Conflicts of Interest:
PJW has no conflicts to disclose. MHB has no conflicts to disclose. NS has been a principal investigator and received research grant from Bayer, and has acted as consultant and/or received honoraria from Allergan, Celgene, Cutera, Cynosure, Eclipse, Endo, EndyMed, Galderma, Nutraceutical Wellness, Venus Concept.

ABSTRACT
Approximately 16 million Americans have rosacea, an inflammatory cutaneous disorder with central facial erythema, papules, pustules, telangiectasia, flushing, and swelling being among the more commonly recognized features. Overexpression of cathelicidin peptide LL-37 has been implicated in the pathophysiology of rosacea. Azelaic acid has been found to inhibit the pathologic expression of cathelicidin, as well as the hyperactive protease activity that cleaves cathelicidin into LL-37. Given these findings, a small prospective, open-label, interventional trial was undertaken to assess the effects of azelaic acid 15% gel on inflammatory lesions of papulopustular rosacea in a real-world setting. Use of azelaic acid was associated with a significant reduction in inflammatory lesions, which persisted beyond the active treatment phase. Overall, azelaic acid 15% gel is an appropriate initial topical therapy for the treatment of moderate facial rosacea. 

Key Words:
atopic dermatitis, biologics, dupilumab, eczema, Th2 related inflammation

Introduction

Rosacea is a common chronic cutaneous disorder that is estimated to affect close to 10% of Americans in the community setting.¹ It is characterized by central facial erythema, papules, pustules, telangiectasia, flushing, and swelling. The precise pathogenesis of rosacea remains unclear. Dysregulation of the innate immune system, overgrowth of commensal skin organisms, and aberrant neurovascular signaling have been implicated in the pathophysiology of rosacea.²

The facial skin of rosacea patients has been documented to exhibit increased baseline expression of cathelicidin antimicrobial peptide, LL-37 (the active form of cathelicidin), and kallikrein 5 (KLK5), the protease responsible for cleaving cathelicidin into LL-37.³ In rosacea skin, KLK5 also cleaves cathelicidin into other abnormal peptide fragments. These forms of LL-37 are pro-inflammatory and stimulate angiogenesis, contributing to the clinical manifestations of rosacea. In addition, increased expression of toll-like receptor 2 (TLR2), a pattern recognition receptor, has been identified.⁴ This may contribute to the enhanced inflammatory responses to exogenous trigger factors seen in rosacea.

Azelaic acid, a naturally occurring, saturated, straight-chained, 9-carbon atom dicarboxylic acid, is used topically for the treatment of papulopustular rosacea (PPR). Azelaic acid has been shown to have anti-inflammatory activity through reduction of the cathelicidin pathway that is upregulated in facial skin of patients with rosacea. In vitro studies performed using murine or human skin showed that azelaic acid directly inhibits KLK5 in cultured keratinocytes, KLK5 gene expression, TLR2 expression, and cathelicidin and LL-37 formation.^5,6 An in vivo study conducted in patients with PPR showed reduction in cathelicidin and KLK5 activity after treatment with azelaic acid 15% gel applied twice daily.⁵Azelaic acid also has known antimicrobial, antioxidant, and anti-keratinization effects.⁷

Clinical trials have shown that azelaic acid 15% gel is an effective and safe first-line topical monotherapy for patients with PPR.⁸ Exposure to azelaic acid 15% gel has been associated with statistically significant reductions in inflammatory lesions of rosacea.⁹ However, there is a lack of data in the literature on the use of azelaic acid 15% gel outside a clinical trial setting, in real-world clinical practice. The objective of this study was, therefore, to assess the effectiveness of azelaic acid 15% gel when used as monotherapy for the treatment of mild to moderate PPR in a real-world setting.

