 12 compared with clindamycin, tretinoin and vehicle.9,10

Simple regimens preferred

Regimen complexity encompasses dosing frequency, number of medications and ease of administration. Dosing frequency is one of the most important characteristics in drug choice. Adherence decreases dramatically as dosing frequency increases. Patients do not enjoy layering multiple products, especially on the face and especially if they have to be applied during daytime.6

Yentzer et al randomised participants (n=26) with mild to moderate acne vulgaris to 12 weeks of a once daily application of combination Clin-RA, or separate daily applications of clindamycin phosphate gel 1% and tretinoin cream 0.025% (C gel + T cream) twice daily.7

The team measured disease severity at baseline and then again at weeks four, eight, and 12. They also monitored adherence using electronic monitoring caps on the medication tubes.7

Their results showed that median adherence in the Clin-RA group was 88% versus 61% in the C gel + T cream group. The group randomised to Clin-RA had a mean reduction of 51% mean in total lesions versus a mean of 32% reduction compared to those in the C gel + T cream group by the end of the study.7

The authors concluded that both Clin-RA and separate applications of C gel + T cream improved mild to moderate acne, however, the use of a once-daily combination product improved adherence and thus clinical outcomes.7

Patient preference

Kellett et al compared patient preferences for four topical antibiotics used for one week, once or twice daily, to treat acne vulgaris. This was a randomised, phase IV, single-centre, cross-over study was performed using conjoint analysis and a traditional patient questionnaire.11

Participants used each of four topical antibiotics for 1 week: erythromycin/zinc solution, clindamycin phosphate lotion, benzoyl peroxide/erythromycin gel (each applied twice daily) and clindamycin phosphate gel (applied once daily) over a four week period.11

The study looked at five different attributes of acne medications: form, storage, product life once opened, method of application and regimen (each with two or three possible options). The researchers identified 108 possible permutations focusing on the five attributes mentioned above and selected, 16 hypothetical medications at random, which were described on printed cards.11

Participants (=67) were asked to rank the cards in order of preference and which hypothetical product they were most likely to use. The ratings were done pre-and post-treatment. The team then calculated product utilities using a multiple regression model for each patient.11

In addition, participants were asked to complete an acceptability questionnaire. They had to rate the product acceptability after one week of treatment with each of the four topical antibiotics. Later, they were asked to rank the medications in order of preference after using all four treatments. Tolerability was assessed using diary cards.11

Of 67 patients recruited, 64 used all four medications and completed the study. The conjoint analysis found that a gel formulation, room temperature storage, product life of up to 18 months once opened, application with fingers and once-daily regimen were the options ranked first for the five product attributes. According to the ranking order (out of 108) for the combination of attributes representing the four study medications, clindamycin phosphate gel had the highest rankings (six and one pre-and post-treatment, respectively) and benzoyl peroxide/erythromycin gel had the lowest rankings (93 and 70 pre-and post-treatment).11

The rankings of clindamycin phosphate lotion and erythromycin/zinc solution worsened from pre- to post-treatment, indicating a shift in patient preference after they experienced products ‘in-use’ during the study.11

Based on the questionnaire, clindamycin phosphate gel was liked best by the highest proportion of patients (33%). In terms of overall satisfaction, the order of preference was: clindamycin phosphate gel, clindamycin phosphate lotion, benzoyl peroxide/erythromycin gel and erythromycin/zinc solution.11

Adverse events related to medication occurred most frequently with erythromycin/zinc solution and benzoyl peroxide/erythromycin gel. Clindamycin phosphate gel was the only product not associated with any episodes resulting in a change of medication or dose.11

Conjoint analysis provided a convenient, reliable tool for assessing patient preferences for topical antibiotics used to treat acne. The patients clearly preferred a gel formulation that could be applied with the fingers once daily and stored at room temperature for as long as 18 months.11

One product (clindamycin phosphate gel) combined all five of the preferred attributes, a preference confirmed by the simulated product rankings. These findings of the conjoint analysis are consistent with the safety profiles and the results of the traditional questionnaire.11

Unmet needs in treating acne

Dr Pholile Mpofu, Dermatologist and clinical researcher

Patient adherence to therapy is a major obstacle in the effective management of acne, leading to high failure rates. Studies show that only 75.8% of patients adhere to topical treatment. Factors that influence patient adherence include:1

Primary causes

Treatment is not started at all
Patient lack of knowledge about his/her condition
Confusion about how to use medication
Weak patient-doctor relationship
Fear of adverse events
Cost

Secondary causes (started, but abandoned)

Delayed results
Complexity of regimens
Side effects (skin irritation and inflammation)
Busy lifestyles
Forgetfulness
Inconvenience
Psychiatry comorbidities.

