Cutis

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

The first botulinum neurotoxin (BoNT) approved by the US Food and Drug Administration (FDA) was onabotulinumtoxinA in 1989 for the treatment of strabismus and blepharospasm. It was not until 1992, however, that the aesthetic benefits of BoNT were first reported in the medical literature by Carruthers and Carruthers,¹ and a cosmetic indication was not approved by the FDA until 2002. Since that time, the popularity of BoNT products has grown rapidly with a nearly 6500% increase in popularity from 1997 to 2015 in addition to the introduction of a variety of new BoNT formulations to the market.² It is estimated by the American Society for Aesthetic Plastic Surgery that there were at least 4,000,000 BoNT injections performed in 2015 alone, making it the most popular nonsurgical aesthetic procedure available.² As the demand for minimally invasive cosmetic procedures continues to increase, we will continue to see the introduction of additional formulations of BoNT products as well as novel administration techniques and delivery devices. In this article, we provide an update on current and upcoming BoNT products and also review the literature on novel administration methods based on studies published from January 1, 2014, to December 31, 2015.

Current Products

To date, there are only 4 FDA-approved formulations of BoNT available for clinical use (eg, cervical dystonia, strabismus, blepharospasm, headache, urinary incontinence) in the United States: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.The FDA-approved dermatologic indications (eg, moderate to severe glabellar or canthal lines, severe axillary hyperhidrosis) for these products are provided in the Table. On a global scale, there are several other commonly utilized formulations of BoNT, including a Korean serotype resembling onabotulinumtoxinA and a Chinese botulinum toxin type A.³ Although there is some evidence to demonstrate comparable efficacy and safety of these latter products, the literature is relatively lacking in comparison to the FDA-approved products.^4,5

Upcoming Products

Currently, there are several new BoNT formulations being studied for clinical use. RT 002 (Revance Therapeutics, Inc) is a novel injectable formulation of onabotulinumtoxinA that consists of the purified neurotoxin in combination with patented TransMTS peptides that have been shown to provide high-binding avidity for the neurotoxin, and thus the product is designed to reduce diffusion to adjacent muscles and diminish unwanted effects. With a reduced level of neurotoxin dissemination, it is theorized that a higher administration of targeted doses can be injected, which may lead to a longer duration of desired effects.⁶ A clinical pilot study done to establish the safety and efficacy of RT 002 for treatment of moderate to severe glabellar lines evaluated 4 equally sized cohorts of 12 participants, each receiving single-dose administration of RT 002 ranging in potency equivalent to 25 U, 50 U, 75 U, and 100 U of abobotulinumtoxinA as determined by the gelatin phosphate method.⁶ It was concluded that RT 002 is both safe and efficacious with an extended duration of action, with a median duration of effect of 7 months observed in the highest dose group (dose equivalent to 100 U of abobotulinumtoxinA). Notably, 80% of all 48 participants maintained a minimum 1-point improvement in investigator-determined glabellar line severity scores at the 6-month time point and 60% achieved wrinkle scores of none or mild at 6 months posttreatment.⁶

DWP 450 (Daewoong Pharmaceutical Co, Ltd) is derived from the wild-type Clostridium botulinum and is reported to be of higher purity than standard onabotulinumtoxinA. An initial 16-week pilot study demonstrated that 20 U of DWP 450 is noninferior and of comparable efficacy and safety to 20 U of onabotulinumtoxinA in the treatment of glabellar lines.⁷

NTC (Botulax [Hugel, Inc]) is the name of the toxin derived from the C botulinum strain CBFC26, which has already been approved in many Asian, European, and Latin American countries for the treatment of blepharospasm. This formulation has demonstrated noninferiority to onabotulinumtoxinA at equivalent 20-U doses for the treatment of moderate to severe glabellar lines in a double-blind, randomized, multicenter, phase 3 trial of 272 participants with a 16-week follow-up.⁸

MT 10109L (Medytox Inc) is a unique product in that it is distributed as a liquid type A botulinum toxin rather than the standard freeze-dried formulation; thus, a major advantage of this product is its convenience, as it does not need reconstitution or dilution prior to administration. In a double-blind, randomized, active drug–controlled, phase 3 study of 168 participants, it was determined that MT 10109L (20 U) is comparable in efficacy to onabotulinumtoxinA (20 U) for the treatment of moderate to severe glabellar lines. No significant difference was seen between the 2 treatment groups when glabellar lines were assessed at rest at 4 and 16 weeks after treatment, but a significantly greater improvement in glabellar lines was seen at maximum frown in the MT 10109L group at the 16-week follow-up (P=.0064).⁹

Administration Techniques

With regard to safe and effective BoNT product administration techniques, a variety of studies have provided insight into optimal practice methods. A 2015 expert consensus statement formed by an American Society for Dermatologic Surgery task force reviewed data from 42 papers and unanimously determined that for all current type A BoNT products available in the United States, a vial of BoNT reconstituted appropriately for the purpose of facial injections can be reconstituted at least 4 weeks prior to administration without contamination risk or decrease in efficacy and that multiple patients can be treated with the same vial.Although the statement was not explicit on whether or not preserved or unpreserved saline is to be used, it is considered routine practice to use preservative-containing saline to reconstitute BoNT, as it has been shown to reduce patient discomfort and is not associated with adverse effects.¹⁰

Pain Minimization
With respect to minimizing the pain associated with BoNT injections, several studies have assessed administration techniques to minimize patient discomfort. A split-face, double-blind study of 20 participants demonstrated that the use of a 32-gauge needle has a significantly greater chance of reducing clinically significant levels of pain as compared to a 30-gauge needle when performing facial injections (P=.04). Overall, however, injections of the face and arms were on average only nominally and not significantly more painful with 30-gauge needles compared to 32-gauge needles.¹¹

Another technique that has been found to reduce patient discomfort is the application of cold packs prior to injection. A study of patients with chronic facial palsy observed a significant reduction in pain with the administration of a cold (3°C–5°C) gel pack for 1 minute compared to a room temperature (20°C) gel pack prior to the administration of onabotulinumtoxinA into the platysma (P<.001).¹² In the matter of injection with rimabotulinumtoxinB, which has been shown to be considerably more painful to receive than its more popularly administered counterpart onabotulinumtoxinA, a split-face pilot study examined the effect of increasing the pH of rimabotulinumtoxinB to 7.5 with sodium bicarbonate from the usual pH of 5.6.^13,14 Pain was reported to be considerably less in the higher pH group and no reduction of efficacy was seen over the 10-week follow-up period.¹⁴

Delivery Methods
Several preliminary studies also have examined novel delivery techniques to identify minimally painful yet effective methods for administering BoNT. It has been reported that standard BoNT formulations are not effective as topical agents in a comparison study in which onabotulinumtoxinA injection was compared to topically applied onabotulinumtoxinA.¹⁵ However, a follow-up prospective study by the same authors has demonstrated efficacy of topical onabotulinumtoxinA following pretreatment with a fractional ablative CO₂ laser for treatment of crow’s-feet. In this randomized, split-face, controlled trial (N=10), participants were first pretreated with topical lidocaine 30% before receiving a single pass of fractional ablative CO₂ laser with no overlap and a pulse energy of 100 mJ. Within 60 seconds of laser treatment, participants then received either 100 U of abobotulinumtoxinA diluted in 0.1 mL of saline or simple normal saline applied topically. A clinically significant improvement in periorbital wrinkles was seen both at 1-week and 1-month posttreatment in the laser and onabotulinumtoxinA–treated group compared to the laser and topical saline–treated group (P<.02).¹⁵

Another unique administration method studied, albeit with less successful results, involves the use of iontophoresis to deliver BoNT painlessly in a transdermal fashion with the assistance of an electrical current.¹⁶ This prospective, randomized, assessor-blinded, split-axilla, controlled trial of 11 participants compared the effectiveness of administering onabotulinumtoxinA via iontophoresis to traditional injection with onabotulinumtoxinA (250 U). Iontophoresis was accomplished with a single electrode pad soaked with 250 U of onabotulinumtoxinA applied directly to the axilla and a second electrode pad soaked in 0.9% saline applied to the hand to complete the circuit. An alternating electrical current was slowly increased for 30 minutes to a maximum current of 15 mA with a voltage of 12 V. Among the 11 participants recruited, the side treated with traditional injection showed a significantly greater percentage reduction in baseline sweating at the 1-week, 1-month, and 6-month posttreatment evaluations compared to iontophoresis (84%, 76%, and 50%, respectively vs 73%, 22%, and 32%, respectively)(P<.05). Despite being less efficacious than standard injection therapy, participants reported that iontophoresis delivery was significantly less painful (P<.05).¹⁶

A high-pressure oxygen delivery device, which utilizes a powerful jet of microdroplets containing water, the drug, air, and oxygen to deliver medication onto the skin surface, also has been studied as a means of delivery of BoNT in a minimally painful manner. In this study, the device was used to assess the efficacy of transdermal delivery of BoNT via jet nebulization in the treatment of primary palmar, plantar, and axillary hyperhidrosis.¹⁷ The 20 participants included in the study were randomized to receive either a combination of lidocaine and onabotulinumtoxinA (50 U) administered through the device or lidocaine delivered through the device followed by multiple transcutaneous injections of onabotulinumtoxinA (100 U). Both treatments significantly reduced sweating compared to baseline as measured by a visual analogue scale at 3-month follow-up (P<.001), but the combination delivery of lidocaine and onabotulinumtoxinA via the device resulted in significantly less procedure-related pain and sweating (P<.001) as well as significantly greater patient satisfaction (P<.001).¹⁷

Optimizing Aesthetic Outcomes
A frequent concern of patients receiving BoNT for cosmetic purposes is a desire to avoid a “frozen” or expressionless look. As such, many clinicians have attempted a variety of techniques to achieve more natural aesthetic results. One such method is known as the multipoint and multilevel injection technique, which consists of utilizing multiple injection sites at varying depths (intramuscular, subcutaneous, or intradermal) and doses (2–6 U) depending on the degree of contractility of the targeted muscle. In a preliminary study of 223 participants using this technique with a total dose of 125 U of abobotulinumtoxinA, good and natural results were reported with perseveration of facial emotion in all participants in addition to a mean overall satisfaction rate of 6.4 of 7 on the Facial Line Treatment Satisfaction Questionnaire with the maximum satisfaction rating possible reported in 66% of cases.¹⁸ It also has been postulated that injection depth of BoNT can affect brow elevation whereupon deeper injection depths can result in inactivation of the brow depressors and allow for increased elevation of the eyebrows. This technique has been applied in attempts to correct brow height asymmetry. However, a prospective, split-face study of 23 women suggested that this method is not effective.¹⁹ Participants received 64 U of onabotulinumtoxinA via 16 injection sites in the glabella, forehead, and lateral canthal area with either all deep or all shallow injections depending on the side treated and whether brow-lift was desired. Results at 4 weeks posttreatment showed no significant difference in brow height, and it was concluded that eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies.¹⁹ Conversely, a 5-year retrospective, nonrandomized study of 227 patients with 563 treatments utilizing a “microdroplet” technique reported success at selectively targeting the eyebrow depressors while leaving the brow elevators unaffected.²⁰ Here, a total dose of 33 U of onabotulinumtoxinA was administered via microdroplets of 10 to 20 μL, each with more than 60 to 100 injections into the brow, glabella, and crow’s-feet area. This method of injection resulted in a statistically significant improvement of forehead lines and brow ptosis and furrowing at follow-up between 10 and 45 days after treatment (P<.0001). Additionally, average brow height was significantly increased from 24.6 mm to 25 mm after treatment (P=.02).²⁰

Conclusion

The use of BoNT products for both on- and off-label cosmetic and medical indications has rapidly grown over the past 2 decades. As demonstrated in this review, a variety of promising new products and delivery techniques are being developed. Given the rise in popularity of BoNT products among both physicians and consumers, clinicians should be aware of the current data and ongoing research.