Methods

This prospective, open-label, interventional study enrolled 20 subjects with PPR. Individuals aged 18 years or older with mild to moderate facial rosacea (as classified by Investigator Global Assessment [IGA]) and who had between 2 and 50 inflammatory facial lesions (papules or pustules) were eligible for participation. Patients with moderate or severe rhinophyma, ocular rosacea requiring topical or systemic antibiotics, or a history of hypersensitivity to any component of the gel were excluded. To prevent any carry-over effects of other medications, patients underwent an adequate washout according to drug type. Concomitant use of any treatments with effects in rosacea was prohibited for the duration of the study.

Subjects were instructed to apply azelaic acid 15% gel (Finacea Gel®) topically to the face twice daily for 12 weeks. They were also advised to avoid known rosacea triggers as much as possible. Clinical evaluations were made at baseline, weeks 4 and 12, and at 4 weeks after completion of active treatment (week 16). Effectiveness endpoints included inflammatory lesion counts, the IGA of rosacea severity, and participant’s subjective evaluation of rosacea improvement. Adverse events were also monitored.

Findings

Treatment with azelaic acid 15% gel was associated with a statistically significant reduction in all lesions types, and the reduction in lesions persisted beyond the treatment period. There was a significant decrease in mean total inflammatory lesion count at all study visits compared to baseline. The greatest decrease was observed at week 12, the conclusion of active treatment, with a difference of -3.4 from baseline (P<0.05). The difference in mean lesion count between week 16 and baseline was -2.4. This reduction in lesions 4 weeks after treatment discontinuation remained significant relative to baseline (P<0.05) (Figure 1).

Most subjects perceived a change in their facial skin over the course of azelaic acid treatment. At week 12, 47% of patients self-reported a moderate to significant improvement while 31% reported a mild improvement (Figure 2).

At the baseline visit, the IGA of rosacea was documented as “moderate” or “mild” for the majority of patients. IGA scores improved at each visit, with all visits showing a significant improvement when compared to the IGA at baseline (P<0.05). By week 16, the majority of IGA scores had become ratings of “almost clear” or “mild” (Figure 3).

Overall, azelaic acid 15% gel was safe and well-tolerated. Adverse events were limited to mild itching and stinging that did not require a disruption of treatment or any additional intervention. No subjects discontinued participation in the study for any reason.

Discussion

Data regarding the effectiveness of therapeutics is typically derived from rigorously administered, randomized, controlled phase 3 trials for FDA approval. While these studies are essential to document the efficacy of topical drugs, it is not always possible to predict the therapeutic benefits of a topical treatment used in the real-world setting.

Azelaic acid 15% gel resulted in a significant reduction in inflammatory lesion counts after 4 weeks of treatment in this study, and IGA scores showed clear improvement in the majority of patients. The effectiveness of azelaic acid 15% gel increases as treatment duration increases. Most patients reported that they had experienced improvement, with none reporting worsening of their condition since the start of the study.

The main limitations of this study were the small sample size, the short study duration, and a single center trial. Further investigations will be needed to observe the long-term efficacy and safety of azelaic acid 15% gel. Additional work is needed to determine patient preference and changes in quality of life associated with use of azelaic acid 15% gel. Future directions may also include real-world effectiveness of azelaic acid 15% gel applied once daily and when used in combination with other agents such as metronidazole.

Conclusion

This study confirms the benefits of azelaic acid 15% gel for the management of mild to moderate PPR in a real-world setting. Treatment with azelaic acid 15% gel applied twice daily to the face was associated with a significant reduction in inflammatory lesions and elicited an effect that persisted beyond the active treatment phase.

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Department of Dermatology, Weill Medical College of Cornell University, New York, USA

ABSTRACT

The role of lasers and intense pulsed light sources has gained increasing popularity in the management of both cosmetic telangiectasias and medically significant symptomatic varicose vein disease. These advances include endovascular technologies, novel cooling technologies, variable spot sizes and pulse durations, as well as the ability to deliver high-energy fluences. These advances have allowed the delivery of sufficient energy allowing more efficient pan-endothelial necrosis without affecting epidermal structures, and yielding a lower complication profile such as post-inflammatory hyperpigmentation and epidermal surface irregularities. The advent of extended-pulse, longer wavelength technologies such as the 1064 Neodymium:Yttrium Aluminum Garnet (Nd:YAG) laser have allowed the treatment of individuals with darker skin phenotypes, as well as treatment of deep blue reticular veins up to 3mm in diameter in a monomodal fashion. Combined approaches of sclerotherapy plus laser treatments performed during the same treatment session may produce synergistic results in selected individuals.

