¹Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
²Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
³Division of Dermatology, University of Calgary, Calgary, AB, Canada
⁴Beacon Dermatology, Calgary, AB, Canada
⁵Toronto Dermatology Centre, Toronto, ON, Canada
⁶Division of Dermatology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
⁷Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada

Conflict of interest: Leah Johnston does not have any conflicts of interest to disclose. Benjamin Barankin has been an advisor and speaker for Paladin Labs.
Jaggi Rao has been an advisor and speaker for Paladin Labs. Andrei Metelitsa has been an advisor and speaker for Abbvie, Clarion, Galderma, Merz Pharma, Paladin Labs.
Susan Poelman has been an advisor and speaker for Abbvie, Galderma, Merz Pharma and Paladin Labs. Geeta Yadav has been an advisor and speaker for Paladin Labs.
Funding sources: None.

Abstract:
Pain management is an important aspect of dermatologic procedures, which are typically performed on awake patients in outpatient settings. The first-line modalities for procedural analgesia during most dermatologic procedures are topical and injectable local anesthetics, such as lidocaine. However, in some medical and cosmetic dermatologic procedures, pain cannot be effectively managed with local anesthetics due to procedure-specific lack of efficacy, large treatment surface areas, high dosage requirements, allergies, or other contraindications. In these circumstances, methoxyflurane inhalers may be highly beneficial. Methoxyflurane (Penthrox^®) has demonstrated efficacy for providing pain relief in randomized controlled trials in patients who presented to emergency departments with acute trauma-related pain, as well as in patients undergoing painful procedures for other medical indications. The limited side effect profile, ease of patient self-administration, rapid onset and quick resolution of central nervous system effects following cessation makes methoxyflurane an ideal choice for analgesia during outpatient dermatologic procedures. This review provides an overview of the supporting evidence for methoxyflurane inhalers and clinical commentary on potential indications for methoxyflurane use in dermatology.

Keywords: methoxyflurane, Penthrox, inhaled analgesia, pain control, dermatology

Introduction

Methoxyflurane is a volatile, halogenated hydrocarbon that can be vaporized and subsequently inhaled for analgesia at low doses and can also be used as an anesthetic agent at high concentrations.¹ Methoxyflurane was widely used as an inhaled anesthetic agent in the 1960s and in 1968, Abbott Laboratories developed the first low-dose methoxyflurane inhaler (Analgizer^®) for self-administration by patients.² However, in the 1970s, use of methoxyflurane as an anesthetic declined due to emerging reports of nephrotoxicity and hepatotoxicity and in 1999, Abbott Laboratories discontinued production and distribution of methoxyflurane inhalers in the United States and Canada.^1,3,4 In 2005, the United States Food and Drug Administration (FDA) responded to reports of methoxyflurane toxicity by formally withdrawing the license for methoxyflurane anesthetic agents, preventing future new drug applications in the United States.^3,4

Medical Developments International re-branded low dose methoxyflurane through the development of the Penthrox^® inhaler for analgesia in 2003. Since then, Penthrox^® has received health regulatory approval in Europe and Canada in 2015 and 2018, respectively. In 2018, the FDA lifted its previous clinical hold on methoxyflurane, allowing Penthrox^® to receive regulatory approval as a new investigational drug.³ This review provides an overview of the evidence on methoxyflurane for analgesia and clinical commentary on applications for its use in dermatology.

Mechanism of Action and Pharmacodynamics of Inhaled Methoxyflurane

Once inhaled into the lungs, methoxyflurane undergoes rapid absorption into the blood, allowing for a quick onset of action that starts after 30 seconds and can be detected by changes in pain scores within the first 2-5 minutes of inhalation.⁵ The exact mechanism of action of methoxyflurane in pain relief has not been fully delineated, but it is theorized to exert its analgesic effects by potentiating activation of gamma-aminobutyric acid (GABA) and glycine receptors in the central nervous system (CNS) and altering the immunoreactivity of substance P and beta-endorphin in the brain.^6-9 Methoxyflurane’s ability to provide analgesia at lower doses (3-6 mL), in addition to its use as an anesthetic at higher doses (40-60 mL), is unique among fluorinated anesthetic agents.^10-13

Based on estimates from disappearance curves, the apparent half-life of methoxyflurane is approximately 15-20 minutes.⁴ Methoxyflurane is highly lipid soluble and diffuses slowly from adipose tissue into the bloodstream, and approximately 50% is metabolized by multiple different cytochrome P450 (CYP450) enzymes in the liver.^4,14 Methoxyflurane undergoes the biochemical processes of oxidative demethylation and defluorination to form the following metabolites: fluoride, oxalic acid, dichloroacetic acid, and 2,2-difluoro-2-methoxyacetic acid.⁴ Methoxyflurane and its metabolites are renally excreted and methoxyflurane may also be metabolized by kidney microsomes, leading to intrarenal fluoride formation.¹⁵

The Penthrox^® Inhaler

In Canada, Penthrox^® is inhaled via an inhalation device (Figure 1).^4,16 Each inhaler device comes with a 3 mL bottle of methoxyflurane, which is poured into the base of the inhaler, as well as an activated carbon (AC) chamber that is attached to the top of the inhaler at the dilutor hole.¹⁶ Once the device is assembled, the patient can then inhale methoxyflurane from the mouthpiece.¹⁶ To minimize exposure of individuals in the surrounding environment to methoxyflurane, patients are instructed to exhale into the inhaler.¹⁶ The exhaled vapor passes through the AC chamber, allowing for adsorption of exhaled methoxyflurane.¹⁶ To provide a stronger dose of methoxyflurane with each inhalation, patients can cover the dilutor hole on the top of the AC chamber with their fingers.¹⁶ The estimated concentration of methoxyflurane provided with each inhalation is 0.2-0.4% with the dilutor hole uncovered and 0.5-0.7% when the dilutor hole is covered.¹² Approximately 6-10 initial breaths are needed to initiate adequate analgesia.¹⁶ The Penthrox^® inhaler can be used continuously for up to 25-30 minutes and, if needed, a second 3 mL inhaler can be utilized to provide ongoing analgesia for up to 54 minutes.^12,17 If used intermittently, a single inhaler may provide up to 1 hour of analgesia.¹⁷ The maximum recommended daily and weekly doses of methoxyflurane are 6 mL and 15 mL, respectively.⁴

Clinical Trials

A summary of randomized controlled trials (RCTs) that have been conducted in human participants using the Penthrox^® brand of methoxyflurane inhalers is provided in Table 1.

Initial studies on Penthrox^® focused on evaluating its use as a potential alternative treatment for procedures requiring sedation. A 2011 randomized, cross-over study conducted by Abdullah et al. investigated the use of methoxyflurane inhalation for conscious sedation and analgesia during third molar surgical extraction, in comparison to treatment with nitrous oxide.¹⁸ The study found that sedation was comparable between the two groups, though patient satisfaction scores demonstrated that methoxyflurane was preferred by patients over nitrous oxide (p<0.05) and had a more favorable side effect profile. In a 2013 study by Nguyen et al. in patients undergoing colonoscopies, methoxyflurane was compared to the standard of care, intravenous (IV) midazolam and fentanyl, for procedural sedation and analgesia.¹⁹ The study found that 92% of patients (n=115/125) in the methoxyflurane group received adequate procedural analgesia and sedation with methoxyflurane alone, and only 10 patients required additional IV sedation.¹⁹ Patients in the methoxyflurane group awoke sooner following the procedure and were also able to be discharged more quickly.¹⁹ In patients undergoing dressing changes following severe burns, a 2016 randomized, pilot cross-over study found that 63% (n=5/8) of patients preferred methoxyflurane inhalation over patient-controlled analgesia with IV 10 mg/mL ketamine and 0.5 mg/mL midazolam for pain control.²⁰

The ‘STOP!’ trial in the United Kingdom was a 2014 placebo-controlled, double-blind, RCT on methoxyflurane use in patients aged 12 years or older who presented to the emergency department with minor traumatic injuries.² A total of 300 patients, including 90 patients between the ages of 12 to 17 years, were enrolled in the study.^2,17,21 Methoxyflurane reduced Visual Analog Scale (VAS) pain severity ratings significantly more than placebo (p<0.0001) at 5, 10, 15 and 20 minutes, with the greatest improvement in pain (-18.5 mean change in VAS rating from baseline) observed at 15 minutes.² The median time to initial pain relief was 4 minutes, which occurred after 1-5 inhalations in 49.7% (n=74) and after 6-10 inhalations in 34.9% of participants (n=52).² Another 2014 placebo-controlled, double-blind, RCT demonstrated the efficacy of methoxyflurane in reducing pain in patients undergoing routine bone marrow biopsies.²²

Safety Profile and Precautions for Use

Cardiorespiratory Depression

Methoxyflurane is contraindicated in individuals with hemodynamic instability and/or respiratory compromise.¹⁶ However, methoxyflurane use may be safe in the context of stable chronic respiratory conditions and it has been safely used in patients with obesity, obstructive sleep apnea, and asthma.^33-36

Nephrotoxicity

Nephrotoxicity has occurred in patients treated with anesthetic doses of methoxyflurane when plasma fluoride ion concentrations exceeded 50 μmol/L.¹⁵ However, nephrotoxicity is not commonly observed in patients treated with sevoflurane, another halogenated inhalational anesthetic, when plasma fluoride ion concentrations surpass a similar threshold.¹⁵ Sevoflurane defluorination by kidney microsomes occurs at a lower rate compared to methoxyflurane, suggesting that the renal toxicity observed with high doses of methoxyflurane may be attributable to increased intrarenal fluoride production during methoxyflurane elimination.¹⁵ In clinical studies that used the Penthrox^® inhaler, participants’ serum fluoride levels remained under 10 μmol/L after inhalation of 3 mL of methoxyflurane and no studies have reported nephrotoxicity from Penthrox^® use.¹⁶ A large retrospective post-authorization study found that Penthrox^® provided a reduced risk of nephrotoxicity compared to other commonly used analgesic agents.³⁴ These studies suggest that with the lower methoxyflurane dose used in the Penthrox^® inhaler, serum methoxyflurane levels and subsequent intrarenal fluoride production remain well below the nephrotoxicity threshold.

Hepatotoxicity

Hepatotoxicity is an established risk that occurs with anesthetic doses of methoxyflurane and previous reports include some fatal cases of methoxyflurane-induced hepatic dysfunction.¹⁶ Penthrox^® has not been associated with an increased risk of hepatotoxicity compared to other analgesic agents in post-authorization studies, however, there have been some cases published in the last 40 years on methoxyflurane-associated hepatitis that occurred following treatment with analgesic doses of methoxyflurane.^16,34 Methoxyflurane should be avoided in patients with evidence of underlying hepatic dysfunction and patients who have had previous hepatic damage following the use of methoxyflurane or other halogenated hydrocarbon anesthesics.¹⁶

Malignant Hyperthermia

A previous personal or family history of malignant hyperthermia in response to methoxyflurane or other halogenated anesthetics is a contraindication to methoxyflurane use.¹⁶

Central Nervous System, Psychomotor and Cognitive Effects

Methoxyflurane may cause transient dizziness, headache, muscle relaxation and sometimes drowsiness following inhalation.¹⁶ Methoxyflurane is contraindicated in individuals with an altered level of consciousness.¹⁶ A 2016 placebo-controlled RCT investigated the psychomotor and cognitive effects following 15 minutes of inhalation of a 3 mL methoxyflurane inhaler.³³ This study found that impairments in psychomotor and cognitive performance, including cognition, hand-eye coordination, and auditory reaction time resolved within 30 minutes of cessation of methoxyflurane inhalation.³³ This finding supports the claim that most patients should be able to safely drive and can return to work on the same day following procedures that use methoxyflurane inhalation for analgesia.³³ However, it is recommended that patients wait for up to 30 minutes after discontinuing methoxyflurane inhalation before driving.³³

Abuse Potential

The CNS side effect of euphoria with methoxyflurane use can be a risk factor for potential misuse and there have been very rare post-marketing reports of abuse related to anesthetic use.¹⁶ However, in comparison to many other analgesics, such as opioids, methoxyflurane has a significantly lower potential for abuse when treating acute pain.²⁵

Pregnancy and Breastfeeding

The potential for long-term effects of fluoride exposure during pregnancy and breastfeeding on offspring development has not been fully delineated.¹⁶ In studies that investigated the use of methoxyflurane during labor, elevated fetal serum and urine fluoride levels were measured post-delivery, though these levels were sub-nephrotoxic and no clinical signs of nephrotoxicity were observed.^37-39 Additionally, a retrospective study in females who received methoxyflurane during pregnancy found that there were no significant differences in maternal and fetal outcomes and rates of congenital abnormalities compared to patients who received fentanyl or no analgesia.⁴⁰ In the perinatal period, methoxyflurane use during labor was associated with reduced perinatal mortality rates and a reduced incidence of fetal distress, compared to cases where no analgesia was administered.⁴⁰