The first botulinum neurotoxin (BoNT) approved by the US Food and Drug Administration (FDA) was onabotulinumtoxinA in 1989 for the treatment of strabismus and blepharospasm. It was not until 1992, however, that the aesthetic benefits of BoNT were first reported in the medical literature by Carruthers and Carruthers,¹ and a cosmetic indication was not approved by the FDA until 2002. Since that time, the popularity of BoNT products has grown rapidly with a nearly 6500% increase in popularity from 1997 to 2015 in addition to the introduction of a variety of new BoNT formulations to the market.² It is estimated by the American Society for Aesthetic Plastic Surgery that there were at least 4,000,000 BoNT injections performed in 2015 alone, making it the most popular nonsurgical aesthetic procedure available.² As the demand for minimally invasive cosmetic procedures continues to increase, we will continue to see the introduction of additional formulations of BoNT products as well as novel administration techniques and delivery devices. In this article, we provide an update on current and upcoming BoNT products and also review the literature on novel administration methods based on studies published from January 1, 2014, to December 31, 2015.

Current Products

To date, there are only 4 FDA-approved formulations of BoNT available for clinical use (eg, cervical dystonia, strabismus, blepharospasm, headache, urinary incontinence) in the United States: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.The FDA-approved dermatologic indications (eg, moderate to severe glabellar or canthal lines, severe axillary hyperhidrosis) for these products are provided in the Table. On a global scale, there are several other commonly utilized formulations of BoNT, including a Korean serotype resembling onabotulinumtoxinA and a Chinese botulinum toxin type A.³ Although there is some evidence to demonstrate comparable efficacy and safety of these latter products, the literature is relatively lacking in comparison to the FDA-approved products.^4,5

Upcoming Products

Currently, there are several new BoNT formulations being studied for clinical use. RT 002 (Revance Therapeutics, Inc) is a novel injectable formulation of onabotulinumtoxinA that consists of the purified neurotoxin in combination with patented TransMTS peptides that have been shown to provide high-binding avidity for the neurotoxin, and thus the product is designed to reduce diffusion to adjacent muscles and diminish unwanted effects. With a reduced level of neurotoxin dissemination, it is theorized that a higher administration of targeted doses can be injected, which may lead to a longer duration of desired effects.⁶ A clinical pilot study done to establish the safety and efficacy of RT 002 for treatment of moderate to severe glabellar lines evaluated 4 equally sized cohorts of 12 participants, each receiving single-dose administration of RT 002 ranging in potency equivalent to 25 U, 50 U, 75 U, and 100 U of abobotulinumtoxinA as determined by the gelatin phosphate method.⁶ It was concluded that RT 002 is both safe and efficacious with an extended duration of action, with a median duration of effect of 7 months observed in the highest dose group (dose equivalent to 100 U of abobotulinumtoxinA). Notably, 80% of all 48 participants maintained a minimum 1-point improvement in investigator-determined glabellar line severity scores at the 6-month time point and 60% achieved wrinkle scores of none or mild at 6 months posttreatment.⁶

DWP 450 (Daewoong Pharmaceutical Co, Ltd) is derived from the wild-type Clostridium botulinum and is reported to be of higher purity than standard onabotulinumtoxinA. An initial 16-week pilot study demonstrated that 20 U of DWP 450 is noninferior and of comparable efficacy and safety to 20 U of onabotulinumtoxinA in the treatment of glabellar lines.⁷

NTC (Botulax [Hugel, Inc]) is the name of the toxin derived from the C botulinum strain CBFC26, which has already been approved in many Asian, European, and Latin American countries for the treatment of blepharospasm. This formulation has demonstrated noninferiority to onabotulinumtoxinA at equivalent 20-U doses for the treatment of moderate to severe glabellar lines in a double-blind, randomized, multicenter, phase 3 trial of 272 participants with a 16-week follow-up.⁸

MT 10109L (Medytox Inc) is a unique product in that it is distributed as a liquid type A botulinum toxin rather than the standard freeze-dried formulation; thus, a major advantage of this product is its convenience, as it does not need reconstitution or dilution prior to administration. In a double-blind, randomized, active drug–controlled, phase 3 study of 168 participants, it was determined that MT 10109L (20 U) is comparable in efficacy to onabotulinumtoxinA (20 U) for the treatment of moderate to severe glabellar lines. No significant difference was seen between the 2 treatment groups when glabellar lines were assessed at rest at 4 and 16 weeks after treatment, but a significantly greater improvement in glabellar lines was seen at maximum frown in the MT 10109L group at the 16-week follow-up (P=.0064).⁹

Administration Techniques

With regard to safe and effective BoNT product administration techniques, a variety of studies have provided insight into optimal practice methods. A 2015 expert consensus statement formed by an American Society for Dermatologic Surgery task force reviewed data from 42 papers and unanimously determined that for all current type A BoNT products available in the United States, a vial of BoNT reconstituted appropriately for the purpose of facial injections can be reconstituted at least 4 weeks prior to administration without contamination risk or decrease in efficacy and that multiple patients can be treated with the same vial.Although the statement was not explicit on whether or not preserved or unpreserved saline is to be used, it is considered routine practice to use preservative-containing saline to reconstitute BoNT, as it has been shown to reduce patient discomfort and is not associated with adverse effects.¹⁰

Pain Minimization
With respect to minimizing the pain associated with BoNT injections, several studies have assessed administration techniques to minimize patient discomfort. A split-face, double-blind study of 20 participants demonstrated that the use of a 32-gauge needle has a significantly greater chance of reducing clinically significant levels of pain as compared to a 30-gauge needle when performing facial injections (P=.04). Overall, however, injections of the face and arms were on average only nominally and not significantly more painful with 30-gauge needles compared to 32-gauge needles.¹¹

Another technique that has been found to reduce patient discomfort is the application of cold packs prior to injection. A study of patients with chronic facial palsy observed a significant reduction in pain with the administration of a cold (3°C–5°C) gel pack for 1 minute compared to a room temperature (20°C) gel pack prior to the administration of onabotulinumtoxinA into the platysma (P<.001).¹² In the matter of injection with rimabotulinumtoxinB, which has been shown to be considerably more painful to receive than its more popularly administered counterpart onabotulinumtoxinA, a split-face pilot study examined the effect of increasing the pH of rimabotulinumtoxinB to 7.5 with sodium bicarbonate from the usual pH of 5.6.^13,14 Pain was reported to be considerably less in the higher pH group and no reduction of efficacy was seen over the 10-week follow-up period.¹⁴

Delivery Methods
Several preliminary studies also have examined novel delivery techniques to identify minimally painful yet effective methods for administering BoNT. It has been reported that standard BoNT formulations are not effective as topical agents in a comparison study in which onabotulinumtoxinA injection was compared to topically applied onabotulinumtoxinA.¹⁵ However, a follow-up prospective study by the same authors has demonstrated efficacy of topical onabotulinumtoxinA following pretreatment with a fractional ablative CO₂ laser for treatment of crow’s-feet. In this randomized, split-face, controlled trial (N=10), participants were first pretreated with topical lidocaine 30% before receiving a single pass of fractional ablative CO₂ laser with no overlap and a pulse energy of 100 mJ. Within 60 seconds of laser treatment, participants then received either 100 U of abobotulinumtoxinA diluted in 0.1 mL of saline or simple normal saline applied topically. A clinically significant improvement in periorbital wrinkles was seen both at 1-week and 1-month posttreatment in the laser and onabotulinumtoxinA–treated group compared to the laser and topical saline–treated group (P<.02).¹⁵

Another unique administration method studied, albeit with less successful results, involves the use of iontophoresis to deliver BoNT painlessly in a transdermal fashion with the assistance of an electrical current.¹⁶ This prospective, randomized, assessor-blinded, split-axilla, controlled trial of 11 participants compared the effectiveness of administering onabotulinumtoxinA via iontophoresis to traditional injection with onabotulinumtoxinA (250 U). Iontophoresis was accomplished with a single electrode pad soaked with 250 U of onabotulinumtoxinA applied directly to the axilla and a second electrode pad soaked in 0.9% saline applied to the hand to complete the circuit. An alternating electrical current was slowly increased for 30 minutes to a maximum current of 15 mA with a voltage of 12 V. Among the 11 participants recruited, the side treated with traditional injection showed a significantly greater percentage reduction in baseline sweating at the 1-week, 1-month, and 6-month posttreatment evaluations compared to iontophoresis (84%, 76%, and 50%, respectively vs 73%, 22%, and 32%, respectively)(P<.05). Despite being less efficacious than standard injection therapy, participants reported that iontophoresis delivery was significantly less painful (P<.05).¹⁶

A high-pressure oxygen delivery device, which utilizes a powerful jet of microdroplets containing water, the drug, air, and oxygen to deliver medication onto the skin surface, also has been studied as a means of delivery of BoNT in a minimally painful manner. In this study, the device was used to assess the efficacy of transdermal delivery of BoNT via jet nebulization in the treatment of primary palmar, plantar, and axillary hyperhidrosis.¹⁷ The 20 participants included in the study were randomized to receive either a combination of lidocaine and onabotulinumtoxinA (50 U) administered through the device or lidocaine delivered through the device followed by multiple transcutaneous injections of onabotulinumtoxinA (100 U). Both treatments significantly reduced sweating compared to baseline as measured by a visual analogue scale at 3-month follow-up (P<.001), but the combination delivery of lidocaine and onabotulinumtoxinA via the device resulted in significantly less procedure-related pain and sweating (P<.001) as well as significantly greater patient satisfaction (P<.001).¹⁷

Optimizing Aesthetic Outcomes
A frequent concern of patients receiving BoNT for cosmetic purposes is a desire to avoid a “frozen” or expressionless look. As such, many clinicians have attempted a variety of techniques to achieve more natural aesthetic results. One such method is known as the multipoint and multilevel injection technique, which consists of utilizing multiple injection sites at varying depths (intramuscular, subcutaneous, or intradermal) and doses (2–6 U) depending on the degree of contractility of the targeted muscle. In a preliminary study of 223 participants using this technique with a total dose of 125 U of abobotulinumtoxinA, good and natural results were reported with perseveration of facial emotion in all participants in addition to a mean overall satisfaction rate of 6.4 of 7 on the Facial Line Treatment Satisfaction Questionnaire with the maximum satisfaction rating possible reported in 66% of cases.¹⁸ It also has been postulated that injection depth of BoNT can affect brow elevation whereupon deeper injection depths can result in inactivation of the brow depressors and allow for increased elevation of the eyebrows. This technique has been applied in attempts to correct brow height asymmetry. However, a prospective, split-face study of 23 women suggested that this method is not effective.¹⁹ Participants received 64 U of onabotulinumtoxinA via 16 injection sites in the glabella, forehead, and lateral canthal area with either all deep or all shallow injections depending on the side treated and whether brow-lift was desired. Results at 4 weeks posttreatment showed no significant difference in brow height, and it was concluded that eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies.¹⁹ Conversely, a 5-year retrospective, nonrandomized study of 227 patients with 563 treatments utilizing a “microdroplet” technique reported success at selectively targeting the eyebrow depressors while leaving the brow elevators unaffected.²⁰ Here, a total dose of 33 U of onabotulinumtoxinA was administered via microdroplets of 10 to 20 μL, each with more than 60 to 100 injections into the brow, glabella, and crow’s-feet area. This method of injection resulted in a statistically significant improvement of forehead lines and brow ptosis and furrowing at follow-up between 10 and 45 days after treatment (P<.0001). Additionally, average brow height was significantly increased from 24.6 mm to 25 mm after treatment (P=.02).²⁰

Conclusion

The use of BoNT products for both on- and off-label cosmetic and medical indications has rapidly grown over the past 2 decades. As demonstrated in this review, a variety of promising new products and delivery techniques are being developed. Given the rise in popularity of BoNT products among both physicians and consumers, clinicians should be aware of the current data and ongoing research.

The first botulinum neurotoxin (BoNT) approved by the US Food and Drug Administration (FDA) was onabotulinumtoxinA in 1989 for the treatment of strabismus and blepharospasm. It was not until 1992, however, that the aesthetic benefits of BoNT were first reported in the medical literature by Carruthers and Carruthers,¹ and a cosmetic indication was not approved by the FDA until 2002. Since that time, the popularity of BoNT products has grown rapidly with a nearly 6500% increase in popularity from 1997 to 2015 in addition to the introduction of a variety of new BoNT formulations to the market.² It is estimated by the American Society for Aesthetic Plastic Surgery that there were at least 4,000,000 BoNT injections performed in 2015 alone, making it the most popular nonsurgical aesthetic procedure available.² As the demand for minimally invasive cosmetic procedures continues to increase, we will continue to see the introduction of additional formulations of BoNT products as well as novel administration techniques and delivery devices. In this article, we provide an update on current and upcoming BoNT products and also review the literature on novel administration methods based on studies published from January 1, 2014, to December 31, 2015.