Key Words: laser, intense pulsed light sources, varicose vein disease

An increasing number of individuals are seeking treatment of lower extremity veins for symptomatic, as well as cosmetic concerns. As part of this increasing demand, lasers and intense pulsed light sources are playing an increasingly important role in this clinical setting. The major areas where these technologies have found increasing popularity have been in the management of:

• non-cannulizable microtelangiectasias
• vessels that are refractory to conventional sclerotherapy treatments
• zones of caution such as the ankles and feet where a high incidence of complications such as hyperpigmentation and ulceration occur
• vessels that arise from prior surgical or sclerotherapy treatment (telangiectatic matting or angiogenic flushing)
• needle phobic patients
• most recently, non-surgical eradication of the greater or lesser saphenous vein (GSV and LSV, respectively).¹

Problems intrinsic to laser and intense pulsed light treatments of leg veins in the past have included:

• inconsistent results despite multiple treatments
• hydrostatic pressures not addressed by light-endothelial interaction
• the deeper location and thickened basal lamina of lower extremity vessels, which make it more difficult to get photons into these locations.²

Improved results with the use of these technologies have been accomplished with appropriate wavelength matching for specific vessel color, and luminal diameter and depth, allowing the delivery of sufficient quantities of energy to yield pan-endothelial necrosis without affecting epidermal structures with adverse effects such as post-inflammatory hyperpigmentation and epidermal surface irregularities.

Lasers and Pulsed Light Sources vs. Sclerotherapy

It is a generally accepted doctrine that lasers and intense pulsed light sources are not substitutes for sclerotherapy. Injections into vascular targets are probably more efficient in terms of being able to eradicate vessels up to 3mm in diameter.3 The theoretical reasons for this are multiple, but include the relatively deeper location of lower extremity vessels, particularly compared to those of facial vessels. Furthermore, it has been shown that lower extremity vessels are generally larger and have thicker basal lamina than facial telangiectasias. Hydrostatic pressure is not addressed by light-endothelial interactions. The result of these postulates is that it is inherently more difficult to get photons safely in sufficient numbers through several layers into the target chromophore, i.e., hemoglobin, in order to ensure effective pan-endothelial vascular obliteration in an efficient reproducible fashion. Also red and blue veins are inherently different. This may be related to several factors including the Tyndall effect, the degree of oxygenated vs. deoxygenated blood in blue vs. red vessels, and vessel depth associated with background variation.

Microsclerotherapy by itself has been associated with a number of adverse effects, including multiple needle punctures, increased pigment dyschromia, and increased bruising and ulcerations, as well as inconsistent results. In this setting, many of the advances discussed in the present treatise substantiate the fact that lasers and intense pulsed light sources deliver improved results in the management of lower extremity vessels that are <3mm in diameter and that they will continue to play an ever expanding role in this setting.⁴

It has been suggested, although not clinically or scientifically proven, that combined approaches of sclerotherapy plus laser treatments performed during the same treatment session may produce synergistic results in selected individuals.

Presently Available Technologies

Basic requirements for a laser or light source to treat leg veins are:

• a wavelength that is proportionately better absorbed by the target (hemoglobin) than by surrounding chromophores
• the ability to penetrate to the full depth of the target blood vessel
• sufficient energy to damage the vessel without damaging the overlying skin
• an exposure duration long enough to slowly coagulate the vessel and its lining without damaging the surrounding tissue (Table 1).

Table 2: Lasers and light sources for leg veins.