A study in Sprague-Dawley rats also did not demonstrate a teratogenic effect of methoxyflurane when used in pregnancy.⁴¹ However, daily 8-hour methoxyflurane exposure at a concentration of 0.08% for the full 21-day gestational period was associated with a 9% reduction in birth weight compared to the control group, while in the 50% nitrous oxide group, a 21% reduction in birth weight was observed.⁴¹ In Swiss/ICR mice, 4-hour daily exposure to methoxyflurane at trace (2 parts per million [ppm]) and subanesthetic (60 ppm) concentrations for 10 days was not associated with adverse effects but at anesthetic concentrations of 2000 ppm, reductions in birth weight, skeletal ossification, and renal maturation, as well as an increased incidence of minor skeletal abnormalities, were observed.⁴²

Based on the current literature, limited methoxyflurane use at analgesic doses during pregnancy does not appear to be associated with an increased risk of maternal or fetal adverse outcomes. However, the long-term effects on offspring development are unknown and therefore methoxyflurane is currently classified as a Pregnancy Category C drug by the FDA, indicating that it is not recommended for use during pregnancy and breastfeeding unless benefits are expected to outweigh potential risks.^16,40

Combination Analgesia and Potential Drug Interactions

Methoxyflurane has been used safely in combination with other analgesic agents, including topical and injectable local anesthetics, acetaminophen, IV morphine and IV fentanyl.^29,43-45 However, methoxyflurane should be used with caution in patients undergoing concomitant treatment with other CNS depressants, such as opioids, sedatives, muscle relaxants, and sedating antihistamines, due to the potential for transient drowsiness and alterations in psychomotor function.¹⁶

Methoxyflurane use should be avoided in individuals who are taking other medications with a potential risk of nephrotoxicity, including contrast dyes, gentamicin, tetracycline, colistin, polymyxin B and amphotericin B, and should be used with caution in patients who are concurrently taking non-steroidal anti-inflammatory drugs.¹⁶ Drugs that induce the activity of CYP2E1 and/or CYP2A6, which are the CYP450 enzyme subtypes that predominantly metabolize methoxyflurane, can also increase the risk of methoxyfluraneinduced nephrotoxicity.¹⁶ These drugs include alcohol, isoniazid, phenobarbital, and rifampicin.¹⁶

Vital Signs

Clinically significant changes in vital sign parameters, including blood pressure, pulse rate, respiratory rate, and peripheral capillary oxygen saturation, have not been observed with Penthrox^® use in clinical trials.^2,19,36 Continuous monitoring of vital signs during and after Penthrox^® use is not required in healthy patients who do not have major comorbidities.^16,23,28,44 However, some healthcare providers may recommend that patients remain in clinic for observation for 10-15 minutes after finishing methoxyflurane inhalation.

Storage, Handling and Preparation

Penthrox^® inhalers have a shelf-life of approximately 36 months, should be stored at temperatures between 5° and 30° Celsius and can be discarded with normal waste disposal.¹⁶ Contact precautions are not required when handling the inhalers. Penthrox^® inhalers may be stored in a clinic setting or patients may obtain their inhalers from a pharmacy prior to appointments. A major advantage of the Penthrox^® inhaler over other methods of analgesia is that minimal preparation of the inhaler device is needed before use. The first step for setting up the inhaler is to insert the AC chamber into the dilutor hole on the top of the inhaler.¹⁶ Administration of Penthrox^® without the AC chamber should be avoided, as this can significantly increase occupational exposure to methoxyflurane.¹⁶ Once the inhaler is assembled, liquid from the Penthrox^® bottle can be poured into the inhaler base, and it is recommended that subsequent use of the inhaler occur shortly after this step.¹⁶ If the inhaler is not used immediately and is stored under open conditions, approximately 50% of methoxyflurane will be lost after 5 hours.⁴⁶ Placement of an assembled inhaler into a low-density polyethylene bag within the inhaler’s original packaging can limit major losses of methoxyflurane for up to 3 days.⁴⁶

Occupational Exposure

The maximum exposure level for methoxyflurane is approximately 15 ppm.^45,47 In Canada, provincial legal limits for methoxyflurane exposure range from 2 ppm per day to 2 ppm over the course of 1 week.³⁷ While occupational exposure to methoxyflurane from patients’ exhalations is a theoretical health risk for healthcare providers, the real-world observed exposure level following 8-hour shifts is much lower than the legal exposure limits, ranging between 0.008 and 0.736 ppm in nurses who supervised methoxyflurane use.⁴⁸ Additionally, serum fluoride levels measured in ambulance paramedics were not significantly elevated above healthy reference ranges.⁴⁹ Typical exposure to methoxyflurane results in serum fluoride level increases that are nearly 50-fold lower than the thresholds that have been associated with nephrotoxicity, suggesting that methoxyflurane exposure has a low risk of negative health effects for healthcare providers when used in well-ventilated environments.^16,47,48 In a study that monitored ambient air in emergency department triage rooms, methoxyflurane concentrations ranged from 0.002 to 0.024 ppm, suggesting that exposure is very low for healthcare providers who work in adjacent rooms.⁴⁸

The long-term risks of methoxyflurane exposure in pregnant healthcare workers who supervise methoxyflurane use have not been studied.³⁷ Currently, it is recommended that pregnant or breastfeeding healthcare workers limit their exposure to methoxyflurane by avoiding direct supervision of Penthrox^® use.³⁷

Environmental Impact and Cost-Effectiveness

In a study that compared the climate change impact of Penthrox^® inhalers to nitrous oxide in terms of all materials and processes involved in manufacturing, clinical use, and disposal, Penthrox^® was found to have a lower environmental impact than nitrous oxide.⁵⁰ The current market cost of Penthrox^® in Canada is $55 per 3 mL inhaler, making it more expensive than the estimated costs per treatment session of IV acetaminophen, opioid analgesics, and nitrous oxide.^51-53 However, although the estimated cost during dermatologic procedures for nitrous oxide use is $20 per session, this estimate does not account for the expensive initial cost of purchasing a nitrous oxide delivery system, which can cost approximately $8,000-$12,000.^52,54,55 Nitrous oxide machines can also take up a significant amount of space in clinic rooms, which is not an issue with methoxyflurane given the small size of the inhaler device. Overall, the favorable efficacy, safety profile, and lower environmental impact of Penthrox^®, in addition to the lack of requirement for an expensive initial purchase of space-occuping equipment to administer Penthrox^®, makes it worth the slightly higher material cost per treatment session (Table 2).^50-53

Applications in Dermatology and Real-World Commentary

Pre-procedural evaluation for pain control is essential prior to the start of dermatologic procedures.⁵⁶ While injections of local anesthetic agents can effectively manage pain during many dermatologic procedures, such as simple punch or shave biopsies, some procedures may require additional interventions to optimize patient comfort. It is important to take into consideration both patient and procedure-specific factors. Pediatric patients, patients with chronic pain, and patients with procedural anxiety are more likely to experience higher levels of pain during and after dermatologic procedures.^57,58 Additionally, procedures where pain cannot be effectively managed with local anesthetic infiltration due to demonstrated lack of efficacy, large treatment surface areas, high dosage requirements or other contraindications, including allergies to local anesthetics, may warrant consideration of alternative analgesic methods. Given the demonstrated efficacy, limited side effect profile, rapid onset, and complete resolution of CNS effects within 30 minutes of cessation, methoxyflurane is an ideal choice for analgesia during many procedures that are performed in outpatient dermatology settings. Presently, no studies have been published on methoxyflurane use during dermatologic procedures. Based on the real-world clinical experience of the authors of this article, we propose that methoxyflurane inhalers are a useful tool to consider for pain relief during a variety of dermatologic procedures.

Potential Indications for Methoxyflurane in Medical Dermatology

Platelet-Rich Plasma and Intralesional Corticosteroid Injections for Hair Loss Disorders

Intradermal injections into the scalp with either intralesional corticosteroids and/or platelet-rich plasma (PRP) are a mainstay of treatment for many hair loss disorders, including alopecia areata, androgenetic alopecia and scarring alopecias. However, the abundance of pain sensory receptors in the scalp contributes to high levels of pain that many patients experience during scalp injections.⁵⁹ Pain, as well as interference of local anesthetics with platelet functionality, limits their use during PRP sessions.⁵⁹ Methoxyflurane may be useful in reducing pain during scalp injections and it does not carry the same risk of local interactions with intradermally-injected therapies.

Botulinum Toxin Injections

Methoxyflurane may also be beneficial for analgesia during botulinum toxin (BTX) injections. Common medical indications for BTX include axillary and palmoplantar hyperhidrosis as well as chronic migraines, which can be treated with a series of standardized injections into sites on the head and neck. BTX treatment sites, especially the palms and soles, can be highly sensitive during BTX injections.⁶⁰ Methoxyflurane inhalation may help to minimize discomfort during BTX injection sessions.

Photodynamic Therapy

Photodynamic therapy (PDT) is commonly used to treat patients with field cancerization and superficial non-melanoma skin cancers, which often occur in sun-exposed areas on the face and scalp. PDT can be painful and previous studies have demonstrated a lack of efficacy of topical anesthetic agents in controlling pain during PDT sessions.⁶¹ One study that used inhaled nitrous oxide during PDT sessions found that it provided a statistically significant reduction in pain levels compared to the control group.⁶² Methoxyflurane inhalation may be similarly beneficial in reducing pain during PDT treatments.

Deroofing Surgery for Hidradenitis Suppurativa

While intraoperative pain during deroofing procedures for hidradenitis suppurativa (HS) can be effectively managed with infiltration of local anesthetic agents, the process of injecting local anesthetics can be very painful given the relatively high levels of pain that HS patients experience from inflamed HS lesions, in addition to the skin sensitivity in the intertriginous areas where HS lesions typically arise.⁶³ Methoxyflurane inhalers may help to provide pain relief during this first step of deroofing surgeries if inhalation is initiated a few minutes prior to and during injections of local anesthetic agents.

Other Minor Surgical Procedures

Depending on provider and patient preferences, methoxyflurane inhalation may be beneficial as an adjuvant to local injectable anesthesia or may be used alone during minor surgical procedures of short duration, including removal of syringomas, skin tags, extensive dermatosis papulosa nigra, and surgical subcision of acne scars. In the pediatric population, methoxyflurane inhalation may be useful during wart removal with liquid nitrogen cryotherapy and laser treatment sessions, as well as prior to local anesthetic injections in individuals with needle phobias.

Potential Indications for Methoxyflurane in Cosmetic Dermatology

Anxiety about pain is a major barrier to patients choosing to undergo cosmetic dermatologic procedures.⁶⁴ Thus, it is important to be able to provide patients with effective options to alleviate procedural pain and discomfort. While pre-treatment application of ice, topical anesthetic creams and injections of local anesthetics can be used for pain management, these modalities often have limited efficacy, and in the case of local anesthetic injections, may require higher than the maximum safe doses to provide adequate analgesia to an entire area.

Methoxyflurane may be useful in many cosmetic procedures, as it can effectively provide widespread analgesia during procedures involving large body surface areas, such as the full face and/or neck. The hand-held inhaler design of Penthrox^® makes it preferable to other delivery methods for inhaled analgesia due to the lack of bulky tubing and masks, which can block treatment sites on the face. Another benefit is that methoxyflurane is relatively less cumbersome for patients to use compared to holding ice packs at treatment sites for several minutes or applying topical anesthetic creams, which often require occlusion to achieve maximal efficacy.⁶⁵ Additionally, methoxyflurane is non-flammable, making it a safe choice for use during cosmetic dermatologic procedures that involve the use of lasers and energy-based devices.¹⁶ Potential procedural indications for methoxyflurane in cosmetic dermatology may include full-face ablative and non-ablative fractional laser resurfacing, laser tattoo removal, laser hair removal, radiofrequency microneedling, radiofrequency and ultrasound skin tightening procedures, sclerotherapy, and dermal filler injections.

Conclusion

In summary, methoxyflurane is an inhaled fluorinated analgesic agent that has demonstrated efficacy in managing pain in RCTs for a variety of different painful medical procedures. It is a compelling choice for analgesia in outpatient dermatology settings given its high efficacy, limited side effect profile, ease of patient self-administration, rapid onset, quick resolution of CNS effects following discontinuation, cost-effectiveness, and lower environmental impact compared to other inhaled analgesics.