Current Products

To date, there are only 4 FDA-approved formulations of BoNT available for clinical use (eg, cervical dystonia, strabismus, blepharospasm, headache, urinary incontinence) in the United States: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB.The FDA-approved dermatologic indications (eg, moderate to severe glabellar or canthal lines, severe axillary hyperhidrosis) for these products are provided in the Table. On a global scale, there are several other commonly utilized formulations of BoNT, including a Korean serotype resembling onabotulinumtoxinA and a Chinese botulinum toxin type A.³ Although there is some evidence to demonstrate comparable efficacy and safety of these latter products, the literature is relatively lacking in comparison to the FDA-approved products.^4,5

Upcoming Products

Currently, there are several new BoNT formulations being studied for clinical use. RT 002 (Revance Therapeutics, Inc) is a novel injectable formulation of onabotulinumtoxinA that consists of the purified neurotoxin in combination with patented TransMTS peptides that have been shown to provide high-binding avidity for the neurotoxin, and thus the product is designed to reduce diffusion to adjacent muscles and diminish unwanted effects. With a reduced level of neurotoxin dissemination, it is theorized that a higher administration of targeted doses can be injected, which may lead to a longer duration of desired effects.⁶ A clinical pilot study done to establish the safety and efficacy of RT 002 for treatment of moderate to severe glabellar lines evaluated 4 equally sized cohorts of 12 participants, each receiving single-dose administration of RT 002 ranging in potency equivalent to 25 U, 50 U, 75 U, and 100 U of abobotulinumtoxinA as determined by the gelatin phosphate method.⁶ It was concluded that RT 002 is both safe and efficacious with an extended duration of action, with a median duration of effect of 7 months observed in the highest dose group (dose equivalent to 100 U of abobotulinumtoxinA). Notably, 80% of all 48 participants maintained a minimum 1-point improvement in investigator-determined glabellar line severity scores at the 6-month time point and 60% achieved wrinkle scores of none or mild at 6 months posttreatment.⁶

DWP 450 (Daewoong Pharmaceutical Co, Ltd) is derived from the wild-type Clostridium botulinum and is reported to be of higher purity than standard onabotulinumtoxinA. An initial 16-week pilot study demonstrated that 20 U of DWP 450 is noninferior and of comparable efficacy and safety to 20 U of onabotulinumtoxinA in the treatment of glabellar lines.⁷

NTC (Botulax [Hugel, Inc]) is the name of the toxin derived from the C botulinum strain CBFC26, which has already been approved in many Asian, European, and Latin American countries for the treatment of blepharospasm. This formulation has demonstrated noninferiority to onabotulinumtoxinA at equivalent 20-U doses for the treatment of moderate to severe glabellar lines in a double-blind, randomized, multicenter, phase 3 trial of 272 participants with a 16-week follow-up.⁸

MT 10109L (Medytox Inc) is a unique product in that it is distributed as a liquid type A botulinum toxin rather than the standard freeze-dried formulation; thus, a major advantage of this product is its convenience, as it does not need reconstitution or dilution prior to administration. In a double-blind, randomized, active drug–controlled, phase 3 study of 168 participants, it was determined that MT 10109L (20 U) is comparable in efficacy to onabotulinumtoxinA (20 U) for the treatment of moderate to severe glabellar lines. No significant difference was seen between the 2 treatment groups when glabellar lines were assessed at rest at 4 and 16 weeks after treatment, but a significantly greater improvement in glabellar lines was seen at maximum frown in the MT 10109L group at the 16-week follow-up (P=.0064).⁹

Administration Techniques

With regard to safe and effective BoNT product administration techniques, a variety of studies have provided insight into optimal practice methods. A 2015 expert consensus statement formed by an American Society for Dermatologic Surgery task force reviewed data from 42 papers and unanimously determined that for all current type A BoNT products available in the United States, a vial of BoNT reconstituted appropriately for the purpose of facial injections can be reconstituted at least 4 weeks prior to administration without contamination risk or decrease in efficacy and that multiple patients can be treated with the same vial.Although the statement was not explicit on whether or not preserved or unpreserved saline is to be used, it is considered routine practice to use preservative-containing saline to reconstitute BoNT, as it has been shown to reduce patient discomfort and is not associated with adverse effects.¹⁰

Pain Minimization
With respect to minimizing the pain associated with BoNT injections, several studies have assessed administration techniques to minimize patient discomfort. A split-face, double-blind study of 20 participants demonstrated that the use of a 32-gauge needle has a significantly greater chance of reducing clinically significant levels of pain as compared to a 30-gauge needle when performing facial injections (P=.04). Overall, however, injections of the face and arms were on average only nominally and not significantly more painful with 30-gauge needles compared to 32-gauge needles.¹¹

Another technique that has been found to reduce patient discomfort is the application of cold packs prior to injection. A study of patients with chronic facial palsy observed a significant reduction in pain with the administration of a cold (3°C–5°C) gel pack for 1 minute compared to a room temperature (20°C) gel pack prior to the administration of onabotulinumtoxinA into the platysma (P<.001).¹² In the matter of injection with rimabotulinumtoxinB, which has been shown to be considerably more painful to receive than its more popularly administered counterpart onabotulinumtoxinA, a split-face pilot study examined the effect of increasing the pH of rimabotulinumtoxinB to 7.5 with sodium bicarbonate from the usual pH of 5.6.^13,14 Pain was reported to be considerably less in the higher pH group and no reduction of efficacy was seen over the 10-week follow-up period.¹⁴

Delivery Methods
Several preliminary studies also have examined novel delivery techniques to identify minimally painful yet effective methods for administering BoNT. It has been reported that standard BoNT formulations are not effective as topical agents in a comparison study in which onabotulinumtoxinA injection was compared to topically applied onabotulinumtoxinA.¹⁵ However, a follow-up prospective study by the same authors has demonstrated efficacy of topical onabotulinumtoxinA following pretreatment with a fractional ablative CO₂ laser for treatment of crow’s-feet. In this randomized, split-face, controlled trial (N=10), participants were first pretreated with topical lidocaine 30% before receiving a single pass of fractional ablative CO₂ laser with no overlap and a pulse energy of 100 mJ. Within 60 seconds of laser treatment, participants then received either 100 U of abobotulinumtoxinA diluted in 0.1 mL of saline or simple normal saline applied topically. A clinically significant improvement in periorbital wrinkles was seen both at 1-week and 1-month posttreatment in the laser and onabotulinumtoxinA–treated group compared to the laser and topical saline–treated group (P<.02).¹⁵

Another unique administration method studied, albeit with less successful results, involves the use of iontophoresis to deliver BoNT painlessly in a transdermal fashion with the assistance of an electrical current.¹⁶ This prospective, randomized, assessor-blinded, split-axilla, controlled trial of 11 participants compared the effectiveness of administering onabotulinumtoxinA via iontophoresis to traditional injection with onabotulinumtoxinA (250 U). Iontophoresis was accomplished with a single electrode pad soaked with 250 U of onabotulinumtoxinA applied directly to the axilla and a second electrode pad soaked in 0.9% saline applied to the hand to complete the circuit. An alternating electrical current was slowly increased for 30 minutes to a maximum current of 15 mA with a voltage of 12 V. Among the 11 participants recruited, the side treated with traditional injection showed a significantly greater percentage reduction in baseline sweating at the 1-week, 1-month, and 6-month posttreatment evaluations compared to iontophoresis (84%, 76%, and 50%, respectively vs 73%, 22%, and 32%, respectively)(P<.05). Despite being less efficacious than standard injection therapy, participants reported that iontophoresis delivery was significantly less painful (P<.05).¹⁶

A high-pressure oxygen delivery device, which utilizes a powerful jet of microdroplets containing water, the drug, air, and oxygen to deliver medication onto the skin surface, also has been studied as a means of delivery of BoNT in a minimally painful manner. In this study, the device was used to assess the efficacy of transdermal delivery of BoNT via jet nebulization in the treatment of primary palmar, plantar, and axillary hyperhidrosis.¹⁷ The 20 participants included in the study were randomized to receive either a combination of lidocaine and onabotulinumtoxinA (50 U) administered through the device or lidocaine delivered through the device followed by multiple transcutaneous injections of onabotulinumtoxinA (100 U). Both treatments significantly reduced sweating compared to baseline as measured by a visual analogue scale at 3-month follow-up (P<.001), but the combination delivery of lidocaine and onabotulinumtoxinA via the device resulted in significantly less procedure-related pain and sweating (P<.001) as well as significantly greater patient satisfaction (P<.001).¹⁷

Optimizing Aesthetic Outcomes
A frequent concern of patients receiving BoNT for cosmetic purposes is a desire to avoid a “frozen” or expressionless look. As such, many clinicians have attempted a variety of techniques to achieve more natural aesthetic results. One such method is known as the multipoint and multilevel injection technique, which consists of utilizing multiple injection sites at varying depths (intramuscular, subcutaneous, or intradermal) and doses (2–6 U) depending on the degree of contractility of the targeted muscle. In a preliminary study of 223 participants using this technique with a total dose of 125 U of abobotulinumtoxinA, good and natural results were reported with perseveration of facial emotion in all participants in addition to a mean overall satisfaction rate of 6.4 of 7 on the Facial Line Treatment Satisfaction Questionnaire with the maximum satisfaction rating possible reported in 66% of cases.¹⁸ It also has been postulated that injection depth of BoNT can affect brow elevation whereupon deeper injection depths can result in inactivation of the brow depressors and allow for increased elevation of the eyebrows. This technique has been applied in attempts to correct brow height asymmetry. However, a prospective, split-face study of 23 women suggested that this method is not effective.¹⁹ Participants received 64 U of onabotulinumtoxinA via 16 injection sites in the glabella, forehead, and lateral canthal area with either all deep or all shallow injections depending on the side treated and whether brow-lift was desired. Results at 4 weeks posttreatment showed no significant difference in brow height, and it was concluded that eyebrow depressor muscles cannot be accurately targeted with deep injection into the muscle belly for correction of eyebrow height discrepancies.¹⁹ Conversely, a 5-year retrospective, nonrandomized study of 227 patients with 563 treatments utilizing a “microdroplet” technique reported success at selectively targeting the eyebrow depressors while leaving the brow elevators unaffected.²⁰ Here, a total dose of 33 U of onabotulinumtoxinA was administered via microdroplets of 10 to 20 μL, each with more than 60 to 100 injections into the brow, glabella, and crow’s-feet area. This method of injection resulted in a statistically significant improvement of forehead lines and brow ptosis and furrowing at follow-up between 10 and 45 days after treatment (P<.0001). Additionally, average brow height was significantly increased from 24.6 mm to 25 mm after treatment (P=.02).²⁰

Conclusion

The use of BoNT products for both on- and off-label cosmetic and medical indications has rapidly grown over the past 2 decades. As demonstrated in this review, a variety of promising new products and delivery techniques are being developed. Given the rise in popularity of BoNT products among both physicians and consumers, clinicians should be aware of the current data and ongoing research.

What does your patient need to know at the first visit?

A thorough patient history is imperative for proper diagnosis of wounds, thus detailed information on the onset, duration, temporality, modifying factors, symptoms, and attempted treatments should be provided. Associated comorbidities that may influence wound healing, such as diabetes mellitus or connective tissue diseases, must be considered when formulating a treatment regimen. Patients should disclose current medications, as certain medications (eg, vascular endothelial growth factor inhibitors) may decrease vascularization or soft tissue matrix regeneration, further complicating the wound healing process. All patients should have a basic understanding of the cause of their wound to have realistic expectations of the prognosis.

What are your go-to treatments?

Treatment ultimately depends on the cause of the wound. In general, proper healing requires a wound bed that is well vascularized and moistened without devitalized tissue or bacterial colonization. Wound dressings should be utilized to reduce dead space, control exudate, prevent bacterial overgrowth, and ensure proper fluid balance. Maintaining good overall health promotes proper healing. Thus, any relevant underlying medical conditions should be properly managed (eg, glycemic control for diabetic patients, management of fluid overload in patients with congestive heart failure).

