Evidence-based update on rosacea comorbidities and their common physiologic pathways.

Rosacea is a common chronic inflammatory disease affecting the facial skin whose etiology and pathophysiology are the subject of much investigation. Risk factors include genetic and environmental elements that may predispose individuals to localized inflammation and abnormal neurovascular responses to stimuli. Recent studies have introduced an array of systemic rosacea comorbidities, such as inflammatory bowel disease and neurologic conditions, that can be challenging to synthesize. We critically review the current data behind reported rosacea comorbidities and identify and highlight underrecognized physiologic mediators shared among rosacea and associated comorbidities. This information may be helpful in addressing patient questions about potential systemic implications of rosacea and can serve as a candidate platform for future research to understand rosacea and improve treatments.

Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics.

Rosacea is a chronic relapsing inflammatory skin disease with high prevalence worldwide. Recent research suggests that dysregulation of innate and adaptive immune pathways as well as neurovascular changes is present, with different degrees of importance in the various subtypes. Neither the aetiology, genetics nor pathophysiological basis of the vascular, inflammatory or fibrotic changes is well understood. The clinical spectrum comprises a huge variability from erythema (vasodilation) to papules/pustules (inflammatory infiltrate) to phymata (fibrosis, glandular hyperplasia) making it a valuable human disease model to understand the interplay between the neurovascular and immune systems as well as the progression from chronic inflammation to fibrosis in skin. The lack of appropriate animal models emphasizes the importance of further translational research validating observed molecular pathways under disease conditions. A wide spectrum of physical (UV, temperature), biological (microbiota, food) and endogenous (genetic, stress) stimuli has been discussed as "trigger factors" of rosacea. Novel findings implicate keratinocytes, smooth muscle cells, endothelial cells, macrophages, mast cells, fibroblasts, Th1/Th17 cells, antibody-producing B cells and neurons in the pathobiology of rosacea. So far, pattern recognition receptors like TLR2, transient receptor potential ion channels, cytokines, chemokines and proteases have been implicated as critical receptors/mediators. However, our understanding of the interactive networks on the molecular level is very limited. Identification of critical molecular components of the inflammatory cascade including antimicrobial peptides, the IL-1ß inflammasome, TNF, IFN-γ, proteases and neuropeptides may provide the basis for novel pathomechanism-based therapeutic approaches for this frequent and bothersome skin disease.

Improved clinical outcome and biomarkers in adults with papulopustular rosacea treated with doxycycline modified-release capsules in a randomized trial.

BACKGROUND: Patients with rosacea have increased amounts of cathelicidin and protease activity but their usefulness as disease biomarkers is unclear. OBJECTIVE: We sought to evaluate the effect of doxycycline treatment on cathelicidin expression, protease activity, and clinical response in rosacea. METHODS: In all, 170 adults with papulopustular rosacea were treated for 12 weeks with doxycycline 40-mg modified-release capsules or placebo in a multicenter, randomized, double-blind, placebo-controlled study. Clinical response was compared with cathelicidin and protease activity in stratum corneum samples obtained by tape strip and in skin biopsy specimens obtained from a random subset of patients. RESULTS: Treatment with doxycycline significantly reduced inflammatory lesions and improved investigator global assessment scores compared with placebo. Cathelicidin expression and protein levels decreased over the course of 12 weeks in patients treated with doxycycline. Low levels of protease activity and cathelicidin expression at 12 weeks correlated with treatment success. Low protease activity at baseline was a predictor of clinical response in the doxycycline treatment group. LIMITATIONS: Healthy control subjects were not studied. CONCLUSIONS: Improved clinical outcome correlated with reduced cathelicidin and protease activity, supporting both the mechanism of doxycycline and the potential of these molecules as biomarkers for rosacea.

Dermatological Adverse Events Associated with Topical Brimonidine Gel 0.33% in Subjects with Erythema of Rosacea: A Retrospective Review of Clinical Studies.