According to Dr Mpofu, studies show that patients prefer treatment that is effective and has a rapid onset of action. Products that address inflammatory and non-inflammatory lesions are also preferred. Furthermore, products that are user-friendly, easy to apply and do not lead to antibiotic resistance, are preferred.1

Dr Mpofu emphasised the importance of managing patient expectations. Explaining to the patient what to expect (eg delayed onset of action) from treatment will improve adherence. It is also extremely important to make patients aware of the consequences of non-adherence to treatment such as permanent scarring.1

It is also extremely important to rule out conditions that may mimic acne, because these conditions require a different approach to treatment. Conditions that may mimic acne include:1

  • Pseudofolliculitis: also known as ‘shaving bumps’, or ‘razor bumps’, is inflammation of hair follicles and surrounding skin, caused by hairs trapped beneath the skin surface. The condition is more common in men and usually occurs on the face. Symptoms include clusters of small, red, or dark bumps around hair follicles. The surrounding skin is often red and inflamed Gram-negative folliculitis: a pustular rash resembling acne caused by a bacterial infection. Lesions are usually found around the area of the upper lip under the nose, to the chin and cheeks
  • Demodex folliculorum: caused by a saprophytic parasitic mite of the pilosebaceous follicle and seborrheic glands and is found mainly on the face of adult men. The condition is characterised by itchy pustules, follicular scaling, and dryness, conglobata demodicosis with nodulocystic lesions, and blepharitis
  • Eosinophilic folliculitis: a non-infectious eosinophilic infiltration of hair follicles. The three variants include classic eosinophilic pustular folliculitis, immunosuppression-associated eosinophilic folliculitis (mostly HIV-related), and infancy-associated eosinophilic folliculitis. Patients with eosinophilic folliculitis develop recurrent crops of sterile pustules and papules. Pruritus develops in half of the patients, in some cases with considerable intensity. The clinical course of eosinophilic folliculitis is characterised by multiple cycles of exacerbations and remissions
  • Pityrosporum: occurs when a specific genus of yeast called Malassezia, which naturally occurs on your skin, infects the hair follicles. Pityrosporum folliculitis lacks comedones, which are the whiteheads and blackheads that are common characteristics of acne. It is very itchy condition and tends to occur in areas where the skin is oilier (T-zone)
  • Peri-oral dermatitis: small, red, pus-filled bumps and mild peeling of the skin around the mouth. The condition can also affect the skin around the nose, cheeks, and eyes
  • Rosacea: a condition that causes redness and often small, red, pus-filled bumps on the face. Key symptoms are facial redness with swollen red bumps and small visible blood vessels
  • Pomade acne: acne eruptions on the forehead and temples consisting mainly of rather uniform closed comedones with occasional papulo-pustules. May be caused by excessive use of hair products. In the majority of cases, pomade acne will resolve when use of products are stopped.
  • Mask acne: a common side effect of using a mask. Taking off the mask regularly (when possible) and good skin hygiene may help to improve skin health
  • Steroid acne: an acne-like skin condition that occurs in people with high levels of circulating corticosteroids. They may have Cushing disease or they may be undergoing treatment with systemic steroid medications. May also be a side effect of the use of anabolic steroids.

Take-home messages

  1. Acne can occur at any age
  2. Acne has a negative effect on emotions and social functioning
  3. Good acne treatment means: Choice of the right drug (effective, fast action, well tolerated, long-term tolerability, easy to use, does not cause antibiotic resistance) leads to improvement of adherence to treatment
  4. Effective patient education should start at the first visit
  5. It is important to eliminate other causes that mimic acne
  6. Managing patient expectations is crucial to the success of treatment.
REFERENCES:

1. Viatris Treclin launch. 16 November 2021. https://cpdlive.co.za/viatris-treclin-launch/
Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol, 2008.

2. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol, 2007.

3. Gollnick HPM, Cunliffe W, Berson D, et al. Global Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol, 2003.

4. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol, 2003.

5. Baldwin HE. Tricks for improving compliance with acne therapy. Dermatologic Therapy, 2006.

6. Yentzer BA, Ade RA, Fountain JM, et al. Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. Cutis, 2010.

7. Del Rosso JQ, Jitpraphai W, Bhambri S, Momin S. Clindamycin phosphate 1.2%- tretinoin 0.025% gel: vehicle characteristics, stability, and tolerability. Cutis, 2008.

8. Dréno B, Bettoli V, Ochsendorf F, et al. Efficacy and safety of clindamycin phosphate 1.2%/tretinoin 0.025% formulation for the treatment of acne vulgaris: pooled analysis of data from three randomised, double-blind, parallel-group, phase III studies. Eur J Dermatol, 2014.

9. Ochsendorf F. Clindamycin phosphate 1.2% / tretinoin 0.025%: a novel fixed-dose combination treatment for acne vulgaris. J Eur Acad Dermatol Venereol, 2015.

10. Kellett N, West F, Finlay AY. Conjoint analysis: a novel, rigorous tool for determining patient preferences for topical antibiotic treatment for acne. A randomised controlled trial. Br J Dermatol, 2006.