When treating wounds, it is important to consider several factors. Although all wounds are colonized with microbes, not all wounds are infected. Thus, antibiotic therapy is not necessary for all wounds and should only be used to treat wounds that are clinically infected. Rule out pyoderma gangrenosum prior to wound debridement, as the associated pathergic response will notably worsen the ulcer. Wound dressings have an impact on the speed of wound healing, strength of repaired skin, and cosmetic appearance. Because no single dressing is perfect for all wounds, physicians should use their discretion when determining the type of wound dressing necessary.

Certain wounds require specific treatments. Off-loading and compression dressings/garments are the main components involved in the treatment of pressure ulcers. Protective wound care in conjunction with glycemic control is imperative for diabetic ulcers. Often, the causes of wounds are multifactorial and may complicate treatment. For instance, it is important to confirm that there is no associated arterial insufficiency before treating venous insufficiency with compression. Furthermore, patients with diabetic ulcers in association with venous insufficiency often have minimal response to hyperbaric oxygen treatment.

Several agents have been implicated to improve wound healing. Timolol, a topically applied beta-blocker, may promote keratinocyte migration and epithelialization of chronic refractory wounds. Recombinant human growth factors, most notably becaplermin (a platelet-derived growth factor), have been developed to promote cellular proliferation and angiogenesis, thereby improving healing of chronic wounds. Wounds that have devitalized tissue or contamination require debridement prior to further management.

How do you keep patients compliant with treatment?

Because recurrence is a common complication of chronic wounds, it is imperative that patients understand the importance of preventive care and follow-up appointments. Additionally, an open patient-physician dialogue may help address potential lifestyle limitations that may complicate wound care treatment. For instance, home care arrangement may be necessary to assist certain patient populations with wound care management.

What do you do if they refuse treatment?

Ultimately, it is hard to enforce treatment if the patient refuses. However, in my experience practicing dermatology, I have found it to be uncommon for patients to refuse treatment without a particular reason. If a patient refuses treatment, try to understand why and then try to alleviate any concerns by clarifying misconceptions and/or recommending alternative therapies.

What resources do you recommend to patients for more information?

Consult the American Academy of Dermatology website (https://www.aad.org/File%20Library/Unassigned/Wound-Dressings_Online-BF-DIR-Summer-2016--FINAL.pdf) for more information.  
Additional resources include:

• Diabetic Wound Care (Source: American Podiatric Medical Association)(http://www.apma.org/Learn/FootHealth.cfm?ItemNumber=981)
• Pyoderma Gangrenosum (Source: Wound Care Centers)(http://www.woundcarecenters.org/article/wound-types/pyoderma-gangrenosum)
• Take the Pressure Off: A Patient Guide for Preventing and Treating Pressure Ulcers (Source: Association for the Advancement of Wound Care)(http://aawconline.org/wp-content/uploads/2012/04/Take-the-Pressure-Off.pdf)
• Wound Healing Society (http://woundheal.org/home.aspx)

What does your patient need to know at the first visit?

A thorough patient history is imperative for proper diagnosis of wounds, thus detailed information on the onset, duration, temporality, modifying factors, symptoms, and attempted treatments should be provided. Associated comorbidities that may influence wound healing, such as diabetes mellitus or connective tissue diseases, must be considered when formulating a treatment regimen. Patients should disclose current medications, as certain medications (eg, vascular endothelial growth factor inhibitors) may decrease vascularization or soft tissue matrix regeneration, further complicating the wound healing process. All patients should have a basic understanding of the cause of their wound to have realistic expectations of the prognosis.

What are your go-to treatments?

Treatment ultimately depends on the cause of the wound. In general, proper healing requires a wound bed that is well vascularized and moistened without devitalized tissue or bacterial colonization. Wound dressings should be utilized to reduce dead space, control exudate, prevent bacterial overgrowth, and ensure proper fluid balance. Maintaining good overall health promotes proper healing. Thus, any relevant underlying medical conditions should be properly managed (eg, glycemic control for diabetic patients, management of fluid overload in patients with congestive heart failure).

When treating wounds, it is important to consider several factors. Although all wounds are colonized with microbes, not all wounds are infected. Thus, antibiotic therapy is not necessary for all wounds and should only be used to treat wounds that are clinically infected. Rule out pyoderma gangrenosum prior to wound debridement, as the associated pathergic response will notably worsen the ulcer. Wound dressings have an impact on the speed of wound healing, strength of repaired skin, and cosmetic appearance. Because no single dressing is perfect for all wounds, physicians should use their discretion when determining the type of wound dressing necessary.

Certain wounds require specific treatments. Off-loading and compression dressings/garments are the main components involved in the treatment of pressure ulcers. Protective wound care in conjunction with glycemic control is imperative for diabetic ulcers. Often, the causes of wounds are multifactorial and may complicate treatment. For instance, it is important to confirm that there is no associated arterial insufficiency before treating venous insufficiency with compression. Furthermore, patients with diabetic ulcers in association with venous insufficiency often have minimal response to hyperbaric oxygen treatment.

Several agents have been implicated to improve wound healing. Timolol, a topically applied beta-blocker, may promote keratinocyte migration and epithelialization of chronic refractory wounds. Recombinant human growth factors, most notably becaplermin (a platelet-derived growth factor), have been developed to promote cellular proliferation and angiogenesis, thereby improving healing of chronic wounds. Wounds that have devitalized tissue or contamination require debridement prior to further management.

How do you keep patients compliant with treatment?

Because recurrence is a common complication of chronic wounds, it is imperative that patients understand the importance of preventive care and follow-up appointments. Additionally, an open patient-physician dialogue may help address potential lifestyle limitations that may complicate wound care treatment. For instance, home care arrangement may be necessary to assist certain patient populations with wound care management.

What do you do if they refuse treatment?

Ultimately, it is hard to enforce treatment if the patient refuses. However, in my experience practicing dermatology, I have found it to be uncommon for patients to refuse treatment without a particular reason. If a patient refuses treatment, try to understand why and then try to alleviate any concerns by clarifying misconceptions and/or recommending alternative therapies.

What resources do you recommend to patients for more information?

Consult the American Academy of Dermatology website (https://www.aad.org/File%20Library/Unassigned/Wound-Dressings_Online-BF-DIR-Summer-2016--FINAL.pdf) for more information.  
Additional resources include:

• Diabetic Wound Care (Source: American Podiatric Medical Association)(http://www.apma.org/Learn/FootHealth.cfm?ItemNumber=981)
• Pyoderma Gangrenosum (Source: Wound Care Centers)(http://www.woundcarecenters.org/article/wound-types/pyoderma-gangrenosum)
• Take the Pressure Off: A Patient Guide for Preventing and Treating Pressure Ulcers (Source: Association for the Advancement of Wound Care)(http://aawconline.org/wp-content/uploads/2012/04/Take-the-Pressure-Off.pdf)
• Wound Healing Society (http://woundheal.org/home.aspx)

What does your patient need to know at the first visit?

A thorough patient history is imperative for proper diagnosis of wounds, thus detailed information on the onset, duration, temporality, modifying factors, symptoms, and attempted treatments should be provided. Associated comorbidities that may influence wound healing, such as diabetes mellitus or connective tissue diseases, must be considered when formulating a treatment regimen. Patients should disclose current medications, as certain medications (eg, vascular endothelial growth factor inhibitors) may decrease vascularization or soft tissue matrix regeneration, further complicating the wound healing process. All patients should have a basic understanding of the cause of their wound to have realistic expectations of the prognosis.

What are your go-to treatments?

Treatment ultimately depends on the cause of the wound. In general, proper healing requires a wound bed that is well vascularized and moistened without devitalized tissue or bacterial colonization. Wound dressings should be utilized to reduce dead space, control exudate, prevent bacterial overgrowth, and ensure proper fluid balance. Maintaining good overall health promotes proper healing. Thus, any relevant underlying medical conditions should be properly managed (eg, glycemic control for diabetic patients, management of fluid overload in patients with congestive heart failure).

When treating wounds, it is important to consider several factors. Although all wounds are colonized with microbes, not all wounds are infected. Thus, antibiotic therapy is not necessary for all wounds and should only be used to treat wounds that are clinically infected. Rule out pyoderma gangrenosum prior to wound debridement, as the associated pathergic response will notably worsen the ulcer. Wound dressings have an impact on the speed of wound healing, strength of repaired skin, and cosmetic appearance. Because no single dressing is perfect for all wounds, physicians should use their discretion when determining the type of wound dressing necessary.

Certain wounds require specific treatments. Off-loading and compression dressings/garments are the main components involved in the treatment of pressure ulcers. Protective wound care in conjunction with glycemic control is imperative for diabetic ulcers. Often, the causes of wounds are multifactorial and may complicate treatment. For instance, it is important to confirm that there is no associated arterial insufficiency before treating venous insufficiency with compression. Furthermore, patients with diabetic ulcers in association with venous insufficiency often have minimal response to hyperbaric oxygen treatment.

Several agents have been implicated to improve wound healing. Timolol, a topically applied beta-blocker, may promote keratinocyte migration and epithelialization of chronic refractory wounds. Recombinant human growth factors, most notably becaplermin (a platelet-derived growth factor), have been developed to promote cellular proliferation and angiogenesis, thereby improving healing of chronic wounds. Wounds that have devitalized tissue or contamination require debridement prior to further management.

How do you keep patients compliant with treatment?

Because recurrence is a common complication of chronic wounds, it is imperative that patients understand the importance of preventive care and follow-up appointments. Additionally, an open patient-physician dialogue may help address potential lifestyle limitations that may complicate wound care treatment. For instance, home care arrangement may be necessary to assist certain patient populations with wound care management.

What do you do if they refuse treatment?

Ultimately, it is hard to enforce treatment if the patient refuses. However, in my experience practicing dermatology, I have found it to be uncommon for patients to refuse treatment without a particular reason. If a patient refuses treatment, try to understand why and then try to alleviate any concerns by clarifying misconceptions and/or recommending alternative therapies.

What resources do you recommend to patients for more information?

Consult the American Academy of Dermatology website (https://www.aad.org/File%20Library/Unassigned/Wound-Dressings_Online-BF-DIR-Summer-2016--FINAL.pdf) for more information.  
Additional resources include:

• Diabetic Wound Care (Source: American Podiatric Medical Association)(http://www.apma.org/Learn/FootHealth.cfm?ItemNumber=981)
• Pyoderma Gangrenosum (Source: Wound Care Centers)(http://www.woundcarecenters.org/article/wound-types/pyoderma-gangrenosum)
• Take the Pressure Off: A Patient Guide for Preventing and Treating Pressure Ulcers (Source: Association for the Advancement of Wound Care)(http://aawconline.org/wp-content/uploads/2012/04/Take-the-Pressure-Off.pdf)
• Wound Healing Society (http://woundheal.org/home.aspx)

Spectators at baseball games may be exposed to excess solar UV radiation (UVR), which has been linked to the development of both melanoma and nonmelanoma skin cancers.^1,2 Although baseball hats traditionally are worn to demonstrate team support, they also may provide some sun protection for the head and face where skin cancers are commonly found.

The importance of protecting the skin from solar UVR has led to sun-protection programs and community education as well as efforts to evaluate the impact of these programs. Major League Baseball (MLB) has partnered with the American Academy of Dermatology since 1999 to promote the importance of sun protection and raise skin cancer awareness through its Play Sun Smart program.³ A study conducted 10 years ago (N=2030) evaluated hat use in spectators at MLB games and noted that less than half of all spectators in seating sections exposed to direct sunlight wore hats.⁴ The purpose of the current study was to evaluate how public education about sun protection has impacted the use of hats by spectators at MLB games in 2015 compared to the prior study in 2006.

Methods

Data were collected during a 3-game series (2 day games, 1 night game) in August 2015 in New York, New York. During one of the day games, 18,000 fans received a free wide-brimmed hat. High-resolution digital photographs of seating sections were obtained using a camera with a 300-mm lens. Using the same methodology as the prior study,⁴ sunny and shaded seating sections were photographed during all 3 games (Figure). Photographs of each section were analyzed by an independent reviewer using a high-resolution computer screen. Spectators wearing head coverings—baseball hats, visors, or hats with circumferential brims—were defined as using hats. The number of spectators wearing hats versus not wearing hats was recorded for all identical sections of interest. Bleacher seating was analyzed separately, as spectators presumably knew in advance of the continuous direct sun exposure during day games, and a subset of young children in the bleachers (<10 years of age) also was assessed. A continuously sunny section also was evaluated at the second and sixth innings to see if hats were presumably purchased during exposure. Statistical significance was determined using χ² tests with P<.05 indicating statistical significance.