Purchase Article PDF for $1.99

¹Faculty of Medicine, University of Alberta, Edmonton, AB,Canada
²Division of Dermatology & Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB, Canada
³Toronto Dermatology Centre, Toronto, ON, Canada

Introduction

Chemical exfoliation has been used for decades to reverse the signs of aging skin and provide a cosmetic benefit. Alpha Hydroxy Acids (AHAs) have been at the forefront in revolutionizing the skin care industry, particularly glycolic acid-based therapies. Daily low dose glycolic acid formulations have been proven safe and effective for at-home use and have become widely popular amongst consumers. Recently, a new product line containing either 5% Encapsulated Glycolic Acid (GA) or 10% GA with the Amphoteric System, has been added to the market. It offers options for those with sensitive skin to benefit from GA therapy, while also providing those familiar with GA regimens to further benefit their skin’s appearance.

Background

• The application of chemicals to the skin in the pursuit of aesthetic improvement can be traced back to ancient times.¹ Alabaster, grape skins, sour milk, salt, and animal oils are just some examples of chemicals used four thousand years ago to rejuvenate the skin.^1,2
• The Romans rubbed the skins of fermented grapes on themselves to enhance their beauty, while Cleopatra allegedly would bathe in sour milk to have smoother skin.² It would later be discovered that tartaric acid in grapes and lactic acid in sour milk, the chemicals responsible for skin enhancement, are both alpha hydroxy acids.^1,2
• The use of alpha hydroxy acids is now well established by dermatologists in products such as chemical peels,³ a form of skin resurfacing or exfoliation that benefits conditions such as acne and melasma, and improves overall skin tone.
• Additionally, initial signs of aging skin begin to appear after the age of 28.⁴ The skin undergoes intrinsic changes which results in atrophy of particular skin components.⁴
• Further, sun exposure, smoking and other environmental factors can greatly accelerate changes in the skin.^4,5
• Consequently, a variety of skin exfoliation technologies containing GA have been developed to reverse the various signs of aging skin, which can be broadly broken down into mechanical and chemical modalities.^2,4
• With any of these approaches an accurate assessment of an individual’s baseline skin condition is crucial for success of the treatment and preventing complications, such as hypertrophic scarring.⁶

Mechanical Exfoliation

• Mechanical exfoliation uses physical or “mechanical” means to abrade the skin and achieve the desired effect.^6,7
• Microdermabrasion and dermabrasion are two examples of mechanical exfoliation and their difference lies in the depths to which they abrade the skin.^6,7
• Microdermabrasion is a non-surgical technique that uses abrasive substances, such as aluminum oxide crystals, to act at the outermost layer of the epidermis, or the stratum corneum.^6,7
• The ablation of the most superficial layer of the skin reveals the underlying healthy skin.^6,7 It is best suited to patients with minimally photo-aged skin that are looking for cosmetic improvements to their skins texture and tone, with minimal inconvenience.^6,7
• Dermabrasion, a more aggressive form of resurfacing, acts at the level of the dermis.⁶ Since this mechanical exfoliation penetrates into the dermis, completely removing the epidermis, it promotes re-epithelialization and collagen remodeling.⁶
• In turn, this technique, when performed by a qualified professional, leads to significant clinical improvements in skin architecture, although more recovery time is usually required.⁶
• Dermabrasion can be used to improve a much wider range of skin conditions than microdermabrasion.⁶
• Various scars, facial rhytides, tattoos, rhinophyma, and actinic keratosis can all be treated with dermabrasion.⁶

Chemical Exfoliation

• Chemical exfoliation, such as chemical peels, abrade the skin at a desired depth to achieve a cosmetic effect.^2,8-10
• Chemical peels can be classified into three groups: superficial, medium and deep, based on the depth to which they penetrate the skin.^2,8,9
• The depth of peeling is dependent not only on the particular chemical used but also on the concentration at which it is used.^8,9
• The deeper the peel, the more discomfort and potential side effects may occur, and consequently, the greater the recovery time. However, deeper peels also provide better cosmetic results. For example, trichloroacetic acid (TCA; also sometimes referred to as bichloroacetic acid) can be used for deep peels, medium-deep peels, or superficial peels depending on the concentration at which it is used.⁸
• By knowing the depth to which a chemical penetrates into the skin, dermatologists are better able to predict which skin abnormalities will benefit the most from a particular exfoliation.²
• In order to achieve the best results, a chemical peel must extend as deep as the skin abnormality to be corrected.²

Superficial Peels

• These peels penetrate into the epidermis and do not extend further than the dermal-epidermal interface.^2,8,9
• Typically, superficial peels are associated with a sensation of heat.⁸ Examples of superficial peels include GA, beta hydroxyl acids, tretinoin, low concentration TCA, and β-lipohydroxy acid.¹¹
• Skin dyschromias, actinic keratosis, active acne, and improvement of skin tone are the predominant clinical indications for superficial peels.⁹
• Since superficial peels are minimally abrasive, they are suitable for all skin types.⁹

Medium-depth Chemical Peels

• These peels penetrate through the epidermis and into the papillary dermis.^2,8,9
• A topical anaesthetic is sometimes required.⁸
• Numerous solar lentigines, dyschromia and melasma, actinic keratoses, acne and altered skin texture are the main indications to perform a medium-depth chemical peel.⁹
• TCA, GA, and augmented TCA (with GA, or Jessner solution) are the most common medium-depth agents.²

Deep Peels

• These peels penetrate through the epidermis, papillary dermis and into the reticular dermis.^2,8,9 As a result, they typically require general anesthesia.⁸
• Deep peeling solutions are comprised of varying concentrations of phenol and croton oil.⁹
• Fine and coarse wrinkling, actinic keratoses, acne scars, and dyschromia are the main indications for a deep chemical peel.⁹
• These peels are the most effective in generating new collagen and deposition of glycosaminoglycans.^2,9
• Inflammation, common to all chemical resurfacing, stimulates the healing process.⁸
• The amount of inflammation is correlated to the depth to which the chemicals penetrate into the skin.⁸
• The inflammatory reaction is characterized by erythema, desquamation, and edema.¹¹
• With superficial peels, inflammation last 1-3 days, whereas with medium to deep peels, inflammation can last 5-10 days.¹¹ These deeper peels can require longer periods of recovery time.^2,11

Side Effects

• Side effects of chemical peels include acneiform eruptions, postinflammatory hyperpigmentation, hypopigmentation, scarring, infection, and persistent erythema.²
• Different ethnicities may not respond in a predictable manner with chemical peels.¹¹ Therefore, a thorough individual history is quite important, with particular attention paid to instances of postinflammatory hyperpigmentation.^{11, 2}
• To minimize complications, it is important to select the most appropriate peel accurately for each patient, and it is critical that any kind of chemical peel be administered by a trained skin professional.
• In general, the deeper a chemical peel penetrates the greater the risk of complications.⁸ However, the deeper a peel extends the greater the potential cosmetic benefit.⁸
• In the care of a trained professional, the outcome with any chemical peel is mostly predictable, and ensures that patients receive the greatest cosmetic benefit possible with minimal chance of adverse reactions.²

Glycolic Acid

• Alpha-hydroxy acids (AHA) are naturally occurring acids found in organic materials such as fruit, milk, and wine.¹²
• Many of these acids are utilized in topical preparations to exfoliate the skin and yield a cosmetic benefit.¹³
• In addition, these acids possess comedolytic effects when used at a particular pH and thus are beneficial in acne-prone patients.¹⁴
• By gently removing the top layers of skin, other concurrent active ingredients will penetrate deeper and provide enhanced effects.
• GA is an AHA originating from sugarcane, and is the most commonly used acid in AHA peels, due to its natural origin and ability to easily penetrate the skin.³
• The use of GA peels on skin yields cosmetic as well as therapeutic benefits attributed to its antioxidant, anti-inflammatory and keratolytic effects.³
• The depth to which the GA penetrates the skin is dependent on its concentration, pH, and amount of time left on the skin.
• A lower pH and increasing concentrations of GA results in deeper exfoliation.³
• Typically, GA peels are superficial in depth, resulting in very little recovery time for patients.³
• A daily regimen of low-dose GA formulations has become widely popularized as a method of reducing signs of photo-aging and improving skin texture and tone.¹⁵
• One particular study showed an improvement to general skin texture and a modest reduction in the signs of photo-aging in patients using a daily 5% GA solution compared to those using a placebo solution.¹⁵
• A separate study showed that patients using a daily 8% GA solution experienced significant overall improvement in the severity of cutaneous photodamage after 22 weeks of use.¹⁶
• In addition to daily low-dose GA formulations showing improvements to photodamaged skin, they also offer benefit to patients suffering from acne.^14,17
• Researchers have demonstrated the comedolytic benefits of this acid using a daily 10% GA formulation in patients with mild acne.¹⁴ One study showed that after 90 days, there was an improvement in acne severity in all patients who received the 10% GA solution (n=59), compared to the placebo group (n=60), with minimal adverse effects.¹⁴
• Therefore, in patients with mild acne, a 10% GA solution could be considered as an alternative monotherapy to current popular regimens.¹⁴

Glycolic Renewal™

• Given how minimally invasive and safe low-dose GA preparations are across all skin phototypes, numerous skin care products have been developed containing low doses of this acid for at-home use.^3,17
• As a result of the benefit they can provide in reducing signs of aging and cutaneous photodamage, low-dose GA preparations have become quite popular amongst consumers.^3,17
• Recently, two new formulations utilizing encapsulated GA at a concentration of 5% have entered the market as well as two formulations with GA at a concentration of 10%.
• The new encapsulation delivery system allows the GA to better penetrate into the epidermis without irritation typical to AHA use.¹⁹
• The 5% encapsulated GA formulation is for patients with sensitive skin, and those whose skin is treatment-naïve to GA. The 10% GA product is for those who have previously used GA therapies.
• Independent research involving patients who applied the 5% GA encapsulated formulation twice daily for 2 weeks, followed by twice daily application of the glycolic renewal 10%.¹⁹ showed that after 28 days, there was a reduction in wrinkles by up to 72%, a visible reduction in total length of wrinkles by up to 68%, and a visible reduction in total area of wrinkles by up to 60%.¹⁹
• After 56 days, skin analyzed on cross polarized images showed up to a 78% improvement in skin tone evenness, based on both clinician and patient evaluation.¹⁹ The glycolic renewal products are available as a cream and lotion in both 5% and 10% formulations, to suit different skin types and seasons.¹⁹
• Patients with normal to dry skin are best suited to the smoothing cream.¹⁹ Patients with combination to oily skin are better suited to the smoothing lotion.¹⁹

Conclusion

The skin care industry underwent a dramatic transformation when AHAs were introduced in the early in the 1970s.¹⁸ Today, AHAs, such as GA, are widely used in cosmetic dermatology to reverse many signs of aging skin, and offer benefit to a wide array of skin diseases.^3,18 GA peels have been researched for decades, and are proven to be a simple, effective, and evidence-based method of providing significant cosmetic and therapeutic benefits to the skin of appropriately selected patients.^3,18 Continued innovation with GA skin care products has resulted in improved delivery systems, reduced adverse effects and better cosmetic benefits.^3,18 NeoStrata’s two new formulations, the glycolic renewal cream and lotion, utilize encapsulated GA and the amphoteric system to provide patients of all skin types with the benefits of AHA therapy.

References

1. Brody HJ, Monheit GD, Resnik SS, et al. Dermatol Surg. 2000;26:405-409.
2. Clark E, Scerri L. Clin Dermatol. 2008;26:209-218.
3. Sharad J. Clin Cosmet Investig Dermatol. 2013;6:281-288.
4. Hirsch RJ, Dayan SH, Shah AR. Facial Plastic Surgery Clinics of North America. 2004;12:311-321.
5. Doherty SD, Doherty CB, Markus JS, et al. Facial Plast Surg. 2009;25:245-251.
6. Smith JE. Facial Plast Surg. 2014;30:35-39.
7. Spencer JM. Am J Clin Dermatol. 2005;6:89-92.
8. Fischer TC, Perosino E, Poli F, et al. 2009. J Eur Acad Dermatol Venereol. 2010;24: 281-292.
9. Landau M. Clin Dermatol. 2008;26:200-208.
10. Mangat DS, Tansavatdi K, Garlich P. Facial Plast Surg. 2011;27:35-49.
11. Rendon MI, Berson DS, Cohen JL, et al. J Clin Aesthet Dermatol. 2010;37: 32-43.
12. Fartasch M, Teal J, Menon GK. Arch Dermatol Res. 1997;289:404-409.
13. Green BA, Yu RJ, Van Scott EJ. Clin Dermatol. 2009;27:495-501.
14. Abels C, Kaszuba A, Michalak I, et al. J Cosmet Dermatol. 2011;10:202-209.
15. Thibault PK, Wlodarczyk J, Wenck A. Dermatol Surg. 1998;24s:573-577; discussion 577-578.
16. Stiller MJ, Bartolone J, Stern R, et al. Arch Dermatol. 1996;132:631-636.
17. Green B. J Cosmet Dermatol. 2005;4:44-45.
18. Robas-Macawile S. http://business.inquirer.net/3934/after-years-of-research-firmrolls-out-products-that-take-away-the-years. Updated June 11, 2011. Accessed 08/03, 2014.
19. NeoStrata. NeoStrata Glycolic Renewal. 2014.