BACKGROUND: The topical α2 adrenergic receptor agonist brimonidine gel 0.33% is an effective and safe pharmacological treatment for the facial erythema of rosacea. However, adverse events of worsened redness have occasionally been reported with its use. OBJECTIVE: A detailed analysis of adverse events is needed to accurately define worsening erythema and the adverse-events profile associated with brimonidine gel treatment. METHODS AND MEASUREMENTS: A retrospective review of related dermatological adverse events occurring in subjects enrolled in the two pivotal four-week Phase 3 studies and the 52-week long-term safety study for brimonidine gel was conducted. Measurements included total adverse-event incidences; number of subjects experiencing adverse events; study discontinuation due to adverse events, severity, onset, episodic duration period; and correlation of adverse events to subject disposition, and rosacea profile. RESULTS: Flushing and erythema were the most commonly reported adverse events, occurring in a total of 5.4 percent of subjects in the Phase 3 studies and in 15.4 percent in the long-term study. Most adverse events were mild or moderate in severity, transient, and intermittent. Adverse events occurred early in treatment, and duration was short-lived in the majority of cases. Adverse-event patterns were not remarkably altered with regard to subject disposition in the long-term study. CONCLUSION: Adverse events of worsening redness are not frequent, are transient in nature, and occur early in the course of treatment with brimonidine gel.

Potential role of microorganisms in the pathogenesis of rosacea.

Rosacea is a skin condition of abnormal inflammation and vascular dysfunction. The active contribution of a microbial agent in the development or progression of rosacea continues to be debated. Research supports the presence of commensal Demodex folliculorum mites at increased density in the skin and associates Helicobacter pylori infection of the gut with rosacea. Fewer studies implicate Staphylococcus epidermidis, Chlamydophila pneumoniae, and the Demodex-associated bacteria Bacillus oleronius. No research, however, provides a mechanism by which colonization by a microorganism translates to manifestation of the condition. Prevailing and emerging principles in the biology of the microbiome and the pathophysiology of rosacea may help to reconcile these lingering questions. Here the microorganisms implicated in rosacea are reviewed and the reaction of the microbiome to inflammation and to changes in microenvironments and macroenvironments are discussed to explain potential roles for microorganisms in rosacea pathophysiology.

Nicotine effects on general semantic priming in Parkinson's disease.

In young healthy nonsmokers, effects of nicotine on semantic processing have been observed under strategy-based priming procedures but not under more general priming procedures (Holmes, Chenery, & Copland, 2008; Holmes, Chenery, & Copland, 2010). Effects of nicotine under general priming procedures, however, may be mediated by baseline priming levels that are below optimum such as when compromised by disease. Nicotinic mechanisms may be involved in the cognitive sequalae of Parkinson's disease (PD). Evidence suggests that semantic processing may be compromised in PD but the potential benefit of nicotinic stimulation is unknown. This study investigated the effects of nicotine on semantic processing in nonsmokers with PD (n = 12) and nonsmoking matched controls (n = 17) using general priming procedures. Specifically, an automatic priming task (0.15 relatedness proportion, RP, and 200 ms stimulus onset asynchrony, SOA) and a controlled priming task (0.8 RP and 1000 ms SOA) were used. Prime-target category relation (category related, noncategory related) was also manipulated. Transdermal nicotine patches (7 mg/24 h) were administered in a double-blind, placebo-controlled, crossover design. For the automatic task, nicotine did not influence priming effects for PD. Unexpectedly, compromised automatic priming for controls was ameliorated. For the controlled task, nicotine influenced priming effects for PD but not controls. The patterns of priming and nicotine effects across the tasks suggest an age-related slowing of the rate of semantic activation for controls, which may be exacerbated in PD. Overall, the findings indicate that nicotine can improve compromised semantic processing in PD, and also influence semantic processing in healthy older individuals.

Acute nicotine enhances strategy-based semantic processing in Parkinson's disease.