Results

This analysis consisted of 3539 spectators. In both the sunny and shaded sections of a day game, there were more spectators wearing hats (49% and 37%, respectively)(P<.001) than in the same sections at night games (35% and 29%, respectively)(Table 1). During the day game, more spectators wore hats in the sunny section than in the adjacent shaded section (49% vs 37%; P<.001). Analysis of the same 2 sections during the night game revealed no significant differences.

Spectators sitting in the bleachers during a day game who presumably knew to anticipate direct sun exposure showed no significant differences in hat-wearing patterns versus the sunny section (44% vs 49%) but were more likely to wear hats compared to those sitting in the bleachers at the night game (44% vs 33%)(P<.001)(Table 1). There was no significant difference in the number of hats worn by spectators in the sunny section in the second inning (43%) versus the same section after continuous sun exposure at the sixth inning (44%)(Table 2). Significantly more children seated in the bleachers during the day game wore hats compared to adults in the same section (64% vs 42%; P<.001)(Table 3). During the hat giveaway day, significantly more spectators wore hats (the majority of which were the free giveaway hats) across all sections studied (P<.001)(Table 4).

Comment

More than 23 million spectators attended daytime MLB games in 2015, with millions more attending minor league and amateur events.⁵Although sun-protection messages tend to be well understood and received by society, many choose to ignore them.⁶

In partnership with the American Academy of Dermatology, the MLB’s Play Sun Smart program has promoted UVR risk awareness at sporting events since 1999.³ Those affiliated with MLB teams also receive annual skin cancer screenings in conjunction with a public education effort in May of each season. However, despite the years of sun-protection education, our study found that less than half of attendees wore hats for UVR protection. In fact, there were no significant differences noted across all of the hat-wearing parameters studied (day vs night game, sunny vs shaded section, sunny section over course of game) between the current study compared to the results from 10 years prior⁴ (Tables 1 and 2). For spectators in the bleacher section, even presumably knowing in advance that seating would be in the sun did not significantly increase hat-wearing behavior. Although skin cancer rates continue to rise, hat-wearing trends remain stable, revealing a concerning trend.

Increased availability of sunscreen has led to improved sun-protective behaviors in many populations.⁷ In our study, the free hat giveaway had the greatest impact on hat wearing, which suggests that improved availability and access to hats can lead to an important opportunity for sun-protection programs to partner with hat manufacturers to augment their use and protective impact.

Sun avoidance during childhood and adolescence has been shown to decrease the risk for melanoma.¹ Young children had the highest rate of hat usage in the current study, possibly due to parental example or dictates. Research has shown the importance of role models in promoting sun safety to young children,^8,9 so perhaps use of hats by parents or MLB players contributed to the hat-wearing behavior observed in this subpopulation.

Given the limited change observed in hat-wearing behaviors over the last decade, a knowledge and behavioral gap appears to exist that may be able to be exploited to enhance future sun protection. Also, based on our findings, the MLB and other sun-protection education campaigns may wish to augment their UVR protective messages by offering hat giveaways, which appear to have a notable impact.

Acknowledgment

The authors thank Jessie Skapik, BS (New York, New York), for her independent review of the spectator photographs.

Spectators at baseball games may be exposed to excess solar UV radiation (UVR), which has been linked to the development of both melanoma and nonmelanoma skin cancers.^1,2 Although baseball hats traditionally are worn to demonstrate team support, they also may provide some sun protection for the head and face where skin cancers are commonly found.

The importance of protecting the skin from solar UVR has led to sun-protection programs and community education as well as efforts to evaluate the impact of these programs. Major League Baseball (MLB) has partnered with the American Academy of Dermatology since 1999 to promote the importance of sun protection and raise skin cancer awareness through its Play Sun Smart program.³ A study conducted 10 years ago (N=2030) evaluated hat use in spectators at MLB games and noted that less than half of all spectators in seating sections exposed to direct sunlight wore hats.⁴ The purpose of the current study was to evaluate how public education about sun protection has impacted the use of hats by spectators at MLB games in 2015 compared to the prior study in 2006.

Methods

Data were collected during a 3-game series (2 day games, 1 night game) in August 2015 in New York, New York. During one of the day games, 18,000 fans received a free wide-brimmed hat. High-resolution digital photographs of seating sections were obtained using a camera with a 300-mm lens. Using the same methodology as the prior study,⁴ sunny and shaded seating sections were photographed during all 3 games (Figure). Photographs of each section were analyzed by an independent reviewer using a high-resolution computer screen. Spectators wearing head coverings—baseball hats, visors, or hats with circumferential brims—were defined as using hats. The number of spectators wearing hats versus not wearing hats was recorded for all identical sections of interest. Bleacher seating was analyzed separately, as spectators presumably knew in advance of the continuous direct sun exposure during day games, and a subset of young children in the bleachers (<10 years of age) also was assessed. A continuously sunny section also was evaluated at the second and sixth innings to see if hats were presumably purchased during exposure. Statistical significance was determined using χ² tests with P<.05 indicating statistical significance.

Results

This analysis consisted of 3539 spectators. In both the sunny and shaded sections of a day game, there were more spectators wearing hats (49% and 37%, respectively)(P<.001) than in the same sections at night games (35% and 29%, respectively)(Table 1). During the day game, more spectators wore hats in the sunny section than in the adjacent shaded section (49% vs 37%; P<.001). Analysis of the same 2 sections during the night game revealed no significant differences.

Spectators sitting in the bleachers during a day game who presumably knew to anticipate direct sun exposure showed no significant differences in hat-wearing patterns versus the sunny section (44% vs 49%) but were more likely to wear hats compared to those sitting in the bleachers at the night game (44% vs 33%)(P<.001)(Table 1). There was no significant difference in the number of hats worn by spectators in the sunny section in the second inning (43%) versus the same section after continuous sun exposure at the sixth inning (44%)(Table 2). Significantly more children seated in the bleachers during the day game wore hats compared to adults in the same section (64% vs 42%; P<.001)(Table 3). During the hat giveaway day, significantly more spectators wore hats (the majority of which were the free giveaway hats) across all sections studied (P<.001)(Table 4).

Comment

More than 23 million spectators attended daytime MLB games in 2015, with millions more attending minor league and amateur events.⁵Although sun-protection messages tend to be well understood and received by society, many choose to ignore them.⁶

In partnership with the American Academy of Dermatology, the MLB’s Play Sun Smart program has promoted UVR risk awareness at sporting events since 1999.³ Those affiliated with MLB teams also receive annual skin cancer screenings in conjunction with a public education effort in May of each season. However, despite the years of sun-protection education, our study found that less than half of attendees wore hats for UVR protection. In fact, there were no significant differences noted across all of the hat-wearing parameters studied (day vs night game, sunny vs shaded section, sunny section over course of game) between the current study compared to the results from 10 years prior⁴ (Tables 1 and 2). For spectators in the bleacher section, even presumably knowing in advance that seating would be in the sun did not significantly increase hat-wearing behavior. Although skin cancer rates continue to rise, hat-wearing trends remain stable, revealing a concerning trend.

Increased availability of sunscreen has led to improved sun-protective behaviors in many populations.⁷ In our study, the free hat giveaway had the greatest impact on hat wearing, which suggests that improved availability and access to hats can lead to an important opportunity for sun-protection programs to partner with hat manufacturers to augment their use and protective impact.

Sun avoidance during childhood and adolescence has been shown to decrease the risk for melanoma.¹ Young children had the highest rate of hat usage in the current study, possibly due to parental example or dictates. Research has shown the importance of role models in promoting sun safety to young children,^8,9 so perhaps use of hats by parents or MLB players contributed to the hat-wearing behavior observed in this subpopulation.

Given the limited change observed in hat-wearing behaviors over the last decade, a knowledge and behavioral gap appears to exist that may be able to be exploited to enhance future sun protection. Also, based on our findings, the MLB and other sun-protection education campaigns may wish to augment their UVR protective messages by offering hat giveaways, which appear to have a notable impact.

Acknowledgment

The authors thank Jessie Skapik, BS (New York, New York), for her independent review of the spectator photographs.

Spectators at baseball games may be exposed to excess solar UV radiation (UVR), which has been linked to the development of both melanoma and nonmelanoma skin cancers.^1,2 Although baseball hats traditionally are worn to demonstrate team support, they also may provide some sun protection for the head and face where skin cancers are commonly found.

The importance of protecting the skin from solar UVR has led to sun-protection programs and community education as well as efforts to evaluate the impact of these programs. Major League Baseball (MLB) has partnered with the American Academy of Dermatology since 1999 to promote the importance of sun protection and raise skin cancer awareness through its Play Sun Smart program.³ A study conducted 10 years ago (N=2030) evaluated hat use in spectators at MLB games and noted that less than half of all spectators in seating sections exposed to direct sunlight wore hats.⁴ The purpose of the current study was to evaluate how public education about sun protection has impacted the use of hats by spectators at MLB games in 2015 compared to the prior study in 2006.

Methods

Data were collected during a 3-game series (2 day games, 1 night game) in August 2015 in New York, New York. During one of the day games, 18,000 fans received a free wide-brimmed hat. High-resolution digital photographs of seating sections were obtained using a camera with a 300-mm lens. Using the same methodology as the prior study,⁴ sunny and shaded seating sections were photographed during all 3 games (Figure). Photographs of each section were analyzed by an independent reviewer using a high-resolution computer screen. Spectators wearing head coverings—baseball hats, visors, or hats with circumferential brims—were defined as using hats. The number of spectators wearing hats versus not wearing hats was recorded for all identical sections of interest. Bleacher seating was analyzed separately, as spectators presumably knew in advance of the continuous direct sun exposure during day games, and a subset of young children in the bleachers (<10 years of age) also was assessed. A continuously sunny section also was evaluated at the second and sixth innings to see if hats were presumably purchased during exposure. Statistical significance was determined using χ² tests with P<.05 indicating statistical significance.

Results

This analysis consisted of 3539 spectators. In both the sunny and shaded sections of a day game, there were more spectators wearing hats (49% and 37%, respectively)(P<.001) than in the same sections at night games (35% and 29%, respectively)(Table 1). During the day game, more spectators wore hats in the sunny section than in the adjacent shaded section (49% vs 37%; P<.001). Analysis of the same 2 sections during the night game revealed no significant differences.

Spectators sitting in the bleachers during a day game who presumably knew to anticipate direct sun exposure showed no significant differences in hat-wearing patterns versus the sunny section (44% vs 49%) but were more likely to wear hats compared to those sitting in the bleachers at the night game (44% vs 33%)(P<.001)(Table 1). There was no significant difference in the number of hats worn by spectators in the sunny section in the second inning (43%) versus the same section after continuous sun exposure at the sixth inning (44%)(Table 2). Significantly more children seated in the bleachers during the day game wore hats compared to adults in the same section (64% vs 42%; P<.001)(Table 3). During the hat giveaway day, significantly more spectators wore hats (the majority of which were the free giveaway hats) across all sections studied (P<.001)(Table 4).

Comment

More than 23 million spectators attended daytime MLB games in 2015, with millions more attending minor league and amateur events.⁵Although sun-protection messages tend to be well understood and received by society, many choose to ignore them.⁶

In partnership with the American Academy of Dermatology, the MLB’s Play Sun Smart program has promoted UVR risk awareness at sporting events since 1999.³ Those affiliated with MLB teams also receive annual skin cancer screenings in conjunction with a public education effort in May of each season. However, despite the years of sun-protection education, our study found that less than half of attendees wore hats for UVR protection. In fact, there were no significant differences noted across all of the hat-wearing parameters studied (day vs night game, sunny vs shaded section, sunny section over course of game) between the current study compared to the results from 10 years prior⁴ (Tables 1 and 2). For spectators in the bleacher section, even presumably knowing in advance that seating would be in the sun did not significantly increase hat-wearing behavior. Although skin cancer rates continue to rise, hat-wearing trends remain stable, revealing a concerning trend.

Increased availability of sunscreen has led to improved sun-protective behaviors in many populations.⁷ In our study, the free hat giveaway had the greatest impact on hat wearing, which suggests that improved availability and access to hats can lead to an important opportunity for sun-protection programs to partner with hat manufacturers to augment their use and protective impact.