Advances in Laser/Intense Pulsed Light Treatment of Lower Extremity Veins

Table 3: Recent technologic advances in laser/intense pulsed light treatment of lower extremity veins.

Cooling Technologies

The advent of improved cooling technologies in the laser management of lower extremity veins has allowed improved results while minimizing side-effect profiles in this setting. This has been achieved by allowing the delivery of higher energy fluences while maintaining improved epidermal protection. This produces a more efficient pan-endothelial destruction of vessels while minimizing epidermal contour changes, as well as post-inflammatory hyperpigmentation. A greater degree of clearing per treatment can be achieved in this fashion. In addition, greater patient procedural comfort can be accomplished utilizing cooling technologies; this is particularly important when utilizing longer wavelength technologies (i.e., 1064 Nd:YAG). Several approaches have been taken in this regard, including water-cooled chambers applied directly to the skin through which the laser beam is directed, cooling coupling gels, air-blowing cooling devices, and refrigerated spray cooling devices.⁴

The length of cryogen delivery can be varied on an individual basis depending on the skin type. For skin types I-III, little-to-no precooling is required because of the minimal amount of melanin in the skin. For skin types IV-VI, 5-20msec of precooling is used for protection of the epidermis. The amount of postcooling varies with vessel size. For smaller vessels, 25-60msec is used because it takes longer for the heat to rise to the surface of the skin. Generally, about 5-10msec of postcooling delay is used after the laser pulse to allow for the time it takes the heat to dissipate. Shorter delay times (approximately 5-10msec) are used for smaller vessels, and longer delay times (approximately 15-20msec) are used for larger vessels.⁵ 

Figure 1: Percent clearance at months-1 and -3 following 1064 Nd:YAG treatment of Class I-III veins; three treatments: >75% improvement
Settings:  Red vessels: Spot size 1.5mm, Fluence 500J/cm2, Pulse Width 40msec, Blue vessels: Spot size 3mm, Fluences 310J/cm2, Pulse Width 55msec

Longer Wavelengths

Longer wavelength technologies such as the 1064 Nd:YAG laser have taken the lead role in the management of lower extremity veins. Such extended wavelengths have several advantages for lower extremity vessel management. In general, these wavelengths allow management of larger lower extremity vessels, which may be up to 4mm in diameter. In addition, these longer wavelengths allow the targeting of deeper located vessels 3-4mm in depth in the dermis. Finally, these longer wavelengths allow treatment of darker skin phenotypes such as Fitzpatrick V and VI.^3,6

Extended Pulse Durations

Similar to longer wavelengths, extended pulse durations allow the delivery of higher energy fluences in a more gentle fashion. This is particularly important in the management of the larger, deeper vessels located in the lower dermis, as well as of those with darker skin phenotypes. Fluences up to 500-600J/cm2 may be delivered in a slow, gentle, non-cavitating fashion, which allows epidermal-bypass and gentle intravascular temperature clamping to produce more uniform pan-endothelial destruction.⁴

Monomodal Approach

Previous studies, including those reported by the author, have advocated a bimodal approach to the treatment of leg veins where shorter wavelengths (500-600nm) are utilized to treat Class I oxygenated red telangiectasias, and longer wavelengths (800-1100 nm) are utilized to treat Class I-III deoxygenated blue venulectasias and reticular veins. However, this approach requires the utilization of two lasers, or a laser plus an intense pulsed light source, in order to achieve the desired effects.² The search subsequently evolved for a monomodal wavelength technology, which would address the varying size, depth, and endothelial integrity associated with lower extremity vessels.

In this regard, high fluences (350-600J/cm2), small spot sizes <2mm, and short pulse durations of 15-30msec are most effective for small red vessels <1mm, which are usually superficial, red, and have a high oxyhemoglobin saturation. For larger blue vessels (1-4mm) that are deeper and have a lower oxygenated hemoglobin content, larger spot sizes (2-8mm), moderate fluences of 100-350J/cm2 and extended pulse durations of 30-50msec are most efficacious.^6,7

In summary, by varying spot size, fluence and pulse duration, and using a long wavelength, the 1064nm Nd:YAG laser can produce excellent results for treating both blue and red lower extremity vessels <3mm in diameter.

