User login
Who is tired of the same old stuff when it comes to acne? Innovation in therapy has been stagnant with a flurry of “me too” reformulated fixed combinations. The only true advance has been in drug delivery, with new vehicles allowing for the solubilization of established drugs such as dapsone or the combination of incompatible actives such as benzoyl peroxide and a retinoid. Before we can welcome new drugs with open arms, we must first expand the construct of acne pathophysiology to identify more appropriate targets for said new drugs. In a recent article published online in the Journal of the American Academy of Dermatology in June, Metiko et al highlight this sentiment. Generations of dermatologists were taught the 3- to 4-step process (depending on the teacher) through which an acne lesion forms: (1) follicular epidermal hyperproliferation, (2) Propionibacterium acnes colonization, and (3) inflammation. However, the molecular underpinnings of this theory have been challenged for more than a decade, with research highlighting the presence of preclinical inflammation, most recently found to be mediated by IL-1ß through a specific inflammasome pathway, NLRP3 (NOD-like receptor family, pyrin domain containing 3). Maybe we are missing a bridge between this stellar basic science and the clinical dermatologist who contends that the pesky microcomedone is the acne instigator. This short but sweet letter once again calls this antiquated prose into question in a highly visible clinical dermatology journal.
In thinking of new pathways and targets, Gupta et al published an article online in Archives of Dermatological Research on May 19 on the role of peroxisome proliferator-activated receptors (PPARs) and PPAR agonists in the treatment of multiple dermatologic diseases. For our purposes, I will highlight the section on acne and will start at the end: More research is needed. Peroxisome proliferator-activated receptors are nuclear hormone receptors that regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorigenesis after binding with specific ligands. With respect to acne specifically, PPARs influence 2 of the pathophysiologic factors—sebum production and inflammation—due to their effect on lipid deposition in the sebocytes and inhibition of proinflammatory gene expression and downregulation of inflammatory cytokines. It appears that activation or inhibition of specific PPAR subtypes can either increase or decrease sebum production or be pro- or anti-inflammatory. The tough part is which receptors to activate and which to inhibit. This review related to an interesting clinical study that evaluated oral zileuton 600 mg administered 4 times daily for 3 months for acne. Zileuton inhibits leukotriene B4 production, which, as it turns out, is a natural ligand for PPARα. The idea here is that this blockade would be anti-inflammatory and indirectly inhibit the sebum production via PPARα suppression. The pilot study was reported as successful, with a decrease in the papulopustular acne severity index in a time-dependent manner in subjects evaluated.
What’s the issue?
So, what’s the point of this long-winded, double-paper review? We need to expand our acne horizons. We need new bench-to-bedside approaches. Which is your favorite target?
Who is tired of the same old stuff when it comes to acne? Innovation in therapy has been stagnant with a flurry of “me too” reformulated fixed combinations. The only true advance has been in drug delivery, with new vehicles allowing for the solubilization of established drugs such as dapsone or the combination of incompatible actives such as benzoyl peroxide and a retinoid. Before we can welcome new drugs with open arms, we must first expand the construct of acne pathophysiology to identify more appropriate targets for said new drugs. In a recent article published online in the Journal of the American Academy of Dermatology in June, Metiko et al highlight this sentiment. Generations of dermatologists were taught the 3- to 4-step process (depending on the teacher) through which an acne lesion forms: (1) follicular epidermal hyperproliferation, (2) Propionibacterium acnes colonization, and (3) inflammation. However, the molecular underpinnings of this theory have been challenged for more than a decade, with research highlighting the presence of preclinical inflammation, most recently found to be mediated by IL-1ß through a specific inflammasome pathway, NLRP3 (NOD-like receptor family, pyrin domain containing 3). Maybe we are missing a bridge between this stellar basic science and the clinical dermatologist who contends that the pesky microcomedone is the acne instigator. This short but sweet letter once again calls this antiquated prose into question in a highly visible clinical dermatology journal.