Sun avoidance during childhood and adolescence has been shown to decrease the risk for melanoma.¹ Young children had the highest rate of hat usage in the current study, possibly due to parental example or dictates. Research has shown the importance of role models in promoting sun safety to young children,^8,9 so perhaps use of hats by parents or MLB players contributed to the hat-wearing behavior observed in this subpopulation.

Given the limited change observed in hat-wearing behaviors over the last decade, a knowledge and behavioral gap appears to exist that may be able to be exploited to enhance future sun protection. Also, based on our findings, the MLB and other sun-protection education campaigns may wish to augment their UVR protective messages by offering hat giveaways, which appear to have a notable impact.

Acknowledgment

The authors thank Jessie Skapik, BS (New York, New York), for her independent review of the spectator photographs.

Case Report

A 24-year-old man was referred to the dermatology department for evaluation of pustules, atrophic scars, and alopecia on the scalp of 6 years’ duration. Six years prior, erythema, scaling, and follicular keratotic papules had appeared on the superciliary arches, and he started to lose hair from the eyebrows. Three months later, he developed mildly pruritic and painful scaling and pustules on the scalp. These lesions resolved with atrophic scarring accompanied by alopecia. One year later, follicular keratotic papules developed on the cheeks, chest, abdomen, back, lateral upper arms, thighs, and axillae. Two years later, direct microscopy of the lesions on the scalp and fungal culture were negative. After 2 weeks of treatment with roxithromycin (0.15 g twice daily), the scalp pustules dried out and resolved; however, they recurred when the patient stopped taking the medication. Six months later, he was started on isotretinoin treatment (10 mg once daily) for half a year, but no improvement was seen. His parents were nonconsanguineous, and no other family members were affected.

Dermatologic examination revealed large areas of atrophic scarring and alopecia on the scalp. Only a few solitary hairs remained on the top of the head, with the follicles surrounded by keratotic papules, pustules, and black scabs. There was sparse hair on the forehead and temples and scattered hair clusters in the occipital region near the hairline. These follicles also were associated with keratotic papules (Figure 1A). Erythema, scales, and follicular keratotic papules of the superciliary arches with sparse eyebrows and axillary hairs were noted. Follicular keratotic papules also were observed on the cheeks, axillae, chest, abdomen, back, lateral upper arms, and thighs. Dental examination revealed a large space between the upper anterior teeth and the lower anterior teeth. The upper anterior teeth were anteverted, there was congenital absence of right lower central incisors, and the anterior teeth were in deep overbite and overjet (Figure 1B). There was gingival atrophy and calculus dentalis in the upper and lower teeth. He had a fissured tongue with atrophic filiform papillae (Figure 1C).

Comment

Folliculitis spinulosa decalvans, along with keratosis follicularis spinulosa decalvans (KFSD), keratosis pilaris atrophicans faciei, and atrophoderma vermiculatum, belongs to a group of diseases that includes keratosis pilaris atrophicans. In 1994, Oranje et al¹ suggested the term folliculitis spinulosa decalvans, with signs including persistent pustules, characteristic keratotic papules, and scarring alopecia of the scalp, which may be exacerbated at puberty. Staphylococcus aureus was isolated from the pustules in one study²; however, in another study, repeated cultures were negative.³ Although the main inheritance pattern of KFSD is X-linked, autosomal-dominant inheritance is more common in FSD. Furthermore, there are certain differences in the clinical manifestations of these 2 conditions. Therefore, it remains controversial if FSD is an independent disease or merely a subtype of KFSD.

Our patient’s symptoms manifested after puberty, primarily pustules as well as atrophic and scarring alopecia of the scalp and follicular keratotic papules on the head, face, trunk, lateral upper arms, and thighs. Pathologic examination showed massive infiltration of plasma cells, neutrophils, and multinucleated giant cells around the hair follicles. The clinical and histopathologic findings met the diagnostic criteria for FSD.

Folliculitis spinulosa decalvans is a rare clinical condition with few cases reported.^3-5 In addition to the aforementioned characteristic clinical manifestations, our patient also had dental anomalies, a fissured tongue, and atrophy of the tongue papillae, which are not known to be associated with FSD. Dental anomalies are characteristic of patients with Down syndrome, ectodermal dysplasia, Papillon-Lefèvre syndrome, and other conditions.⁶ Fissured tongue is a normal variant that occurs in 5% to 11% of individuals. It also is a classic but nonspecific feature of Melkersson-Rosenthal syndrome and may occur in psoriasis, Down syndrome, acromegaly, and Sjögren syndrome.⁷ Atrophy of the tongue papillae is associated with anemia, pellagra, Sjögren syndrome, candidiasis, and other conditions.⁸ Because there are no known reports of associations between FSD and any of these oral manifestations, it is possible that they were unrelated to FSD in our patient.

Folliculitis spinulosa decalvans usually is recurrent and there is no consistently effective treatment for it. Kunte et al⁴ reported that dapsone (100 mg/d) led to resolution of scalp inflammation and pustules within 1 month. Romine et al² reported that a 3-week course of dichloroxacillin (250 mg 4 times daily) induced disappearance of pustules around the hair follicles. However, Hallai et al⁵ reported a patient who was resistant to isotretinoin treatment. In our case, after 1 month of treatment with clarithromycin, metronidazole, viaminate, and fusidic acid cream, the pustules had resolved and the black scabs had fallen off, leaving atrophic scars. The long-term efficacy of this regimen is still under observation.

Conclusion

We report a case of FSD with dental anomalies, a fissured tongue, and atrophy of tongue papillae, none of which have previously been reported in association with FSD. We, therefore, believe that our patient’s oral manifestations are unrelated to FSD.

Case Report

A 24-year-old man was referred to the dermatology department for evaluation of pustules, atrophic scars, and alopecia on the scalp of 6 years’ duration. Six years prior, erythema, scaling, and follicular keratotic papules had appeared on the superciliary arches, and he started to lose hair from the eyebrows. Three months later, he developed mildly pruritic and painful scaling and pustules on the scalp. These lesions resolved with atrophic scarring accompanied by alopecia. One year later, follicular keratotic papules developed on the cheeks, chest, abdomen, back, lateral upper arms, thighs, and axillae. Two years later, direct microscopy of the lesions on the scalp and fungal culture were negative. After 2 weeks of treatment with roxithromycin (0.15 g twice daily), the scalp pustules dried out and resolved; however, they recurred when the patient stopped taking the medication. Six months later, he was started on isotretinoin treatment (10 mg once daily) for half a year, but no improvement was seen. His parents were nonconsanguineous, and no other family members were affected.

Dermatologic examination revealed large areas of atrophic scarring and alopecia on the scalp. Only a few solitary hairs remained on the top of the head, with the follicles surrounded by keratotic papules, pustules, and black scabs. There was sparse hair on the forehead and temples and scattered hair clusters in the occipital region near the hairline. These follicles also were associated with keratotic papules (Figure 1A). Erythema, scales, and follicular keratotic papules of the superciliary arches with sparse eyebrows and axillary hairs were noted. Follicular keratotic papules also were observed on the cheeks, axillae, chest, abdomen, back, lateral upper arms, and thighs. Dental examination revealed a large space between the upper anterior teeth and the lower anterior teeth. The upper anterior teeth were anteverted, there was congenital absence of right lower central incisors, and the anterior teeth were in deep overbite and overjet (Figure 1B). There was gingival atrophy and calculus dentalis in the upper and lower teeth. He had a fissured tongue with atrophic filiform papillae (Figure 1C).

Comment

Folliculitis spinulosa decalvans, along with keratosis follicularis spinulosa decalvans (KFSD), keratosis pilaris atrophicans faciei, and atrophoderma vermiculatum, belongs to a group of diseases that includes keratosis pilaris atrophicans. In 1994, Oranje et al¹ suggested the term folliculitis spinulosa decalvans, with signs including persistent pustules, characteristic keratotic papules, and scarring alopecia of the scalp, which may be exacerbated at puberty. Staphylococcus aureus was isolated from the pustules in one study²; however, in another study, repeated cultures were negative.³ Although the main inheritance pattern of KFSD is X-linked, autosomal-dominant inheritance is more common in FSD. Furthermore, there are certain differences in the clinical manifestations of these 2 conditions. Therefore, it remains controversial if FSD is an independent disease or merely a subtype of KFSD.

Our patient’s symptoms manifested after puberty, primarily pustules as well as atrophic and scarring alopecia of the scalp and follicular keratotic papules on the head, face, trunk, lateral upper arms, and thighs. Pathologic examination showed massive infiltration of plasma cells, neutrophils, and multinucleated giant cells around the hair follicles. The clinical and histopathologic findings met the diagnostic criteria for FSD.

Folliculitis spinulosa decalvans is a rare clinical condition with few cases reported.^3-5 In addition to the aforementioned characteristic clinical manifestations, our patient also had dental anomalies, a fissured tongue, and atrophy of the tongue papillae, which are not known to be associated with FSD. Dental anomalies are characteristic of patients with Down syndrome, ectodermal dysplasia, Papillon-Lefèvre syndrome, and other conditions.⁶ Fissured tongue is a normal variant that occurs in 5% to 11% of individuals. It also is a classic but nonspecific feature of Melkersson-Rosenthal syndrome and may occur in psoriasis, Down syndrome, acromegaly, and Sjögren syndrome.⁷ Atrophy of the tongue papillae is associated with anemia, pellagra, Sjögren syndrome, candidiasis, and other conditions.⁸ Because there are no known reports of associations between FSD and any of these oral manifestations, it is possible that they were unrelated to FSD in our patient.

Folliculitis spinulosa decalvans usually is recurrent and there is no consistently effective treatment for it. Kunte et al⁴ reported that dapsone (100 mg/d) led to resolution of scalp inflammation and pustules within 1 month. Romine et al² reported that a 3-week course of dichloroxacillin (250 mg 4 times daily) induced disappearance of pustules around the hair follicles. However, Hallai et al⁵ reported a patient who was resistant to isotretinoin treatment. In our case, after 1 month of treatment with clarithromycin, metronidazole, viaminate, and fusidic acid cream, the pustules had resolved and the black scabs had fallen off, leaving atrophic scars. The long-term efficacy of this regimen is still under observation.

Conclusion

We report a case of FSD with dental anomalies, a fissured tongue, and atrophy of tongue papillae, none of which have previously been reported in association with FSD. We, therefore, believe that our patient’s oral manifestations are unrelated to FSD.

Case Report

A 24-year-old man was referred to the dermatology department for evaluation of pustules, atrophic scars, and alopecia on the scalp of 6 years’ duration. Six years prior, erythema, scaling, and follicular keratotic papules had appeared on the superciliary arches, and he started to lose hair from the eyebrows. Three months later, he developed mildly pruritic and painful scaling and pustules on the scalp. These lesions resolved with atrophic scarring accompanied by alopecia. One year later, follicular keratotic papules developed on the cheeks, chest, abdomen, back, lateral upper arms, thighs, and axillae. Two years later, direct microscopy of the lesions on the scalp and fungal culture were negative. After 2 weeks of treatment with roxithromycin (0.15 g twice daily), the scalp pustules dried out and resolved; however, they recurred when the patient stopped taking the medication. Six months later, he was started on isotretinoin treatment (10 mg once daily) for half a year, but no improvement was seen. His parents were nonconsanguineous, and no other family members were affected.

Dermatologic examination revealed large areas of atrophic scarring and alopecia on the scalp. Only a few solitary hairs remained on the top of the head, with the follicles surrounded by keratotic papules, pustules, and black scabs. There was sparse hair on the forehead and temples and scattered hair clusters in the occipital region near the hairline. These follicles also were associated with keratotic papules (Figure 1A). Erythema, scales, and follicular keratotic papules of the superciliary arches with sparse eyebrows and axillary hairs were noted. Follicular keratotic papules also were observed on the cheeks, axillae, chest, abdomen, back, lateral upper arms, and thighs. Dental examination revealed a large space between the upper anterior teeth and the lower anterior teeth. The upper anterior teeth were anteverted, there was congenital absence of right lower central incisors, and the anterior teeth were in deep overbite and overjet (Figure 1B). There was gingival atrophy and calculus dentalis in the upper and lower teeth. He had a fissured tongue with atrophic filiform papillae (Figure 1C).