¹Faculty of Medicine, University of Alberta, Edmonton, AB, Canada
²Division of Dermatology & Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB, Canada
³Toronto Dermatology Centre, Toronto, ON, Canada

ABSTRACT

Rosacea is a common, chronic cutaneous condition that affects the face. Two topicals and one oral medication are currently approved for the treatment of rosacea, including azelaic acid, metronidazole, and sub-antimicrobial dose of doxycycline. Identification of subtypes can help guide treatment strategies. It is essential for psychosocial implications of rosacea to be considered and conservative management, such as nonpharmacologic routine skin care, must form an important part of the overall care. Recently, new insights into the pathophysiology of rosacea have led to the emergence of etiologically oriented treatments. Ivermectin, an acaricidal agent that has been shown to be effective against rosacea refractory to other therapies, is currently in Phase 3 trials. Brimonidine, which was US FDA approved last year and recently sanctioned by Health Canada, has filled an essential therapeutic void in the targeted treatment of diffuse facial erythema.

Key Words:
alpha-2 adrenergic receptor agonists, anti-bacterial agents, antiparasitic agent, erythema, inflammation, rosacea, telangiectasia

Introduction

Rosacea is a common chronic cutaneous condition that primarily affects the central facial area, including the cheeks, nose, eyes, chin, and forehead.¹ Primary cutaneous manifestations include sensitive skin, flushing, persistent erythema, papules, pustules, and telangiectases. Although symptoms may wax and wane in the short-term, rosacea is slowly progressive in the long-term for many patients.²

The National Rosacea Society has classified rosacea into four main subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular.³ Progression from one subtype to another is possible.⁴ Proper identification of subtypes may help guide therapeutic strategies.

Rosacea affects up to 10% of the general population and onset is typically between the ages of 30 and 50 years.⁵ It is especially common in light-skinned individuals of Northern European descent,⁶ with women more frequently affected,⁵ but men are more prone to develop thickening and distorting phymatous skin changes, especially of the nose. Although infrequent, some cases have been diagnosed in darker skin types; however, underdiagnosis and low reported incidence may be attributable to sampling bias and decreased visibility of clinical signs (e.g., erythema and telangiectasias).⁷

The pathophysiology is multifactorial and currently not fully understood. Multiple factors have been proposed to play a role, including vascular abnormalities, gastrointestinal disorders, matrix degeneration, pilosebaceous gland abnormalities, microbial activity, and altered innate immune response.^8,9 A new understanding of rosacea pathogenesis is emerging and alongside it the development of novel agents that target specific pathogenic factors and the symptoms they induce.

Rosacea can create psychosocial burdens, such as embarrassment, anxiety, and low self-esteem that adversely affect quality of life. These negative impacts should be taken into consideration when treating rosacea patients.^10,11 Conservative measures, such as trigger avoidance, proper skin care, and the use of camouflaging cosmetics and photoprotection should also be incorporated in the management plan.¹²

Conventional Therapies

Topical Metronidazole

Metronidazole was first shown to be an effective treatment against rosacea in the 1980s.¹³ Despite being an antibacterial and antiprotozoal agent, metronidazole’s therapeutic benefits in rosacea are mostly derived through its anti-inflammatory and antioxidant effects.¹⁴ Multiple trials have demonstrated that topical metronidazole significantly decreases the number of inflammatory lesions and reduces erythema compared to placebo, is generally well tolerated, has a low incidence of adverse effects, and is effective in maintaining remission.^15-18 Importantly, different formulations of metronidazole have been demonstrated to have similar efficacy, regardless of vehicle type (cream, gel, or lotion) or concentration (0.75% or 1%).^19-21 Once-daily dosing was also confirmed to be similarly effective as twice-daily application.^19,22 In addition, when combined with a sun protection factor 15 sunscreen, metronidazole may reduce the development of facial telangiectasia.²³ Of note, topical metronidazole is a pregnancy category B medication.

Topical Azelaic Acid

Azelaic acid is a naturally occurring dicarboxylic acid approved in the last decade for the treatment of mild to moderate rosacea.²⁴ Mostly applied as a 15% gel or a 20% cream, azelaic acid can attribute its efficacy to anti-inflammatory, anti-keratinizing, and antibacterial effects.²⁴ Multiple trials have demonstrated that azelaic acid is more effective than placebo at reducing the number of inflammatory lesions and degree of erythema.^25-27 The pooled rates of patients showing marked improvements with azelaic acid treatment were 70-80%, compared with 50-55% in the placebo group.²⁸ Azelaic acid also has a relatively low incidence of adverse effects, with burning, stinging, and irritation being the most commonly reported.²⁶ The incidence of side effects is greater with azelaic acid compared with metronidazole, but these effects are generally mild and transient.²⁹ Although the conventional regimen is twice-daily application of azelaic acid, once-daily dosing has been found to be equally effective.³⁰ Further studies are needed to support the use of azelaic acid as a maintenance therapy.²⁸ It is listed as a pregnancy B category medication.

Tetracyclines

Off-label use of oral antibiotics has been recognized for more than 50 years as an effective treatment for rosacea. Therapeutic benefits of tetracyclines in rosacea are primarily a consequence of their anti-inflammatory rather than antibacterial mechanisms, as there is insufficient evidence to support a bacterial infection in disease pathogenesis.³¹ Tetracycline-family antibiotics should particularly be considered in the presence of ocular rosacea, which typically affects greater than 50% of patients with rosacea. Tetracyclines, which are contraindicated in pregnant women, are the most frequently used class of antibiotics and are most effective against inflammatory papules and pustules.

Second-generation tetracyclines, including minocycline and in particular doxycycline, are especially safe and effective oral therapies for rosacea. Unlike the parent tetracycline, they have greater bioavailability,³² rapid onset of action, and can be taken with food, which minimizes gastrointestinal side effects. Additionally, second-generation tetracyclines only require oncedaily dosing, which may improve compliance. Most importantly, they are effective at a sub-antimicrobial dose, thereby avoiding disruption of the endogenous flora and, of global importance, the propagation of antibacterial resistance.³³

Recently, two Phase 3, multicenter, randomized, double-blinded, placebo-controlled clinical trials³³ demonstrated that a subantimicrobial dose of 40 mg doxycycline administered daily to patients with moderate to severe rosacea significantly reduced total inflammatory papule and pustule counts compared with placebo after 16 weeks of treatment, with significant improvements observed at 3 weeks. Prevalence of adverse effects was low and only marginally higher than placebo, with nasopharyngitis (4.8%), diarrhea (4.4%), and headaches (4.4%) being the most commonly reported. There were no cases of photosensitivity or vaginal candidiasis. A separate study demonstrated that the efficacy of 40 mg doxycycline is comparable to that of 100 mg doxycycline in rosacea.³⁴ Subantimicrobial dose of 40 mg doxycycline is approved in both US and Canada for the treatment of rosacea. In contrast, minocycline is not approved for this indication and has five times greater rates of adverse effects compared with doxycycline, with the most commonly reported being hyperpigmentation, hepatotoxicity, and drug-induced lupus.³⁵

Further study is needed to investigate the effectiveness of combination therapy with sub-antimicrobial dose of doxycycline and topical metronidazole, which has been shown in a small-scale study to induce a faster onset of action and be more effective at clearing inflammatory lesions compared with metronidazole alone.³⁶

New and Emerging Therapies

Topical Ivermectin

Several topical acaricidal agents (permethrin 5%, crotamiton 10%, and ivermectin 1%) have been studied for the treatment of rosacea, all of which primarily target Demodex folliculorum and Demodex brevis mites. The potential etiological role of these mites in rosacea has been debated for many years.⁹ There is renewed interest in Demodex mites due to recent studies that demonstrated antigenic proteins produced by a Demodexisolated bacterium (Bacillus oleronius) may aggravate the inflammatory responses in papulopustular and ocular rosacea,³⁷ as well as in erythematotelangiectatic rosacea.³⁸ This pathogenic scenario implicating the bacterium rather than the Demodex mites themselves may explain the efficacy of antibacterial therapies in rosacea.

Numerous case reports^39-41 have been published on the successful treatment of rosacea with topical acaricidal agents refractory to other therapies, however, data from controlled, randomized trials are lacking. Phase 3 randomized clinical trials studying the impact of topical ivermectin 1% cream in rosacea are underway, which compare its efficacy and safety with metronidazole 0.75% cream and azelaic acid 15% gel.^42-44 Results are expected to be available in the near future.

Topical Brimonidine and Oxymetazoline

Diffuse and persistent facial erythema has long been a clinical challenge in rosacea therapy.⁵ One contributing factor to diffuse facial erythema is abnormal cutaneous vasomotor responses, which leads to enlarged superficial facial blood vessels.⁴⁵ Importantly, however, these blood vessels remain responsive to vasoactive stimuli, hence, the growing interest in alpha (α)-2 adrenergic receptor agonists as a therapeutic option to manage the nontransient erythema.⁴⁵

Brimonidine tartrate 0.33% gel, approved by the US FDA in August 2013 and by Health Canada in February 2014, is the latest addition to the treatment armamentarium and the first topical agent approved for the treatment of facial erythema of rosacea. Brimonidine (initially available in prescription eye drops for the treatment of glaucoma) is a highly selective α-2 adrenergic receptor agonist with potent vasoconstrictive activity.⁴⁶

In two Phase 3 randomized, double-blind pivotal trials, topical brimonidine tartrate (BT) gel 0.5% once-daily was found to be significantly more effective than vehicle over a 4 week treatment period.⁴⁷ In the two trials, approximately 24.82% of the patients using BT gel 0.5% (vs. 9.76%; p<0.05) were assessed on day 29 to have at least a two-grade improvement by both clinicians and patients over 12 hours after drug application, with peak improvements observed at 3 and 6 hours. Noticeable improvement (one-grade based on Clinician’s Erythema Assessment and Patient’s Self-Assessment) was observed (28.2% vs. 5.9%; p<0.01) as early as 30 minutes after the first application on day 1. Adverse events were mildly elevated in the active treatment group, but events were mostly skin-related, transient, and mild, with the most commonly reported being worsening of erythema (5.1%), pruritus (5.0%), skin irritation (1.2%), and worsening of rosacea (1.1%). There was no evidence of tachyphylaxis, rebound, or aggravation of telangiectasia or inflammatory lesions. Additionally, recently published data from a 12-month, multicenter, open-label study reported sustained efficacy with no incidence of tachyphylaxis in the long-term treatment of moderate to severe erythema of rosacea.⁴⁸

Phase 2 clinical trial for another promising α-adrenergic receptor agonist, called oxymetazoline, has recently been completed.⁴⁹ Results should be available in the near future.

Other Therapies

Topical sodium sulfacetamide 10% with sulfur 5% has been used for more than 50 years for its clinical efficacy and safety in the treatment of rosacea, although its mechanism of action is not well understood. In an 8-week study, sulfacetamide 10% with sulfur 5% has been shown to significantly reduce inflammatory lesions (78% vs. 36%; p<0.001) and facial erythema (83% vs. 31%; p<0.001) compared to vehicle.⁵⁰ However, studies evaluating this therapy are limited and generally of poor quality.²⁸

Oral isotretinoin can be used off-label for the treatment of more severe or persistent cases of papulopustular rosacea and may help slow or halt the progression of rhinophyma. In a large scale, randomized, double-blind, 12-week study comparing different doses of isotretinoin to doxycycline and placebo in the treatment of rosacea, isotretinoin 0.3 mg/kg demonstrated non-inferiority to doxycycline (p=0.00001) and was well tolerated.⁵¹ However, isotretinoin should only be prescribed with close monitoring and, particularly in women with childbearing potential, an appropriate contraception strategy is essential due to its teratogenic potential.

Laser and light therapies have been used successfully for many years to treat the vascular manifestations of rosacea. In a randomized, controlled, single-blind, split-face trial, both pulsed dye laser and intense pulse light modalities were found to be effective, with similar efficacy, in reducing erythema and telangiectasia in patients with erythematotelangiectatic rosacea.⁵²

In a double-blind, randomized, vehicle-controlled, 12-week clinical trial,⁵³ off-label use of topical benzoyl peroxide 5% with clindamycin 1% once-daily was shown to be effective in reducing papule and pustule count in patients with rosacea compared to vehicle alone (71.3% vs. 19.3%; p=0.0056). Adverse events were only mildly elevated in the treatment group, with localized burning and itching being the most commonly reported.