In thinking of new pathways and targets, Gupta et al published an article online in Archives of Dermatological Research on May 19 on the role of peroxisome proliferator-activated receptors (PPARs) and PPAR agonists in the treatment of multiple dermatologic diseases. For our purposes, I will highlight the section on acne and will start at the end: More research is needed. Peroxisome proliferator-activated receptors are nuclear hormone receptors that regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorigenesis after binding with specific ligands. With respect to acne specifically, PPARs influence 2 of the pathophysiologic factors—sebum production and inflammation—due to their effect on lipid deposition in the sebocytes and inhibition of proinflammatory gene expression and downregulation of inflammatory cytokines. It appears that activation or inhibition of specific PPAR subtypes can either increase or decrease sebum production or be pro- or anti-inflammatory. The tough part is which receptors to activate and which to inhibit. This review related to an interesting clinical study that evaluated oral zileuton 600 mg administered 4 times daily for 3 months for acne. Zileuton inhibits leukotriene B4 production, which, as it turns out, is a natural ligand for PPARα. The idea here is that this blockade would be anti-inflammatory and indirectly inhibit the sebum production via PPARα suppression. The pilot study was reported as successful, with a decrease in the papulopustular acne severity index in a time-dependent manner in subjects evaluated.
What’s the issue?
So, what’s the point of this long-winded, double-paper review? We need to expand our acne horizons. We need new bench-to-bedside approaches. Which is your favorite target?
Who is tired of the same old stuff when it comes to acne? Innovation in therapy has been stagnant with a flurry of “me too” reformulated fixed combinations. The only true advance has been in drug delivery, with new vehicles allowing for the solubilization of established drugs such as dapsone or the combination of incompatible actives such as benzoyl peroxide and a retinoid. Before we can welcome new drugs with open arms, we must first expand the construct of acne pathophysiology to identify more appropriate targets for said new drugs. In a recent article published online in the Journal of the American Academy of Dermatology in June, Metiko et al highlight this sentiment. Generations of dermatologists were taught the 3- to 4-step process (depending on the teacher) through which an acne lesion forms: (1) follicular epidermal hyperproliferation, (2) Propionibacterium acnes colonization, and (3) inflammation. However, the molecular underpinnings of this theory have been challenged for more than a decade, with research highlighting the presence of preclinical inflammation, most recently found to be mediated by IL-1ß through a specific inflammasome pathway, NLRP3 (NOD-like receptor family, pyrin domain containing 3). Maybe we are missing a bridge between this stellar basic science and the clinical dermatologist who contends that the pesky microcomedone is the acne instigator. This short but sweet letter once again calls this antiquated prose into question in a highly visible clinical dermatology journal.
In thinking of new pathways and targets, Gupta et al published an article online in Archives of Dermatological Research on May 19 on the role of peroxisome proliferator-activated receptors (PPARs) and PPAR agonists in the treatment of multiple dermatologic diseases. For our purposes, I will highlight the section on acne and will start at the end: More research is needed. Peroxisome proliferator-activated receptors are nuclear hormone receptors that regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorigenesis after binding with specific ligands. With respect to acne specifically, PPARs influence 2 of the pathophysiologic factors—sebum production and inflammation—due to their effect on lipid deposition in the sebocytes and inhibition of proinflammatory gene expression and downregulation of inflammatory cytokines. It appears that activation or inhibition of specific PPAR subtypes can either increase or decrease sebum production or be pro- or anti-inflammatory. The tough part is which receptors to activate and which to inhibit. This review related to an interesting clinical study that evaluated oral zileuton 600 mg administered 4 times daily for 3 months for acne. Zileuton inhibits leukotriene B4 production, which, as it turns out, is a natural ligand for PPARα. The idea here is that this blockade would be anti-inflammatory and indirectly inhibit the sebum production via PPARα suppression. The pilot study was reported as successful, with a decrease in the papulopustular acne severity index in a time-dependent manner in subjects evaluated.
What’s the issue?
So, what’s the point of this long-winded, double-paper review? We need to expand our acne horizons. We need new bench-to-bedside approaches. Which is your favorite target?