Comment

Folliculitis spinulosa decalvans, along with keratosis follicularis spinulosa decalvans (KFSD), keratosis pilaris atrophicans faciei, and atrophoderma vermiculatum, belongs to a group of diseases that includes keratosis pilaris atrophicans. In 1994, Oranje et al¹ suggested the term folliculitis spinulosa decalvans, with signs including persistent pustules, characteristic keratotic papules, and scarring alopecia of the scalp, which may be exacerbated at puberty. Staphylococcus aureus was isolated from the pustules in one study²; however, in another study, repeated cultures were negative.³ Although the main inheritance pattern of KFSD is X-linked, autosomal-dominant inheritance is more common in FSD. Furthermore, there are certain differences in the clinical manifestations of these 2 conditions. Therefore, it remains controversial if FSD is an independent disease or merely a subtype of KFSD.

Our patient’s symptoms manifested after puberty, primarily pustules as well as atrophic and scarring alopecia of the scalp and follicular keratotic papules on the head, face, trunk, lateral upper arms, and thighs. Pathologic examination showed massive infiltration of plasma cells, neutrophils, and multinucleated giant cells around the hair follicles. The clinical and histopathologic findings met the diagnostic criteria for FSD.

Folliculitis spinulosa decalvans is a rare clinical condition with few cases reported.^3-5 In addition to the aforementioned characteristic clinical manifestations, our patient also had dental anomalies, a fissured tongue, and atrophy of the tongue papillae, which are not known to be associated with FSD. Dental anomalies are characteristic of patients with Down syndrome, ectodermal dysplasia, Papillon-Lefèvre syndrome, and other conditions.⁶ Fissured tongue is a normal variant that occurs in 5% to 11% of individuals. It also is a classic but nonspecific feature of Melkersson-Rosenthal syndrome and may occur in psoriasis, Down syndrome, acromegaly, and Sjögren syndrome.⁷ Atrophy of the tongue papillae is associated with anemia, pellagra, Sjögren syndrome, candidiasis, and other conditions.⁸ Because there are no known reports of associations between FSD and any of these oral manifestations, it is possible that they were unrelated to FSD in our patient.

Folliculitis spinulosa decalvans usually is recurrent and there is no consistently effective treatment for it. Kunte et al⁴ reported that dapsone (100 mg/d) led to resolution of scalp inflammation and pustules within 1 month. Romine et al² reported that a 3-week course of dichloroxacillin (250 mg 4 times daily) induced disappearance of pustules around the hair follicles. However, Hallai et al⁵ reported a patient who was resistant to isotretinoin treatment. In our case, after 1 month of treatment with clarithromycin, metronidazole, viaminate, and fusidic acid cream, the pustules had resolved and the black scabs had fallen off, leaving atrophic scars. The long-term efficacy of this regimen is still under observation.

Conclusion

We report a case of FSD with dental anomalies, a fissured tongue, and atrophy of tongue papillae, none of which have previously been reported in association with FSD. We, therefore, believe that our patient’s oral manifestations are unrelated to FSD.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

Atopic dermatitis (AD) is the most common inflammatory skin disease in both adults and children.¹ Unfortunately, the current treatment armamentarium is largely confined to topical calcineurin inhibitors, topical and systemic steroids, phototherapy, cyclosporine (not approved by the US Food and Drug Administration for AD), and other oral immunosuppressants.² The availability of partially helpful and highly toxic treatments creates a huge unmet need for more effective and safer treatments, particularly for patients with moderate to severe AD who often require systemic approaches.

Recent extensive translational (bench top to bedside and back) investigations in skin of AD patients has shown that skin phenotype is characterized by increased T-cell infiltration and related inflammatory cytokines as well as epidermal abnormalities (eg, hyperplasia, aberrant differentiation).³ Clinical improvement of AD has been demonstrated with broad T-cell targeted therapeutics, such as cyclosporine and narrowband UVB, coupled with decreases of T-cell infiltrates and inflammatory gene products as well as improvement of the pathologic epidermal phenotype.^4,5

In the past, AD was conceptualized as a T helper cell T_H2 (acute disease)/T_H1 (chronic disease) bipolar cytokine disorder.⁶ Acute lesions are characterized by high T_H2, T_H22, and some T_H17 signals, with intensification of these axes and T_H1 augmentation orchestrating the chronic phenotype.⁷ The identification of the inflammatory pathways underlying AD has led to the development and testing of more than 10 broad or targeted therapeutics (Table).⁸ Phase 1 and phase 2 studies of dupilumab (targeting IL-4Rα) have shown not only tremendous AD improvement (~70%) but also tissue reversal of the immune and barrier abnormalities, including inflammatory cytokines and epidermal hyperplasia.^9-11 As a result, other T_H2 axis inhibitors (anti–IL-13/tralokinumab, anti–IL-31RA/CIM 331) are now in clinical trials. The identification of IL-22 in AD lesions has prompted trials with an anti–IL-22 (ILV 094) and an IL-12/IL-23p40 (ustekinumab) inhibitor.¹² For psoriasis, ustekinumab showed 75% improvement in approximately 70% of patients,¹³ but for AD, despite clear clinical and molecular effects, differences compared to placebo were not statistically significant,¹² probably due to underdosing of the drug in an excessively immune-activated disease¹⁴ as well as allowing topical steroids in patients, which may minimize the differences in treatment effect between drug and placebo.

The developments seen in AD are now moving into other inflammatory skin diseases, particularly alopecia areata (AA), a T-cell–mediated disease that shares phenotypic similarities with AD and often is associated with it.¹⁵ There is a paucity of effective, remission-sustaining treatments of AA, particularly for patients with severe disease who rarely experience spontaneous hair regrowth and who have a limited response to topical interventions.^16,17 Our clinical experience showed that successfully treating patients with concurrent AD and AA has led to hair regrowth. Inspired by these clinical observations and by results obtained in AD,^9-12 studying AA skin showed an upregulation of not only the traditionally suspected culprit T_H1 but also T_H2 and T_H9 axes, IL-23 cytokines, and phosphodiesterase 4.¹⁸ Subsequently, a pilot study of 3 patients with extensive AA treated with ustekinumab showed that all 3 patients not only experienced hair regrowth but also had a reduction in inflammatory markers in scalp lesions.¹⁹ Although these results are promising, AA is an immunologically complex disease and it is yet to be determined if therapeutically targeting 1 (eg, IL-4) rather than a wide array of cytokines can reverse disease phenotype. There are ongoing clinical trials directed at different pathogenic targets (eg, Jak inhibitors, IL-13 antagonist, IL-17 antagonist, phosphodiesterase 4 antagonist); some showed some efficacy in small studies.^20,21

The finding of a commonly upregulated T_H2 pathway in both AD and AA will pave the way for studies with T_H2 antagonists in AA patients. Future targeted therapeutic studies will shed light on the pathogenic pathways of this devastating skin disease and answer the extensive unmet therapeutic need it presents.

Atopic dermatitis (AD) is the most common inflammatory skin disease in both adults and children.¹ Unfortunately, the current treatment armamentarium is largely confined to topical calcineurin inhibitors, topical and systemic steroids, phototherapy, cyclosporine (not approved by the US Food and Drug Administration for AD), and other oral immunosuppressants.² The availability of partially helpful and highly toxic treatments creates a huge unmet need for more effective and safer treatments, particularly for patients with moderate to severe AD who often require systemic approaches.

Recent extensive translational (bench top to bedside and back) investigations in skin of AD patients has shown that skin phenotype is characterized by increased T-cell infiltration and related inflammatory cytokines as well as epidermal abnormalities (eg, hyperplasia, aberrant differentiation).³ Clinical improvement of AD has been demonstrated with broad T-cell targeted therapeutics, such as cyclosporine and narrowband UVB, coupled with decreases of T-cell infiltrates and inflammatory gene products as well as improvement of the pathologic epidermal phenotype.^4,5

In the past, AD was conceptualized as a T helper cell T_H2 (acute disease)/T_H1 (chronic disease) bipolar cytokine disorder.⁶ Acute lesions are characterized by high T_H2, T_H22, and some T_H17 signals, with intensification of these axes and T_H1 augmentation orchestrating the chronic phenotype.⁷ The identification of the inflammatory pathways underlying AD has led to the development and testing of more than 10 broad or targeted therapeutics (Table).⁸ Phase 1 and phase 2 studies of dupilumab (targeting IL-4Rα) have shown not only tremendous AD improvement (~70%) but also tissue reversal of the immune and barrier abnormalities, including inflammatory cytokines and epidermal hyperplasia.^9-11 As a result, other T_H2 axis inhibitors (anti–IL-13/tralokinumab, anti–IL-31RA/CIM 331) are now in clinical trials. The identification of IL-22 in AD lesions has prompted trials with an anti–IL-22 (ILV 094) and an IL-12/IL-23p40 (ustekinumab) inhibitor.¹² For psoriasis, ustekinumab showed 75% improvement in approximately 70% of patients,¹³ but for AD, despite clear clinical and molecular effects, differences compared to placebo were not statistically significant,¹² probably due to underdosing of the drug in an excessively immune-activated disease¹⁴ as well as allowing topical steroids in patients, which may minimize the differences in treatment effect between drug and placebo.

The developments seen in AD are now moving into other inflammatory skin diseases, particularly alopecia areata (AA), a T-cell–mediated disease that shares phenotypic similarities with AD and often is associated with it.¹⁵ There is a paucity of effective, remission-sustaining treatments of AA, particularly for patients with severe disease who rarely experience spontaneous hair regrowth and who have a limited response to topical interventions.^16,17 Our clinical experience showed that successfully treating patients with concurrent AD and AA has led to hair regrowth. Inspired by these clinical observations and by results obtained in AD,^9-12 studying AA skin showed an upregulation of not only the traditionally suspected culprit T_H1 but also T_H2 and T_H9 axes, IL-23 cytokines, and phosphodiesterase 4.¹⁸ Subsequently, a pilot study of 3 patients with extensive AA treated with ustekinumab showed that all 3 patients not only experienced hair regrowth but also had a reduction in inflammatory markers in scalp lesions.¹⁹ Although these results are promising, AA is an immunologically complex disease and it is yet to be determined if therapeutically targeting 1 (eg, IL-4) rather than a wide array of cytokines can reverse disease phenotype. There are ongoing clinical trials directed at different pathogenic targets (eg, Jak inhibitors, IL-13 antagonist, IL-17 antagonist, phosphodiesterase 4 antagonist); some showed some efficacy in small studies.^20,21

The finding of a commonly upregulated T_H2 pathway in both AD and AA will pave the way for studies with T_H2 antagonists in AA patients. Future targeted therapeutic studies will shed light on the pathogenic pathways of this devastating skin disease and answer the extensive unmet therapeutic need it presents.

Atopic dermatitis (AD) is the most common inflammatory skin disease in both adults and children.¹ Unfortunately, the current treatment armamentarium is largely confined to topical calcineurin inhibitors, topical and systemic steroids, phototherapy, cyclosporine (not approved by the US Food and Drug Administration for AD), and other oral immunosuppressants.² The availability of partially helpful and highly toxic treatments creates a huge unmet need for more effective and safer treatments, particularly for patients with moderate to severe AD who often require systemic approaches.

Recent extensive translational (bench top to bedside and back) investigations in skin of AD patients has shown that skin phenotype is characterized by increased T-cell infiltration and related inflammatory cytokines as well as epidermal abnormalities (eg, hyperplasia, aberrant differentiation).³ Clinical improvement of AD has been demonstrated with broad T-cell targeted therapeutics, such as cyclosporine and narrowband UVB, coupled with decreases of T-cell infiltrates and inflammatory gene products as well as improvement of the pathologic epidermal phenotype.^4,5

In the past, AD was conceptualized as a T helper cell T_H2 (acute disease)/T_H1 (chronic disease) bipolar cytokine disorder.⁶ Acute lesions are characterized by high T_H2, T_H22, and some T_H17 signals, with intensification of these axes and T_H1 augmentation orchestrating the chronic phenotype.⁷ The identification of the inflammatory pathways underlying AD has led to the development and testing of more than 10 broad or targeted therapeutics (Table).⁸ Phase 1 and phase 2 studies of dupilumab (targeting IL-4Rα) have shown not only tremendous AD improvement (~70%) but also tissue reversal of the immune and barrier abnormalities, including inflammatory cytokines and epidermal hyperplasia.^9-11 As a result, other T_H2 axis inhibitors (anti–IL-13/tralokinumab, anti–IL-31RA/CIM 331) are now in clinical trials. The identification of IL-22 in AD lesions has prompted trials with an anti–IL-22 (ILV 094) and an IL-12/IL-23p40 (ustekinumab) inhibitor.¹² For psoriasis, ustekinumab showed 75% improvement in approximately 70% of patients,¹³ but for AD, despite clear clinical and molecular effects, differences compared to placebo were not statistically significant,¹² probably due to underdosing of the drug in an excessively immune-activated disease¹⁴ as well as allowing topical steroids in patients, which may minimize the differences in treatment effect between drug and placebo.