Pimecrolimus 1% cream was demonstrated in an open-labeled, uncontrolled, 4-week trial to be effective and well tolerated in the treatment of rosacea.⁵⁴ Adverse events were transient and mild, which included local burning, itching, dryness, and stinging.

Conclusion

There are numerous treatment options available for rosacea, however, only a handful of agents are substantiated with quality research. If available, therapeutic decision-making should be guided by high-level evidence and patient-specific factors, such as rosacea subtype, severity, treatment expectations, tolerance, cost, and previous response to therapy. Topical azelaic acid and metronidazole are considered safe and efficacious first-line therapies. Sub-antimicrobial dose of doxycycline is the best research-supported oral therapeutic option and can be used to treat moderate to severe forms of papulopustular or ocular rosacea, or in patients who may be more adherent on a systemic regimen. Low-dose isotretinoin or surgical interventions may be indicated for the phymatous type. Light and laser-based therapies can play a major clinical role in the treatment of the telangiectatic component. The novel therapy, brimonidine, provides targeted treatment of facial diffuse erythema of rosacea. A comprehensive treatment plan must also incorporate non-drug strategies aimed at quality of life improvements and include trigger avoidance, proper daily skin care, camouflaging and photoprotection. Further research is needed on the effectiveness of combination treatments, isotretinoin, sulfacetamide, light-based options, and newly emergent agents compared with conventional therapies.

References

1. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41; quiz 42-4.
2. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005 Feb 24;352(8):793- 803.
3. Wilkin J, Dahl M, Detmar M, et al. Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2004 Jun;50(6):907-12.
4. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002 Apr;46(4):584-7.
5. Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol Venereol. 2005 May;19(3):273-85.
6. Jansen T, Plewig G. Rosacea: classification and treatment. J R Soc Med. 1997 Mar;90(3):144-50.
7. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1):S27-35.
8. Gallo R, Drago F, Paolino S, et al. Rosacea treatments: What’s new and what’s on the horizon? Am J Clin Dermatol. 2010;11(5):299-303.
9. Layton A, Thiboutot D. Emerging therapies in rosacea. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1):S57-65.
10. Aksoy B, Altaykan-Hapa A, Egemen D, et al. The impact of rosacea on quality of life: effects of demographic and clinical characteristics and various treatment modalities. Br J Dermatol. 2010 Oct;163(4):719-25.
11. Wolf JE, Jr., Del Rosso JQ. The CLEAR trial: results of a large community-based study of metronidazole gel in rosacea. Cutis. 2007 Jan;79(1):73-80.
12. Gooderham M. Rosacea and its topical management. Skin Therapy Lett. 2009 Feb;14(2):1-3.
13. Nielsen PG. Treatment of rosacea with i% metronidazole cream. A doubleblind study. Br J Dermatol. 1983 Mar;108(3):327-32.
14. Narayanan S, Hunerbein A, Getie M, et al. Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system. J Pharm Pharmacol. 2007 Aug;59(8):1125-30.
15. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintains remissions of rosacea. Arch Dermatol. 1998 Jun;134(6):679-83.
16. Breneman DL, Stewart D, Hevia O, et al. A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea. Cutis. 1998 Jan;61(1):44-7.
17. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol. 1987 May;123(5):609-14.
18. Rowe-Jones DC, Peel AL, Kingston RD, et al. Single dose cefotaxime plus metronidazole versus three dose cefuroxime plus metronidazole as prophylaxis against wound infection in colorectal surgery: multicentre prospective randomised study. BMJ. 1990 Jan 6;300(6716):18-22.
19. Yoo J, Reid DC, Kimball AB. Metronidazole in the treatment of rosacea: do formulation, dosing, and concentration matter? J Drugs Dermatol. 2006 Apr;5(4):317-9.
20. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999 Jun;40(6 Pt 1):961-5.
21. Dahl MV, Jarratt M, Kaplan D, et al. Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea. J Am Acad Dermatol. 2001 Nov;45(5):723-30.
22. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial. J Am Acad Dermatol. 1998 Sep;39(3):502-4.
23. Tan JK, Girard C, Krol A, et al. Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. J Cutan Med Surg. 2002 Nov-Dec;6(6):529-34.
24. Fitton A, Goa KL. Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs. 1991 May;41(5):780-98.
25. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003 Jun;48(6):836-45.
26. Carmichael AJ, Marks R, Graupe KA, et al. Topical azelaic acid in the treatment of rosacea. J Dermatolog Treat. 1993;4(suppl):S19-S22.
27. Bjerke R, Fyrand O, Graupe K. Double-blind comparison of azelaic acid 20% cream and its vehicle in treatment of papulo-pustular rosacea. Acta Derm Venereol. 1999 Nov;79(6):456-9.
28. van Zuuren EJ, Kramer S, Carter B, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2011(3):CD003262.
29. Colon LE, Johnson LA, Gottschalk RW. Cumulative irritation potential among metronidazole gel 1%, metronidazole gel 0.75%, and azelaic acid gel 15%. Cutis. 2007 Apr;79(4):317-21.
30. Thiboutot DM, Fleischer AB, Jr., Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008 Jun;7(6):541-6.
31. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004 Oct;51(4):499-512; quiz 3-4.
32. Maibach H. Second-generation tetracyclines, a dermatologic overview: clinical uses and pharmacology. Cutis. 1991 Nov;48(5):411-7.
33. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007 May;56(5):791-802.
34. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008 Jun;7(6):573-6.
35. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005 Sep;27(9):1329-42.
36. Sanchez J, Somolinos AL, Almodovar PI, et al. A randomized, double-blind, placebo-controlled trial of the combined effect of doxycycline hyclate 20-mg tablets and metronidazole 0.75% topical lotion in the treatment of rosacea. J Am Acad Dermatol. 2005 Nov;53(5):791-7.
37. Lacey N, Delaney S, Kavanagh K, et al. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007 Sep;157(3): 474-81.
38. O’Reilly N, Menezes N, Kavanagh K. Positive correlation between serum immunoreactivity to Demodex-associated Bacillus proteins and erythematotelangiectatic rosacea. Br J Dermatol. 2012 Nov;167(5):1032-6.
39. Allen KJ, Davis CL, Billings SD, et al. Recalcitrant papulopustular rosacea in an immunocompetent patient responding to combination therapy with oral ivermectin and topical permethrin. Cutis. 2007 Aug;80(2):149-51.
40. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999 Nov;41(5 Pt 1):775-7.
41. Karincaoglu Y, Bayram N, Aycan O, et al. The clinical importance of demodex folliculorum presenting with nonspecific facial signs and symptoms. J Dermatol. 2004 Aug;31(8):618-26.
42. Galderma. Randomized, double-blind, parallel-group, vehicle-controlled, dose-finding study investigating the pharmacodynamics and safety of three concentrations of CD07805/47 topical gel (0.07%, 0.18%, and 0.50%), applied in subjects with moderate to severe erythematotelangiectatic rosacea. In: ClinicalTrials.gov, Identifier: NCT00989014. Last updated September 19, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT00989014. Accessed: March 9, 2014.
43. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded extension comparing the long term safety of CD5024 1% cream versus azelaic Acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01493687. Last updated January 27, 2014. Available at: http://clinicaltrials.gov/ct2/show/NCT01493687?term=NCT01493687&rank=1. Accessed: March 10, 2014.
44. Galderma. Efficacy and safety of CD5024 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea over 16 weeks treatment, followed by a 36-week extension period (ATTRACT).In: ClinicalTrials.gov, Identifier: NCT01493947. Last updated December 20, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT01493947?term=NCT01493947&rank=1. Accessed: March 9, 2014.
45. Del Rosso JQ. Advances in understanding and managing rosacea: part 2: the central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea. J Clin Aesthet Dermatol. 2012 Mar;5(3):26-36.
46. Rahman MQ, Ramaesh K, Montgomery DM. Brimonidine for glaucoma. Expert Opin Drug Saf. 2010 May;9(3):483-91.
47. Fowler J, Jr., Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehiclecontrolled pivotal studies. J Drugs Dermatol. 2013 Jun 1;12(6):650-6.
48. Moore A, Kempers S, Murakawa G, et al. Long-term safety and efficacy of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of a 1-year open-label study. J Drugs Dermatol. 2014 Jan;13(1):56-61.
49. Allergan. Safety and tolerability of AGN-199201 in patients with erythema associated with rosacea. In: Clinical Trials.gov, Identifier: NCT01579084. Last updated September 12, 2013. Available at: http://clinicaltrials.gov/ct2/show/NCT01579084?term=NCT01579084&rank=1. Accessed: March 10, 2014.
50. Sauder DN, Miller R, Gratton D, et al. The treatment of rosacea: the safety and efficacy of sodium sulfacetamide 10% and sulfur 5% lotion (Novacet) is demonstrated in a double-blind study. J Dermatolog Treat. 1997;8(2):79-85.
51. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea – doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010 Jul;8(7):505-15.
52. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009 Jun;35(6):920-8.
53. Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehiclecontrolled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol. 2004 May;43(5):381-7.
54. Kim MB, Kim GW, Park HJ, et al. Pimecrolimus 1% cream for the treatment of rosacea. J Dermatol. 2011 Dec;38(12):1135-9.

¹Faculty of Medicine, University of Alberta, Edmonton, AB
²Division of Dermatology and Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB
³Toronto Dermatology Centre, Toronto, ON

Introduction

Rosacea is a common, chronic cutaneous condition that affects the face. Several topical medications are currently approved for the treatment of rosacea, including azelaic acid and metronidazole. Systemic therapy utilizing a sub-antimicrobial dose of doxycycline is also effective in treating rosacea. Identification of subtypes can help guide treatment strategies. Psychosocial implications of rosacea must be considered and conservative management, such as skin care, must form an important part of the overall care. Recently, new insights into the pathophysiology of rosacea have led to the emergence of etiologically oriented treatments, including the newly approved brimonidine gel 0.33% (Onreltea™).

Background

• Rosacea is a common chronic cutaneous condition that primarily affects the central facial area, including the cheeks, nose, eyes, chin and forehead.¹
• Primary cutaneous manifestations include sensitive skin, flushing, persistent erythema, papules, pustules and telangiectases.
• Although symptoms may wax and wane in the short-term, rosacea is slowly progressive in the long-term for many patients.²
• The National Rosacea Society has classified rosacea into four main subtypes: ³
  1. Erythematotelangiectatic
  2. Papulopustular
  3. Phymatous
  4. Ocular
• Progression from one subtype to another is possible.⁴ Proper identification of subtypes may help guide therapeutic strategies.
• Rosacea affects up to 10% of the general population and the onset is typically between the ages of 30 and 50 years.⁵
• It is especially common in light-skinned individuals of northern European descent, with women more frequently affected.^5,6 However, men are more prone to develop thickening and distorting phymatous skin changes, especially of the nose.
• While rosacea was considered rare in people of colour, a recent increase in case reports documenting rosacea in patients with Fitzpatrick Skin Types IV-VI, suggests that it is more common in darker skinned individuals than previously thought, and may have been under-recognized and unreported in the dermatology literature.^7,8
• Rosacea pathophysiology is multifactorial and currently not fully understood. Factors proposed to play a role include vascular abnormalities, gastrointestinal disorders, matrix degeneration, pilosebaceous gland abnormalities, microbial activity, and altered innate immune response.^9,10
• Rosacea can create psychosocial burdens, such as embarrassment, anxiety and low self-esteem, and adversely affect quality-of-life, which should be taken into consideration when treating these patients.^11,12 Conservative measures, such as trigger avoidance, proper skin care, camouflaging cosmetics, and photo-protection should also be incorporated into the management plan.¹³

Conventional Therapies

Topical Metronidazole

• Metronidazole (Noritate® 1% Cream, Dermik; MetroGel 1%, Metrocream™ 0.75% Cream, Metrolotion® 0.75% Lotion, Metrogel® 0.75% gel), first demonstrated efficacy against rosacea in the 1980s.¹⁴
• Despite being an antibacterial and antiprotozoal agent, metronidazole confers its therapeutic efficacy mostly through its anti-inflammatory and antioxidant effects.¹⁵
• Multiple trials have demonstrated that topical metronidazole significantly decreases the number of inflammatory lesions and reduces erythema compared to placebo; is generally well tolerated; has a low incidence of adverse effects; and is effective in maintaining remission.^16-19
• Importantly, different formulations of metronidazole have demonstrated similar efficacy, regardless of vehicle type (cream, gel, or lotion) or concentration (0.75% or 1%).^20,22
• Once- and twice-daily applications have similar efficacy.^20,23
• Metronidazole 1% has demonstrated less cumulative potential for irritation over a 21-day period, (similar to that of white petrolatum) compared with metronidazole gel 0.75%.²⁴
• When combined with sunscreen SPF 15, metronidazole may reduce development of facial telangiectasia.²⁵
• Topical metronidazole is a pregnancy category B medication.