Nicotinic mechanisms may play a role in the cognitive deficits of Parkinson's disease (PD). Recently, on a cognitively demanding strategy-based priming task, nicotine selectively affected controlled semantic processing in young adult non-smokers as reported by Holmes et al. (International Journal of Neuropsychopharmacology 11, 389-399, 2008). Such controlled semantic processing is compromised in PD. This study investigated the effects of acute transdermal nicotine on controlled semantic processing in non-smokers with PD (n = 10) and non-smoking matched controls (n = 16) using a strategy-based semantic priming paradigm. Transdermal nicotine patches (7 mg/24 h) were administered in a double-blind, placebo-controlled, crossover design. Participants were instructed to expect target words from specified semantic categories based on the primes, while unexpected targets were also presented. Priming conditions included those concurring with trained expectations (expected-related and expected-unrelated), those which did not (unexpected-related and unexpected-unrelated), and neutral-baseline conditions. Controls evidenced significant expectancy effects (i.e. reaction-time differences for expected vs. unexpected conditions) under both drug states. An expectancy effect was not evident for PD under placebo due to a lack of reaction-time slowing for unexpected conditions. However, under nicotine an expectancy effect was present for PD at a level comparable to controls. Overall the findings indicate that nicotine can improve impaired controlled semantic processing in PD possibly via enhanced expectancy or inhibitory mechanisms.

Nicotine does not enhance basic semantic priming.

RATIONALE: Utilising a cognitively demanding strategy-based priming paradigm, we recently observed that acute transdermal nicotine selectively influenced controlled semantic processing but not related-word links within semantic memory per se as reported by Holmes et al. (Int J Neuropsychopharmacol 11:389-399, 2008). OBJECTIVE: The current study employed a less cognitively demanding priming paradigm to investigate whether nicotine influences the activation/access of links within semantic memory, and if the selective nicotinic influence on controlled but not automatic semantic processing could also be observed with these more general priming procedures. METHODS: Transdermal nicotine patches (7 mg/24 h) were administered to healthy young adults in a double-blind, placebo-controlled, crossover design. The automatic priming task ( n = 18) had a low relatedness proportion (RP) and was presented at a short stimulus onset asynchrony (SOA), while the controlled priming task ( n = 18) had a high RP and long SOA. RESULTS: The patterns of priming effects indicated that automatic and controlled processing were operating for the respective tasks. However, a nicotinic influence on semantic processing was not evident for either task, nor was interplay of nicotine and relatedness observed. CONCLUSIONS: Together, the findings from the previous and current study suggest that an influence of nicotine on semantic processing may only emerge when effortful controlled processing is invoked. Furthermore, the findings suggest that nicotinic modulation of links within semantic memory may only be mediated by mnemonic processes.

Transdermal nicotine modulates strategy-based attentional semantic processing in non-smokers.

Nicotine has been shown to improve various aspects of cognitive processing such as attention and memory, however, its effects on lexical-semantic processing are relatively uncharted. Recent investigations of mnemonic processing in minimally deprived smokers suggest that nicotine might selectively modulate processes concerned with associative memory. This study investigated the effects of nicotine on lexical-semantic processing in non-smokers using a strategy-based lexical-decision priming paradigm. Transdermal nicotine patches (7 mg/24 h) were administered within a double-blind, placebo-controlled, cross-over design. Participants were trained to expect target words to come from a specified semantic category based on the prime word, although in some instances trained expectations were not met. Participants were presented with the stimuli at either a short or long stimulus onset asynchrony (SOA) to target automatic and attentional processing, respectively (n=12 and 17 for the short and long SOAs, respectively). Nicotine was found to selectively affect priming condition reaction times at the long SOA, indicating a nicotinic modulation of attentional mechanisms. Specifically, facilitation effects were dominant under placebo compared to a dominance of inhibition effects under nicotine. These results suggest that nicotine supports inhibitory attentional mechanisms in cognitively demanding semantic processing paradigms.