The developments seen in AD are now moving into other inflammatory skin diseases, particularly alopecia areata (AA), a T-cell–mediated disease that shares phenotypic similarities with AD and often is associated with it.¹⁵ There is a paucity of effective, remission-sustaining treatments of AA, particularly for patients with severe disease who rarely experience spontaneous hair regrowth and who have a limited response to topical interventions.^16,17 Our clinical experience showed that successfully treating patients with concurrent AD and AA has led to hair regrowth. Inspired by these clinical observations and by results obtained in AD,^9-12 studying AA skin showed an upregulation of not only the traditionally suspected culprit T_H1 but also T_H2 and T_H9 axes, IL-23 cytokines, and phosphodiesterase 4.¹⁸ Subsequently, a pilot study of 3 patients with extensive AA treated with ustekinumab showed that all 3 patients not only experienced hair regrowth but also had a reduction in inflammatory markers in scalp lesions.¹⁹ Although these results are promising, AA is an immunologically complex disease and it is yet to be determined if therapeutically targeting 1 (eg, IL-4) rather than a wide array of cytokines can reverse disease phenotype. There are ongoing clinical trials directed at different pathogenic targets (eg, Jak inhibitors, IL-13 antagonist, IL-17 antagonist, phosphodiesterase 4 antagonist); some showed some efficacy in small studies.^20,21

The finding of a commonly upregulated T_H2 pathway in both AD and AA will pave the way for studies with T_H2 antagonists in AA patients. Future targeted therapeutic studies will shed light on the pathogenic pathways of this devastating skin disease and answer the extensive unmet therapeutic need it presents.

Review the PDF of the fact sheet on adult photosensitivity disorders with board-relevant, easy-to-review material. This month's fact sheet will review important disorders in the adult population where photosensitivity is a major feature.

Practice Questions

1. A 50-year-old woman with a history of alcoholism and new-onset diarrhea developed a painful, scaly, erythematous, and hyperpigmented eruption on the photoexposed areas on the chest and hands. A similar presentation can occur in patients on which medications?

a. azathioprine

b. fluorouracil

c. pyrazinamide

d. A and C only

e. all of the above

2. A college student presents with a streaky blistering rash on the arms and legs. He is on summer vacation and recently started a side job of mowing lawns. This phototoxic eruption requires which light spectrum?

a. 200–290 nm

b. 290–315 nm

c. 315–400 nm

d. 400–700 nm

e. none of the above

3. A middle-aged man with psoriasis complains of new onset of redness of the hands and face that occurs within hours of going outside. The patient may be taking which medications?

a. doxepin

b. NSAIDS

c. tar shampoo

d. terbinafine

e. A, B, and C

f. B, C, and D

4. A patient with metastatic melanoma was just started on vemurafenib. Which side effect is most likely to occur from this medication?

a. cough

b. myalgia

c. panniculitis

d. photosensitivity

e. squamous cell carcinoma

5. A 30-year-old black woman reports an itchy, flesh-colored, bumpy rash on the extensor forearms that appears 24 hours after sun exposure. There was no prior exposure to systemic or topical photoallergens. Which of the following is false regarding this condition?

a. classified as a type IV hypersensitivity reaction

b. condition improves with subsequent exposures (hardening)

c. histology is characterized by mucin deposition

d. rash is generally nonscarring

e. similar reaction localized to the helices may occur in adolescent boys

Answers to practice questions provided on next page

Practice Question Answers

1. A 50-year-old woman with a history of alcoholism and new-onset diarrhea developed a painful, scaly, erythematous, and hyperpigmented eruption on the photoexposed areas on the chest and hands. A similar presentation can occur in patients on which medications?

a. azathioprine

b. fluorouracil

c. pyrazinamide

d. A and C only

e. all of the above

2. A college student presents with a streaky blistering rash on the arms and legs. He is on summer vacation and recently started a side job of mowing lawns. This phototoxic eruption requires which light spectrum?

a. 200–290 nm

b. 290–315 nm

c. 315–400 nm

d. 400–700 nm

e. none of the above

3. A middle-aged man with psoriasis complains of new onset of redness of the hands and face that occurs within hours of going outside. The patient may be taking which medications?

a. doxepin

b. NSAIDS

c. tar shampoo

d. terbinafine

e. A, B, and C

f. B, C, and D

4. A patient with metastatic melanoma was just started on vemurafenib. Which side effect is most likely to occur from this medication?

a. cough

b. myalgia

c. panniculitis

d. photosensitivity

e. squamous cell carcinoma

5. A 30-year-old black woman reports an itchy, flesh-colored, bumpy rash on the extensor forearms that appears 24 hours after sun exposure. There was no prior exposure to systemic or topical photoallergens. Which of the following is false regarding this condition?

a. classified as a type IV hypersensitivity reaction

b. condition improves with subsequent exposures (hardening)

c. histology is characterized by mucin deposition

d. rash is generally nonscarring

e. similar reaction localized to the helices may occur in adolescent boys

Review the PDF of the fact sheet on adult photosensitivity disorders with board-relevant, easy-to-review material. This month's fact sheet will review important disorders in the adult population where photosensitivity is a major feature.

Practice Questions

1. A 50-year-old woman with a history of alcoholism and new-onset diarrhea developed a painful, scaly, erythematous, and hyperpigmented eruption on the photoexposed areas on the chest and hands. A similar presentation can occur in patients on which medications?

a. azathioprine

b. fluorouracil

c. pyrazinamide

d. A and C only

e. all of the above

2. A college student presents with a streaky blistering rash on the arms and legs. He is on summer vacation and recently started a side job of mowing lawns. This phototoxic eruption requires which light spectrum?

a. 200–290 nm

b. 290–315 nm

c. 315–400 nm

d. 400–700 nm

e. none of the above

3. A middle-aged man with psoriasis complains of new onset of redness of the hands and face that occurs within hours of going outside. The patient may be taking which medications?

a. doxepin

b. NSAIDS

c. tar shampoo

d. terbinafine

e. A, B, and C

f. B, C, and D

4. A patient with metastatic melanoma was just started on vemurafenib. Which side effect is most likely to occur from this medication?

a. cough

b. myalgia

c. panniculitis

d. photosensitivity

e. squamous cell carcinoma

5. A 30-year-old black woman reports an itchy, flesh-colored, bumpy rash on the extensor forearms that appears 24 hours after sun exposure. There was no prior exposure to systemic or topical photoallergens. Which of the following is false regarding this condition?

a. classified as a type IV hypersensitivity reaction

b. condition improves with subsequent exposures (hardening)

c. histology is characterized by mucin deposition

d. rash is generally nonscarring

e. similar reaction localized to the helices may occur in adolescent boys

Answers to practice questions provided on next page

Practice Question Answers

1. A 50-year-old woman with a history of alcoholism and new-onset diarrhea developed a painful, scaly, erythematous, and hyperpigmented eruption on the photoexposed areas on the chest and hands. A similar presentation can occur in patients on which medications?

a. azathioprine

b. fluorouracil

c. pyrazinamide

d. A and C only

e. all of the above

2. A college student presents with a streaky blistering rash on the arms and legs. He is on summer vacation and recently started a side job of mowing lawns. This phototoxic eruption requires which light spectrum?

a. 200–290 nm

b. 290–315 nm

c. 315–400 nm

d. 400–700 nm

e. none of the above

3. A middle-aged man with psoriasis complains of new onset of redness of the hands and face that occurs within hours of going outside. The patient may be taking which medications?

a. doxepin

b. NSAIDS

c. tar shampoo

d. terbinafine

e. A, B, and C

f. B, C, and D

4. A patient with metastatic melanoma was just started on vemurafenib. Which side effect is most likely to occur from this medication?

a. cough

b. myalgia

c. panniculitis

d. photosensitivity

e. squamous cell carcinoma

5. A 30-year-old black woman reports an itchy, flesh-colored, bumpy rash on the extensor forearms that appears 24 hours after sun exposure. There was no prior exposure to systemic or topical photoallergens. Which of the following is false regarding this condition?

a. classified as a type IV hypersensitivity reaction

b. condition improves with subsequent exposures (hardening)

c. histology is characterized by mucin deposition

d. rash is generally nonscarring

e. similar reaction localized to the helices may occur in adolescent boys

Review the PDF of the fact sheet on adult photosensitivity disorders with board-relevant, easy-to-review material. This month's fact sheet will review important disorders in the adult population where photosensitivity is a major feature.

Practice Questions

1. A 50-year-old woman with a history of alcoholism and new-onset diarrhea developed a painful, scaly, erythematous, and hyperpigmented eruption on the photoexposed areas on the chest and hands. A similar presentation can occur in patients on which medications?

a. azathioprine

b. fluorouracil

c. pyrazinamide

d. A and C only

e. all of the above

2. A college student presents with a streaky blistering rash on the arms and legs. He is on summer vacation and recently started a side job of mowing lawns. This phototoxic eruption requires which light spectrum?

a. 200–290 nm

b. 290–315 nm

c. 315–400 nm

d. 400–700 nm

e. none of the above

3. A middle-aged man with psoriasis complains of new onset of redness of the hands and face that occurs within hours of going outside. The patient may be taking which medications?

a. doxepin

b. NSAIDS

c. tar shampoo

d. terbinafine

e. A, B, and C

f. B, C, and D

4. A patient with metastatic melanoma was just started on vemurafenib. Which side effect is most likely to occur from this medication?

a. cough

b. myalgia

c. panniculitis

d. photosensitivity

e. squamous cell carcinoma

5. A 30-year-old black woman reports an itchy, flesh-colored, bumpy rash on the extensor forearms that appears 24 hours after sun exposure. There was no prior exposure to systemic or topical photoallergens. Which of the following is false regarding this condition?

a. classified as a type IV hypersensitivity reaction

b. condition improves with subsequent exposures (hardening)

c. histology is characterized by mucin deposition

d. rash is generally nonscarring

e. similar reaction localized to the helices may occur in adolescent boys

Answers to practice questions provided on next page

Practice Question Answers

1. A 50-year-old woman with a history of alcoholism and new-onset diarrhea developed a painful, scaly, erythematous, and hyperpigmented eruption on the photoexposed areas on the chest and hands. A similar presentation can occur in patients on which medications?

a. azathioprine

b. fluorouracil

c. pyrazinamide

d. A and C only

e. all of the above

2. A college student presents with a streaky blistering rash on the arms and legs. He is on summer vacation and recently started a side job of mowing lawns. This phototoxic eruption requires which light spectrum?

a. 200–290 nm

b. 290–315 nm

c. 315–400 nm

d. 400–700 nm

e. none of the above

3. A middle-aged man with psoriasis complains of new onset of redness of the hands and face that occurs within hours of going outside. The patient may be taking which medications?

a. doxepin

b. NSAIDS

c. tar shampoo

d. terbinafine

e. A, B, and C

f. B, C, and D

4. A patient with metastatic melanoma was just started on vemurafenib. Which side effect is most likely to occur from this medication?

a. cough

b. myalgia

c. panniculitis

d. photosensitivity

e. squamous cell carcinoma

5. A 30-year-old black woman reports an itchy, flesh-colored, bumpy rash on the extensor forearms that appears 24 hours after sun exposure. There was no prior exposure to systemic or topical photoallergens. Which of the following is false regarding this condition?

a. classified as a type IV hypersensitivity reaction

b. condition improves with subsequent exposures (hardening)

c. histology is characterized by mucin deposition

d. rash is generally nonscarring

e. similar reaction localized to the helices may occur in adolescent boys