Topical Azelaic Acid

• Azelaic acid (Finacea®) is a naturally occurring dicarboxylic acid approved in the last decade for the treatment of mild to moderate rosacea.²⁶
• Mostly applied as a 15% gel or a 20% cream, azelaic acid has anti-inflammatory, antikeratinizing, and antibacterial effects.²⁶
• Multiple trials have demonstrated that azelaic acid is more effective than placebo at reducing the number of inflammatory lesions and degree of erythema.^27-29 The pooled rates of patients showing marked improvements with azelaic acid treatment were 70-80%, compared to 50-55% with placebo.³⁰
• Azelaic acid also has a relatively low incidence of adverse effects, with burning, stinging and irritation being the most commonly reported.²⁸ However, data from Colon et al, show that azelaic acid gel 15% caused significantly more irritation than white petrolatum when administered over a 21-day period, as well as both concentrations of metronidazole (p<.0001 for all comparisons).²⁴
• Although the conventional regimen is twice-daily application, once-daily dosing has been found to be equally effective.³¹
• Further studies are needed to support the use of azelaic acid as a maintenance therapy.³⁰
• It is currently a pregnancy B category medication.

Tetracycline

• While not indicated for the treatment of rosacea, oral antibiotics have been recognized for the past 50 years as an effective treatment and are thought to exert their therapeutic effects primarily via anti-inflammatory rather than antibacterial mechanisms.³²
• Because the role of micro-organisms in rosacea pathogenesis remains unclear, the use of antibiotics at standard doses is not an ideal approach.
• However, the tetracycline-family of antibiotics is effective in treating ocular rosacea, which typically affects greater than 50% of patients with rosacea.
• Tetracyclines are the most frequently used class of antibiotics with greatest efficacy against inflammatory papules and pustules.
• Tetracyclines are contraindicated in pregnant women.
• Second-generation tetracyclines, including minocycline and in particular doxycycline, are especially safe and effective oral therapies for rosacea.
• Unlike the parent, second generation tetracyclines have greater bioavailability, rapid onset of action, and can be taken with food, which minimizes gastrointestinal side effects.³³
• Second-generation tetracyclines require once-daily dosage, which may improve compliance.
• Most importantly, they are effective at a sub-antimicrobial dose, which avoids disruption of the endogenous flora and, of global importance, the propagation of antibacterial resistance.³⁴
• Recently, two phase 3, multicenter, randomized, doubleblind, placebo-controlled clinical trials demonstrated that a daily sub-antimicrobial dose of 40 mg doxycycline (Apprilon™), administered to patients with moderate to severe rosacea, significantly reduced total inflammatory papule and pustule counts compared with placebo after 16-weeks treatment, with significant improvements evident at 3 weeks.³⁴
• Prevalence of adverse effects was low and only marginally higher than placebo, with nasopharyngitis (4.8%), diarrhea (4.4%) and headaches (4.4%) being the most commonly reported.
• No cases of photosensitivity or vaginal candidiasis occurred.
• A separate study demonstrated that the effectiveness of 40 mg doxycycline is comparable to that of 100 mg doxycycline in rosacea but with a lower incidence of gastrointestinal side effects.³⁵

New Therapies

Brimonidine

• Diffuse facial erythema has long posed an unmet need in rosacea management.⁵
• One contributing factor is abnormal cutaneous vasomotor responses, which leads to persistently enlarged facial blood vessels.³⁶ These blood vessels remain responsive to vasoactive stimuli, hence the growing interest in α2-adrenergic receptor agonists as a possible therapeutic option.³⁶
• Brimonidine 0.33% gel (Mirvaso™), approved by FDA in August 2013, is the latest addition to the therapeutic armamentarium and the first topical agent approved for the treatment of facial erythema of rosacea. This formulation was recently approved by Health Canada with the trade name Onreltea®, for the topical treatment of facial erythema of rosacea in adults 18 years of age or older.¹² (*Notethe literature refers to both brimonidine gel 0.33% and brimonidine tartrate gel 0.5%. This is the same product and the terms are interchangeable.)
• Brimonidine is a highly selective α2-adrenergic receptor agonist with potent vasoconstrictive activity and is also found in prescription eye drops for the treatment of glaucoma.³⁷
• In two phase 3 randomized, double-blind pivotal trials, topical brimonidine tartrate gel 0.5% once daily was significantly more effective than vehicle over a 4-week treatment period.³⁸ In the two trials, approximately 24.82% of the patients using brimonidine tartrate gel 0.5% versus (vs.) 9.76%; p<0.05) on day 29 were assessed to have at least a two-grade improvement by both clinicians and patients over 12 hours after drug application, with peak improvements observed at 3 and 6 hours (Fig. 1 and 2).
• Noticeable improvement (one-grade Clinician’s Erythema Assessment and 5 point Patient Self Assessessment Scale) was observed (28.2% vs. 5.9%; p<0.01) as early as 30 minutes after the first application on day one.
• Adverse events were mildly elevated in the treatment group but were largely cutaneous, transient and mild, with the most commonly reported being worsening of erythema (5.1%), pruritus (5.0%), skin irritation (1.2%), and rosacea (1.1%).
• There was no evidence of tachyphylaxis, rebound, or aggravation of telangiectasia or inflammatory lesions.
• Data from a 12-month, multi-center, open-label study also show no incidence of tachyphylaxis, with efficacy maintained over the long-term.³⁹

Figure 1: Baseline

Figure 2: 3 hours post-Brimonidine treatment

Other Therapies

• Topical sodium sulfacetamide 10% with sulfur 5% has been used for over 50 years for its clinical efficacy and safety in the treatment of rosacea, although its mechanism of action is not well understood.
• In an 8-week study, sulfacetamide 10% with sulfur 5% has been shown to significantly reduce inflammatory lesions (78% vs. 36%; p<0.001) and facial erythema (83% vs. 31%; p<0.001) compared to vehicle.^4,40 Studies evaluating this therapy, however, are limited and generally of poor quality.³⁰
• Laser and light therapies have been used successfully for many years to treat the vascular manifestations of rosacea.
• In a randomized, controlled, single-blind, split-face trial, both pulsed dye laser and intense pulse light were found to be effective, with similar efficacy in reducing erythema and telangiectasia in patients with erythematotelangiectatic rosacea.⁴¹

Conclusion

Therapeutic decision-making in the treatment of rosacea should be guided by high-level evidence, where available, and will depend on subtype, severity, patient expectations, tolerance, budget and previous therapy used. Topical azelaic acid and metronidazole are considered safe and efficacious first-line therapies. A sub-antimicrobial dose of doxycycline is the best research-supported oral therapeutic indicated for the treatment of rosacea and provides a safe and convenient option for patients who prefer oral to topical therapy. Light and laserbased therapies play a major clinical role in the treatment of the telangiectatic component. The promising novel therapy, brimonidine, fills a much-needed niche in the targeted treatment of facial diffuse erythema of rosacea.

References

1. Crawford GH, et al. J. Am Acad Dermatol. 2004:(51); 327-341; quiz 342-324,
   doi:10.1016/j.jaad.2004.03.030.
2. Powell FC, N Eng J Med. 2005;(352):793-803.
3. Wilkin J, et al. J Am Acad Dermatol. 2004;(50):907-912.
4. Wilkin J, et al. J Am Acad Dermatol. 2002;(46):584-587.
5. Gupta AK, et al. J Eur Acad Dermatol Venereol. 2005;(19):273-285.
6. Jansen T, et al. J R Soc Med. 1997;(90):144-150.
7. Jayawant SS, et al. J Dermatol Treatment. 2008;(19):267-273.
8. Sanchez J, et al. J Am Acad Dermatol. 2005;(53):791-797.
9. Gallo R, et al. Am J Clin Dermatol. 2010;(11):99-303.
10. Layton A, et al. J. Am. Acad. Dermato. 2013;(69):S57-65.
11. Aksoy B, et al. Br J Dermatol. 2010;(163):719-725.
12. Wolf JE, Jr. et al. Cutis. 2007;(79):73-80.
13. Gooderham M, Skin therapy letter. 2009;(14):1-3.
14. Nielsen PG, Br J Dermatol. 1983;(108):327-332.
15. Narayanan S, et al. JPharm Pharmacol. 2007;(59):1125-1130.
16. Dahl MV, et al. Arch Dermatology. 1988;(134):679-683.
17. Breneman DL, et al. Cutis. 1988;(61):44-47.
18. Bleicher PA, et al. Arch. Dermatol. 1987;(123):609-614.
19. Rowe-Jones DC, et al. BMJ. 2009;(300):18-22.
20. Yoo J, et al. J Drugs Dermatol. 2006; (5):317-319.
21. Maddin SA. J Am Acad Dermatol. 1999; (40):961-965.
22. Dahl M V, et al. J Am Acad Dermatol. 2001;(45):723-730.
23. Jorizzo J L, et al. J. Am Acad Dermatol. 1998;(39):502-504.
24. Colon L E, et al. Cutis. 2007;79:317-321.
25. Tan JK, et al. J Cutan Med Surg. 2002;(6):529-534.
26. Fitton A, et al. Drugs. 1991;(41):780-798.
27. Thiboutot D, et al. J Am Acad Dermatol. 2003;(48):836-845.
28. Carmichael AJ, et al. J. Dermatol Treat. 1993;(4):S19-S22.
29. Bjerke R, et al. Acta dermato-venereologica. 1999;(79):456-459.
30. van Zuuren EJ, et al. 2011. The Cochrane database of systematic reviews, CD003262, doi:10.1002/14651858.CD003262.pub4.0
31. Thiboutot DM, et al. J Drugs Dermatol. 2008; (7):541-546.
32. Pelle MT, et al. J Am Acad Dermatol. 2004;(51):499-512.
33. Maibach H. Cutis. 1991;(48):411-417.
34. Del Rosso JQ, et al. J Am Acad Dermatol. 2007;(56):791-802.
35. Del Rosso JQ, et al. J Drugs Dermatol. 2008;(7):573-576.
36. Del Rosso JQ. J Clin Aesthet Dermatol. 2012;(5):26-36.
37. Rahman MQ, et al. Expert Opin Drug Saf. 2010;(9):483-491.
38. Fowler J Jr, et al. J Drugs Dermatol. 2012;(12):650-656.
39. Moore A, et al. J Drugs Dermatol. 2014;13(1):56-61.
40. Sauder DN, et al. J Dermatol Treat. 1997;(8):79-85.
41. Neuhaus IM,et al. Dermatol Surg. 2009;(35):920-928.

¹Faculty of Medicine, University of Alberta, Edmonton, AB
²Division of Dermatology & Cutaneous Sciences, Department of Medicine, University of Alberta, Edmonton, AB
³Toronto Dermatology Centre, Toronto, ON

Introduction

Actinic keratosis (AK) is a prevalent skin condition that warrants 5.2 million office visits in the US each year.¹ Strongly associated with ultraviolet (UV) exposure, AK is widely regarded as a premalignant condition that can progress to squamous cell carcinoma (SCC).^2-8 Data regarding the risk of progression to malignant disease ranges from 0.025% to 16% per year.⁷ Prevalence of AK has been reported to be as high as 38% and 46% in certain Dutch and Australian communities respectively.^9,10 Given the prevalence and risk of progression to invasive disease, general consensus is that treatment and prevention^11-14 of AK in a timely manner is important in reducing the incidence of non-melanoma skin cancer. Studies have shown that a large proportion of SCC lesions arise from pre-existing AK.^4,5,15

Presentation & Diagnosis of AK

• AK is characterized by abnormal proliferation of keratinocytes that have large and variably shaped nuclei, found in the basal cell layer of the epidermis.¹²
• It typically presents as pink-red dry, rough, scaly papules or plaques measuring a few millimetres in diameter to no larger than 1 cm.^12,16
• Lesions can sometimes be sensitive.
• AK is found more commonly on areas of the body exposed to the sun, such as the face, upper chest, and dorsal surface of the arms and hands.¹²
• Diagnosis is typically made on a clinical basis but one study demonstrated high sensitivity and specificity (95.6% and 95% respectively) with use of dermoscopy.¹¹
• The differential diagnosis for AK includes SCC, Bowen’s disease, basal cell carcinoma (BCC), and lentigo maligna melanoma.¹²
• Many risk factors have been linked to the development of AK, most notably sun exposure, fair skin, male gender, and older age.^9,17-19
• UV radiation from the sun is damaging to skin DNA and has been directly implicated in the pathogenesis of AK.
• UV radiation hampers the natural immune response and increases immunosuppression, ultimately increasing the risk of SCC.²⁰ Therefore, sunscreen use as well as clothing, hats and sunglasses have long been encouraged as a preventative measure against AK.¹⁴

