Acne: Pathogenesis Revisited

Panelists: James Del Rosso, MD, Alan Shalita, MD, Guy Webster, MD, PhD

For decades the pathogenesis of acne has centered on the formation of the microcomedones as the initiating event followed by an inflammatory cascade. This dogma is now being questioned in a “chicken vs. egg” scenario as being raised as to whether the microcomedone came first or was it precipitated by inflammation that came first.  Data coming out of the lab of Sewon Kang has taken a close look at the issue of what initiates the acne process.  In their work using immunohistochemical and histologic methods, they looked at patients with active acne lesions, normal skin in acne patients and compared them to a control group of people without acne. It was found that in acne patients there appeared a population of inflammatory cells with an absence of neutrophils in the majority of the locations that were evaluated.  This inflammation appeared before the development of hyperkeratinization and microcomedone formation indicating that the microcomedone might not be the initiating lesion. Dr. Kang’s group tracked the development of acne lesions and they found that about three out of ten of the lesions developed into an inflammatory lesion without a visible comedonal lesion.

The take home point is that when looking at an acne patient even normal appearing skin may be harboring inflammation in the follicle that can lead to follicular hyperkeratosis and microcomedone formation so it is important to treat the entire acne prone area proactively and possibly more aggressively.

Case Study

A 33 year-old Asian female presents with a several year history of late onset facial acne and had “clear skin as a teen”.  Her acne has been poorly responsive to treatment with over-the-counter medications as well as topical BPO gel and 0.025% tretinoin cream (“irritates my sensitive skin”) and only modestly response to a 3-month course of oral doxycycline.  She notes some flaring around menses. Her frustration led her to stop all meds and she is not on oral contraception and has two children.

It was noted by the panel that this age group of women have a high level of frustration regarding their acne and several management issues need to be considered including pregnancy.  These “issues” include resistance to the idea of taking oral antibiotics, oral contraceptives and potentially oral medications like spironolactone. Skin sensitivity is also clearly an issue patients such as this one.

Topical Formulations for this Patient Subset

Data for tretinoin 0.05% aqueous gel show that the percent of patients reporting adverse reactions over the 12-week treatment period experienced significantly less incidence of skin related adverse events than with tretinoin microsphere gel 0.1%.

Other topical retinoids available for use with lower potential for cutaneous irritation include Tretinoin Microsphere Gel 0.04%, Adapalene Lotion 0.1%, and Adapalene Gel 0.3%.

Data looking at Clindamycin/Tretinoin 0.025% Gel over one year show that the researchers did see patient improvement increased over time. The percentage of patients with “clear” or “almost clear” skin increased with longer use of CLIN/RA Gel. 57% of patients had “clear” or “almost clear” skin at 12 months. The majority of the patients (78%) were being treated with CLIN/RA Gel as monotherapy; 22% were receiving one or more products (oral antibiotics [12%]; topical therapy [9%]; and isotretinoin [<1%]).

One important consideration is that of P. acnes and antibiotic resistance. Results from a 16-week single-center, double-blind, randomized, parallel-group study of 79 patients with acne who used either a 1% clindamycin/5% BPO gel or clindamycin 1% gel alone show that the combination gel reduced total mean baseline P. acnes count by 99% at week 4, and this was maintained throughout the study. In the clindamycin monotherapy group, the total mean bacterial count was reduced by 87.9% at week 16. Clindamycin-resistant P. acnes counts remained at or below baseline values with the combination gel throughout the treatment while they increased to >1600% of baseline by week 16 with clindamycin monotherapy (P=0.018 vs. combination gel). In addition, drug-resistant, coagulase-negative staphylococci were increased to > 3500% of baseline by week 16. (P<0.001)

A pooled data analysis from pivotal studies stratified by gender looked at male and female patients aged 12 and older with facial acne vulgaris who were randomized to receive either topical dapsone gel (n = 1453; 48% male/52% female) or vehicle gel (n = 1445; 47% male/53% female). The results show that females tended to have better results than males, in both treatment arms. The researchers have not broken the study down by age at this point, nor can they confirm that the results were related to better adherence/compliance.

Hormonal Therapy for Post-teen Acne

Spironolactone is highly effective in post-teenage acne in females. The majority of patients will do well at or below 100mg/day. It is important that clinicians realize that this therapy is highly individualized based upon what dose works best for each patient. Spironolactone can also be used in combination with other topical treatments and oral antibiotics. Safety considerations for oral spironolactone include pregnancy plans and any underlying disorders such as PCOS or endocrinopathies, a risk for hyperkalemia (e.g., use of ACE inhibitors, cardiac disease, diabetes), high intake of K+ containing sports drinks and any significant or potential drug interactions.  There is a question as whether or not clinicians should monitor serum K+ levels. Generally it is not needed, provided there are no risk factors; however, that is the decision of the individual clinician. The general consensus regarding breast cancer history and oral spironolactone is that there does not appear to be a risk; yet, there is no definitive answer about that at this point.

 

Update on Topical Therapies:

The panel discussed vehicle selection, active ingredients, combination regimens, regimens for application/sequencing, and long term data. The major players in the topical therapy playing field today are benzoyl peroxide (BP), retinoids, and clindaymycin (1%). Combination therapy provides incremental improvement and tolerability is based upon selecting products with favorable vehicles.

Can Benzoyl Peroxide reduce comedonal acne lesions?

Yes, and sometimes, markedly.  Sometimes, using BP can give patients a “jump-start” to getting a quicker effect against comedonal lesions.

Is Benzoyl Peroxide 2.5 Enough?

Yes, but it depends largely on the formulation’s ability to deliver the BPO. Combining multiple therapies can provide patients with a faster and greater response. Several studies have demonstrated this benefit.

Studies have shown that Clindamycin has a therapeutic benefit. A thorough literature reviewof five recent studies (N>2000)² have shown a relative benefit in combination with other agents and it adds to efficacy of benzoyl peroxide/retinoid.

Optimal Oral Antibiotic Use for Acne

Dermatologists prescribe less than 1% of all oral antibiotics, but dermatologists do prescribe 20% of the oral tetracyclines for treating acne and rosacea. Doxycycline and minocycline are the two most commonly prescribed.  Oral antibiotics are used to augment the therapeutic benefit and to speed up the response for moderate -to-severe acne vulgaris, especially for inflammatory lesions. Reduction of P. acnes correlates with therapeutic benefit.

It is important to remember that doxycycline has reported adverse events of serious ulcerations and esophagitis, so it is extremely important to remind your patients to take this medication with large glasses of water and not before reclining. Patient education is key to the therapeutic success of this drug. Minocycline does have a higher risk of drug-induced hypersensitivity however a few cases that have also been reported with doxycycline. Both doxycycline and minocycline have a “grandfathered” approval for acne by the FDA.