Table 4: Monomodal approach to lower extremity veins (1064nm ND:YAG technologies)

Captured Pulsing

By matching thermal relaxation times with vessel diameters and target chromophores (i.e., hemoglobin), one can deliver the high fluences of energy necessary to targeted vessels in order to cause full-thickness endothelial damage while inducing gentle cavitation, thus circumventing the development of cosmetically disfiguring purpura.⁴

Large-Beam Diameters

Newer laser and intense light technologies incorporate larger spot sizes (IPL 10x45mm lasers up to 10mm). These larger beam diameters allow deeper penetration for treatment of larger diameter vessels deeper in the dermis. It also allows delivery of a more uniform beam of laser energy.⁴

High-Energy Fluences

The ability to deliver high-energy fluences of up to 600 J/cm2 has allowed more efficient pan-endothelial destruction. This has resulted in more consistent results with fewer treatments in eradicating lower extremity vessels with light sources.⁶

Endovascular Technologies

Although beyond the scope of this treatise, endovascular diode and infrared laser fibers are now being utilized to cannulate both the greater and lesser saphenous veins and correct insufficiency at the associated saphenofemoral and saphenopopliteal junctions. This procedure is performed under Duplex guidance utilizing tumescent anesthesia. Mid-term results (3 years) show long-term closure rates that are at least as good as, or better than, those seen in the surgical ligation /stripping population (Figure 2).⁸

Figure 2: Introduction of an 810nm diode laser fiber into the greater saphenous vein under tumescent anesthesia allows for non-invasive correction of GSV incompetence.

Improved Topical Anesthetics

Patient discomfort has been a major issue utilizing long wavelength (i.e., 1064nm) technologies. Newer, more potent agents such as the S-Caine peel (70mg Lidocaine, 70mg Tetracaine, Zars Inc.) have been studied by the author and been found to be extremely effective in minimizing patient discomfort in this setting.

Conclusion

The important technical modifications presented in this paper have improved both patient and physician satisfaction concerning laser and intense pulsed light source treatment of lower extremity veins. Newer treatments on the horizon such as combined laser/radiofrequency technologies are presently being explored and will likely play a role in the future management of lower extremity venous disease.

References

1. Dover JS, Sadick NS, Goldman MP. The role of lasers and light sources in the treatment of leg veins. Dermatol Surg 24(4):328-36 (1999 Apr).
2. Sadick NS. A dual wavelength approach for laser/intense pulsed light source treatment of lower extremity veins. J Am Acad Dermatol 46(1):66-72 (2002 Jan).
3. Sadick NS. Vasculight and other 1064 nm wavelength lasers for treatment of lower extremity veins. Scope Phlebol Lymphol 29:175-8 (2000).
4. Sadick NS, Weiss RA, Goldman MP. Advances in laser surgery for leg veins: Bimodal wavelength approach to lower extremity vessels, new cooling techniques, and longer pulse durations. Dermatol Surg 28(1):16-20 (2002 Jan).
5. Chess C, Chess Q. Cool laser optics treatment of large telangiectasia of the lower extremities. J Dermatol Surg Oncol 19(1):74-80 (1993 Jan).
6. Sadick NS. Laser treatment with a 1064-nm laser for lower extremity Class I-III veins employing variable spots and pulse width parameters. Dermatol Surg 29(9):916-9 (2003 Sep).
7. Sadick NS. A dual wavelength approach for laser/intense pulsed light source treatment of lower extremity veins. J Am Acad Dermatol 46(1):66-72 (2002 Jan).
8. Min RJ, Zimmet SE, Isaacs MN, Forrestal MD. Endovenous laser treatment of the incompetent greater saphenous vein. J Vas Inter Radiol 12(10):1167-71 (2001 Oct).