Overview of Treatment Options

Treatment for AK can be divided into two categories:

1. Targeted (local) therapy
2. Field therapy

Targeted Therapy

• Examples of targeted treatment include cryotherapy with liquid nitrogen and curettage with electrodessication.
• One limitation is that only a small number of lesions can be treated at once.
• Additionally, because subclinical changes can occur to the DNA of skin (also known as field cancerization²⁰), targeted therapy is not ideal for extensive UV-damaged skin.²

Field Therapy

• Field therapy can address both clinically apparent as well as occult disease.
• It encompasses topical treatments such as 5-fluorouracil, imiquimod, ingenol mebutate, and diclofenac sodium gel.
• Although many of the field therapies have been shown to be highly efficacious, targeted therapy (specifically cryosurgery) continues to be the mainstay first-line treatment for AK.
• There is a growing literature to show that a combination of targeted and field therapy has an advantage over either of the therapies as standalone.¹²

Local Treatments

Cryotherapy Treatment Regimen:

1. One freeze-thaw cycle, 5-15 seconds, and 1mm margin.²¹

Overview

• Cryotherapy is a widely used treatment option that involves cold temperature to physically destroy cells of skin lesions.
• It is one of the most commonly used treatments for AK.22,23
• Liquid nitrogen is sprayed onto the lesion, bringing the skin to a temperature where cell death occurs. Early studies suggested that temperatures of -30°C to -40°C were needed to kill keratinocytes.²¹ However, more recent studies have demonstrated good clearance with a temperature of -5°C.²⁴
• Cryotherapy has been shown to be both highly efficacious and tolerable but the range of clearance rates varies significantly (39-100%^24,25). Another study demonstrated a complete clearance rate of 75% at 3 months.²⁶
• The duration of freezing likely has an effect on the response to treatment.²⁵
• Side effects include hypopigmentation, erythema, crusting, blistering, and ulceration.²⁴
• As a stand-alone therapy, cryotherapy is better suited for disease that involves only a small number of lesions. When combined sequentially with a field-directed treatment, AK lesion clearance increases and recurrence diminishes.^27-30

Curettage with Electrodessication

• Curettage and electrodessication involve the scraping down of an AK lesion followed by electrocautery
• This procedure is often reserved for hypertrophic AK and has the potential for scarring.³¹
• Curettage can also be performed on hypertrophic lesions prior to administration of a field-therapy such as photodynamic therapy, which is better suited for superficial lesions.

Field-Directed Treatments

Imiquimod Treatment Regimens:

1. Imiquimod 5% cream (Aldara®): Treatment should be limited to areas ≤25 cm² ; apply twice weekly for 16 weeks. Apply at bed-time and leave on skin for approximately 8 hours, then remove with soap and water.
2. Imiquimod 3.75% cream (Zyclara®): Treatment is indicated for a surface area of up to 200 cm².³² Apply once daily for 2 weeks, then 2 weeks off, then daily for 2 more weeks. Apply at bed-time and leave on skin for approximately 8 hours, then remove with soap and water. Treatment holidays of several days are possible with this formulation, allowing for the management of any possible skin reactions.
3. Imiquimod 3.75% solution is also available in a pump formulation for easier dispensing and improved adherence.

Overview

• Imiquimod is an immunomodulator that has been shown to stimulate immune function by inducing cytokine expression, particularly interferon-α (IFN-α), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α).³³ Consequently, this topical agent exhibits both antitumor and antiviral effects.
• Imiquimod 5% cream was initially approved for use in Human papillomavirus genital warts in Canada in 1999, and was approved for treatment of AK in 2004.
• Numerous studies have shown that imiquimod is both efficacious and tolerable.^34-37
• Results from two randomized control trials demonstrated a mean initial reduction of AK lesions of 83%.³⁷
• Because AK lesions have a high recurrence rate, researchers have also performed longitudinal studies to look at sustained clearance rates. One study demonstrated that imiquimod has both a high initial clearance rate (85%) as well as sustained clearance rate at 1 year (73%).³⁶
• Several studies also show added benefit when imiquimod is combined with another therapy. When preceded by phototherapy, better clinical as well as histological outcomes are achieved.³⁶
• Additionally, imiquimod combined with cryotherapy is more effective in treating hypertrophic AK compared to cryotherapy alone.²⁸
• Common side effects of imiquimod therapy include erythema, crusting and dryness.³⁷
• Patients receiving imiquimod are generally satisfied with the outcome.³⁵

5-Fluorouracil Treatment Regimens:

1. Efudex®: apply to lesions twice daily for 2-4 weeks; complete healing may not be evident for 1-2 months following treatment.
2. Fluoroplex®: apply to lesions twice daily for 2-6 weeks.

Overview

• 5-fluorouracil (5FU) is an antimetabolite drug used as chemotherapy for treatment of colorectal cancer.³⁹
• 5FU is taken up by cells as if it were uracil. Its active metabolites are subsequently incorporated into DNA and RNA, thereby disrupting replication and causing cell destruction.
• Besides its role in cancer treatment, 5FU has been used for many years in treating dermatological conditions, including AK, warts, keratoacanthoma, and SCC.⁴⁰
• 5FU has been shown to significantly reduce AK lesions initially but is less effective in long-term clearance. One study found that 5FU resulted in a reduction of AK lesions by 83% and a sustained clearance rate of 53% after one month.⁴¹ Another study showed a very high initial clearance rate (96%) but much lower sustained clearance rate (54%) at one year follow-up.³⁸
• Like other field therapies, 5FU is more effective and results in lower recurrence rates when combined with targeted therapy such as cryotherapy.²⁷
• Common nuisance side effects include erythema, burning, and eye irritation.⁴¹ Despite these side effects, discontinuation rates are low.⁴²

Ingenol Mebutate Treatment Regimens:⁴²

1. Ingenol mebutate gel (Picato®) 0.015% for face and scalp: apply to affected area once daily for 3 consecutive days.
2. Ingenol mebutate gel (Picato®) 0.05% for trunk and extremities: apply to affected area once daily for 2 consecutive days.

Overview

• Ingenol mebutate is indicated for a 25 cm² contiguous field.⁴⁷
• Ingenol mebutate is the naturally occurring active substance found in the sap of Euphorbia peplus. This plant has been used for many decades in Australia as a natural remedy for AK, and early subjective reports on its use indicate good outcomes.⁴⁴
• Ingenol mebutate is the newest field therapy. The short duration of application lasting 2 or 3 days is appealing, however patient response can be brisk and may last for 2 weeks, although it typically peaks at day 4.^44,46
• The quick action of ingenol mebutate is thought to arise because of two simultaneous mechanisms of action: direct cytotoxicity leading to cell death and activation of a neutrophil-mediated inflammatory response.⁴⁶
• Results of two phase II and III trials have demonstrated promise.^45,47,48 Pooled analysis of the two phase III trials show a complete clearance of 42% on the face and scalp and 34% on the trunk and extremities. In a long-term follow-up study at 1 year, lesion clearance rates were approximately 87% for the face, scalp, trunk or extremities.⁴⁹ Further lesions either developed or recurred in the treated field in 53.9% of patients. Skin reactions of up to 2 weeks were generally mild to moderate, and the most common side effects were erythema, dryness, and flaking.⁴⁷

Diclofenac Sodium 3% Gel Treatment Regimen:

1. Diclofenac sodium 3% (Solaraze® gel): apply to affected area twice daily for 60-90 days.

Overview

• Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) widely used for its analgesic properties.
• It is a non-selective cyclooxygenase (COX) inhibitor which also exhibits antitumor effects, given that COX-2 has been implicated in keratinocyte proliferation.^50,51
• Diclofenac has also been shown to induce apoptosis via death receptor signalling.⁵²
• A number of studies have demonstrated that diclofenac is a well-tolerated and effective field therapy for AK.^53-55
• One study showed no difference in efficacy between topical diclofenac 3% sodium and imiquimod 5%.⁵³
• Another study comparing diclofenac with imiquimod demonstrated similar clearance rates between the two drugs but recurrence occurred quicker following diclofenac treatment.⁵⁴
• As is the case with other field therapy options, diclofenac used sequentially with cryotherapy increases clearance rates as well as decreases recurrence rates.^29,30
• Side effects are usually tolerable and may include dryness, itchiness and erythema.^53,55

Photodynamic Therapy (PDT)

Treatment procedure:

1. Prior to PDT: curettage of hypertrophic AK or acetone scrubs or microdermabrasion.
2. Apply methyl-aminolevulinate (MAL) (Metvix®) or 5-aminolevulinic acid (ALA), 1mm thick, 10-15mm margins.
3. Allow 1-3 hours for MAL/ALA to penetrate.
4. Remove MAL / ALA.
5. Illuminate with blue or red light emitting diode, or use other laser/light sources or even daylight activation for MAL.

Overview

• PDT uses a combination of a topical photosensitizer, such as ALA or MAL, and a light source to treat AK lesions. These photosensitizers are converted to protoporphyrin IX (PpIX), which then induce apoptosis and necrosis.^56,57
• PDT has been shown to be similar in efficacy to cryotherapy.⁵⁸
• One of the drawbacks of PDT is that its use is limited to superficial lesions and is less effective in hypertrophic AK.⁵⁹
• The most common side effects are erythema, edema and crusting.⁶⁰
• The procedure can be painful for patients, but spraying cold water on the treatment site has been shown to improve tolerability.⁵⁶ Otherwise, PDT is quite well tolerated and results in good cosmetic outcome with minimal downtime.

Conclusion

AK is a premalignant skin condition that should be identified and treated promptly. Untreated AKs can lead to SCC. There are many treatment options that all have comparable efficacy. Cryosurgery is often first-line therapy for disease with a small number of lesions. Field-directed therapy is recommended when the skin is extensively photodamaged or there are many AK lesions or frequent AK recurrences. Combining a local treatment such as cryotherapy with a topical agent has been shown to be more effective than either therapy alone.

References

1. Warino L, et al. Dermatol Surg. 2006;32(8):1045-1049.
2. Berman B, et al. J Fam Pract. 2006;55(5):su.
3. Criscione VD, et al. Cancer. 2009;115(11):2523-2530.
4. Mittelbronn MA, et al. Int J Dermatol. 1998;37(9):677-681.
5. Guenthner ST, et al. J Am Acad Dermatol. 1999;41(3 Pt 1):443-448.
6. Traianou A, et al. Br J Dermatol. 2012;167(Suppl 2):36-42.
7. Glogau RG. J Am Acad Dermatol. 2000;42(1 Pt 2):23-24.
8. Werner RN, et al. Br J Dermatol. 2013;169(3):502-518.
9. Flohil SC, et al. J Invest Dermatol. 2013;133(8):1971-1978.
10. Frost C, et al. J Invest Dermatol. 2000;115(2):273-277.
11. Rigel DS, et al. 2013;68(1 Suppl 1):S20-27.
12. Stockfleth E, et al. Eur J Dermatol.2006;16(6):599-606.
13. Rosen T, et al. J Am Acad Dermatol. 2013;68(1 Suppl 1):S2-9.
14. Thompson SC, et al. N Engl J Med. 1993;329(16):1147-1151.
15. Dinehart SM, et al. Cancer. 1997;79(5):920-923.
16. Frost CA, et al. Br J Dermatol. 1994;131(4):455-464.
17. Lebwohl M. Br J Dermatol. 2003;149 Suppl 66:31-33.
18. Memon AA, et al. Br J Dermatol. 2000;142(6):1154-1159.
19. Armstrong BK, et al. J Photochem Photobiol B. 2001;63(1-3):8-18.
20. Vatve M, et al. Br J Dermatol. 2007;157(Suppl 2):21-24.
21. Sinclair RD, et al. Australas J Dermatol. 1995;36(3):133-142.
22. Freeman M, et al. J Dermatol Treat. 2003;14(2):99-106.
23. Jorizzo JL. J Cutan Med Surg. 2004;8(Suppl 3):13-21.
24. Goldberg LH, et al. Dermatol Surg. 2010;36(12):1956-1961.
25. Thai KE, et al. Int J Dermatol. 2004;43(9):687-692.
26. Szeimies RM, et al. J Am Acad Dermatol. 2002;47(2):258-262..
27. Jorizzo J, et al. Arch Dermatol. 2004;140(7):813-816.
28. Goldenberg G, et al. J Clin Aesthet Dermatol. 2013;6(2):36-43.
29. Berlin JM, et al. J Drugs Dermatol. 2008;7(7):669-673.
30. Mastrolonardo M. Clin Exp Dermatol. 2009;34(1):33-35.
31. Ceilley RI, et al. J Am Acad Dermatol. 2013;68(1 Suppl 1):S28-38.
32. Stockfleth E. J Drugs Dermatol. 2012; 11(12): 1462-1467
33. Sauder DN. J Am Acad Dermatol. 2000;43(1 Pt 2):S6-11.
34. Gupta AK, et al. J Cutan Med Surg. 2005;9(5):209-214.
35. Serra-Guillen C, et al. Br J Dermatol. 2011;164(2):429-433.
36. Serra-Guillen C, et al. J Am Acad Dermatol. 2012;66(4):e131-7.
37. Lebwohl M, et al. J Am Acad Dermatol. 2004;50(5):714-721.
38. Krawtchenko N, et al. Br J Dermatol. 2007;157 Suppl 2:34-40.
39. Longley DB, et al. Nat Rev Cancer. 2003;3(5):330-338.
40. Moore AY. J Dermatolog Treat. 2009;20(6):328-335.
41. Gupta AK, et al. Skin Therapy Lett. 2001;6(9):1-4.
42. Stough D, et al. J Clin Aesthet Dermatol. 2008;1(2):16-21.
43. Keating GM. Drugs. 2012;72(18):2397-2405.
44. Green AC, et al. Australas J Dermatol. 1988;29(3):127-130.
45. Siller G, et al. Australas J Dermatol. 2009;50(1):16-22.
46. Rosen RH, et al. J Am Acad Dermatol. 2012;66(3):486-493.
47. Lebwohl M, et al. N Engl J Med. 2012;366(11):1010-1019.
48. Anderson L, et al. J Am Acad Dermatol. 2009;60(6):934-943.
49. Lebwohl M, et al. JAMA Dermatol. 2013:1-5.
50. Maltusch A, et al. J Deutschen Dermatologischen Gesellschaft. 2011;9(12):1011-1017.
51. Tripp CS, et al. J Invest Dermatol. 2003;121(4):853-861.
52. Fecker LF, et al. J Invest Dermatol. 2010;130(8):2098-2109.
53. Kose O, et al. J Dermatol Treat. 2008;19(3):159-163.
54. Akarsu S, et al. Clin Exp Dermatol. 2011;36(5):479-484.
55. Nelson C, et al. J Drugs Dermatol. 2004;3(4):401-407.
56. Miller IM, et al. J Eur Acad Dermatol Venereol. 2011;25(11):1275-1281.
57. Nakaseko H, et al. Br J Dermatol. 2003;148(1):122-127.
58. Morton C, et al. Br J Dermatol. 2006;155(5):1029-1036.
59. Wiegell SR, et al. Br J Dermatol. 2012;166(6):1327-1332.
60. Dragieva G, et al. Br J Dermatol. 2004;151(1):196-200.

ERRATA

In the adapted version “Ceramide-based Moisturizers as Treatment for Pediatric Atopic Dermatitis” published in the May 2013 issue of Skin Therapy Letter (Family Practice Edition) by Dušan Sajic, MD, PhD and Sandy Skotnicki-Grant, MD, FRCPC, the following correction should be made:

On page 3, left column, under Other Non-steroidal Barrier Repair Products, the second bullet should read “Similar findings were seen in another recent study that demonstrated non-superiority of topical pimecrolimus when compared to a prescription medical device cream containing a combination of OTC components, suggesting that correction of numerous epidermal barrier derangements may be an effective way of controlling AD.¹⁴“

¹McMaster University, Hamilton, ON, Canada
²Toronto Dermatology Centre, Toronto, ON, Canada

Introduction

Psoriasis is a chronic, inflammatory skin condition prone to periods of skin flaring. As with any chronic disease, it requires long-term patient adherence with prescribed management to ensure optimal clinical benefits. There are many safe and effective topical treatment options that provide control of mild-to-moderate psoriatic disease. As our understanding of the etiology of psoriasis becomes clearer, the treatment regimes can be better tailored to control the disease and address psychological fears of patients, thus, resulting in greater clinical outcomes and patient satisfaction.

Etiology of Psoriatic Inflammation

• In the past few decades, much progress has been made in both the understanding and the treatment of psoriasis.
• In general, psoriasis is characterized by four skin abnormalities: redness or erythema, inflammation, hyperproliferation of the keratinocytic layer, and altered epidermal differentiation.¹
• Psoriasis is no longer regarded as a chronic primary dysregulation of keratinocyte proliferation as was originally thought, but now, is attributed to a combination of genetic (numerous loci have been isolated) and environmental factors (such as streptococcal infections, stress, or drugs including beta-blockers and lithium) that promote a systemic T cell-mediated autoimmune response in the skin with innate immune responses playing an important role.²
• The hypothesis for the pathogenesis of psoriasis proposes that a pro-inflammatory stimulus leads to the development of ‘immunological synapses’ between dendritic and T cells with subsequent antigen-specific T cell activation.²
• The subsequent release of cytokines and growth factors initiates the proliferation and altered differentiation of keratinocytes, which further promotes the activation of T cells and antigen-presenting cells (mainly dendritic cells) within the psoriatic plaque.
• The clinical success of anti-TNF therapy in the treatment of psoriasis has further validated the role of these cytokines in psoriasis pathogenesis.³

General Treatment Paradigms

• The main goal of treatment in psoriasis is to gain rapid control of the disease and reduce its signs and symptoms.
• This can be achieved by decreasing erythema, scaling, and induration of plaques; reducing the frequency and intensity of psoriatic flare-ups; reducing the extent of body surface area (BSA) disease involvement; and effectively managing side-effects.
• Tailoring treatment to a format that is acceptable to the patient is important.
• These needs var y depending on body location, characteristics of the psoriasis being treated, including lesion thickness, degree of erythema, and amount of scaling, as well as patient preferences.

Topical Treatment Options

Corticosteroids

• High-potency corticosteroids have been a mainstay in the topical treatment of psoriasis for decades. Their efficacy can be attributed to multiple mechanisms of action, including their anti-inflammatory, immunosuppressive, and antiproliferative effects.³ Corticosteroids are formulated in a variety of vehicles (e.g., cream, lotion, ointment, gel, shampoo, and spray) to address the possible combinations of treatment conditions. Appropriate selection can promote adherence and improve outcomes.
• The disease severity, location being treated, ease of use, cosmetic acceptability, and patient age and preferences should be taken into consideration when choosing a suitable potency of corticosteroid treatment.⁴

Coal Tar

• Coal tar has been used since ancient times to treat various skin diseases and for approximately 100 years in the treatment of psoriasis.⁴
• Although the mechanism of action of coal tar is not well understood, it is known to suppress DNA synthesis by lessening the mitotic labeling index of keratinocytes.⁴
• Often, coal tar products are not well tolerated by patients due to cosmetic inelegance, including staining of clothes and a potent tar odour that is present in almost all products to some degree.
• Other potential adverse effects include irritant contact dermatitis, folliculitis, and photosensitivity to UVA.

Retinoids

• Retinoids are a unique class within the armamentarium of antipsoriatic treatments, which are largely dominated by immunomodulatory therapies.
• The mechanism of action of retinoids in psoriasis may include direct suppression of inflammation, as well as inhibition of proliferation and normalization of differentiation in the epidermal layer.³
• The topical retinoid approved for psoriasis is tazarotene gel and cream and is available in 0.05% and 0.1% formulations. Due to the common side-effect of irritation, they are not frequently used.

Calcineurin Inhibitors

• There are two topical preparations of calcineurin inhibitors: tacrolimus ointment (0.03% and 0.1%) and pimecrolimus cream (1.0%).
• The initial trials indicated treatment efficacy in patients with psoriasis when used under occlusion. Hence, it led to the belief that the penetration of topical calcineurin inhibitors into thick psoriatic plaques was limited.
• Consequently, tacrolimus and pimecrolimus have been used in areas of skin where greater topical penetration is improved, such as on flexural or facial skin.⁵
• Side-effects for calcineurin inhibitors include a burning sensation and pruritus with initial treatments in some patients; however, this discomfort is generally reduced with ongoing use.⁵

Justification for Long-term Treatment Options

Long-term topical treatment options are necessary as psoriasis is a chronic disease requiring ongoing patient adherence to better maintain optimal clinical outcomes. Early intervention can limit flares and minimize progression to more severe disease. As well, over time, psoriasis can become recalcitrant to treatment, requiring more potent medicines that expose the patient to greater risk for adverse side-effects.

Corticosteroids

• Several potencies of corticosteroid treatment are available, ranging from Class 1 (highest potency) to Class 7 (lowest potency).
• Superpotent steroids are suitable for intermittent/pulse therapy or as a component of sequential therapy. Chronic recalcitrant plaques, control of flares, or thickened lesions (i.e., palms and soles) generally require treatment with the higher potency corticosteroids (i.e., Classes 1 and 2). Available data demonstrate safety and efficacy of Class 1 topical steroids when used short-term (2 to 4 weeks); however, the risk of both cutaneous and systemic adverse effects increases if they are used continuously for longerperiods of time.⁴
• The ability to vary strength and administration method gives steroids the versatility to mildly treat sensitive and thin-skinned areas, such as the face and body folds, and the option to provide stronger treatment to more resistant areas of the body, such as extensor surfaces and the palmoplantar areas.⁶
• Fear of side-effects is a key reason patients use steroids less often than prescribed, leading to decreased efficacy. Counseling patients on proper usage (e.g., dosing, application, and duration) and the therapeutic objectives can promote treatment adherence.
• Local side-effects to look for include skin atrophy, telangiectasia, striae distensae, folliculitis, acne, and purpura. Systemic side-effects of corticosteroids include hypertension, osteoporosis, Cushing’s syndrome, cataracts, glaucoma, diabetes, and avascular necrosis of the hip.⁵

Steroid-sparing Options: Vitamin D3 Derivatives

• Vitamin D analogs are known to play an important role in the treatment of chronic plaque psoriasis, as they have shown to provide good clinical efficacy without the side-effects typically seen with long-term corticosteroid use.
• Vitamin D analogs work through the stimulation of cellular differentiation, inhibition of proliferation, and immunomodulation.⁵
• Their discovery was prompted by the realization that oral vitamin D had a therapeutic effect on psoriatic plaques.
• However, parent vitamin D3 might not be suitable for treating psoriasis owing to the potential for hypercalcemia.⁶ Hence, several vitamin D3 analogues have been developed for the treatment of psoriasis.
• Vitamin D analogues, such as calcipotriol and calcitriol, inhibit corneocyte proliferation and stimulate corneocyte differentiation in vitro.⁵ In addition, these analogues have only minimal effects on calcium levels and calcium excretion.
• Vitamin D analogs are also valuable and clinically effective in combination therapy, especially with topical corticosteroids, thus allowing for a steroid-sparing effect.⁷
• Newer topical treatments that contain vitamin D analogs and have shown good clinical efficacy and safety profiles include:
  • Calcitriol ointment (Silkis™) – a naturally occurring derivative of vitamin D
  • Calcipotriol + betamethasone dipropionate gel (Xamiol®) – a two-compound scalp formulation containing a synthetic vitamin D3 with a potent topical steroid

Calcitriol Ointment

• Calcitriol 3μg/g ointment is a naturally occurring active form of Vitamin D3 demonstrated to be as effective as other vitamin D analogs, but calcitriol has the advantage of increased tolerability in sensitive areas such as the face, hairline, and postauricular and flexural areas.⁸
• The use of a tolerable vitamin D3 analog in sensitive areas may minimize corticosteroid use in these skin regions, allowing for better individualization of a psoriasis regimen.
• It is indicated to treat mild-to-moderate plaque-type psoriasis in adults ≥18 years of age with up to 35% body surface area involvement and is suitable for long-term therapy.
• Calcitriol ointment has been extensively evaluated for the treatment of chronic plaque-type psoriasis and has been shown to be effective, safe, and well-tolerated in a number of short-term and long-term clinical trials.⁹
• In a 52-week uncontrolled, open label study of 324 patients, efficacy did not appear to diminish over time.¹⁰
• Recommended dosing is twice-daily (morning and evening) to affected areas. The maximum weekly dose should not exceed 200g and improvement may be seen as early as 2 weeks after initiating therapy.
• Pharmacokinetic studies in patients with psoriasis and healthy control subjects have demonstrated that topical calcitriol ointment produces little systemic absorption of calcitriol and does not result in systemic hypercalcemia even when applied to approximately one-third of the body surface area.⁹

Calcipotriol + Betamethasone Dipropionate Gel

• This once-daily lipophilic gel is specially formulated for the scalp and contains the active ingredients calcipotriol 0.005% and betamethasone dipropionate 0.05%.¹¹ Studies have shown that the two agents in combination have a more rapid onset of action and greater efficacy than monotherapy with either agent.^12,13
• A study investigating the combination of betamethasone dipropionate 0.5mg/g plus calcipotriol 50μg/g in a new gel formulation showed that 92% of patients achieved marked improvement to clearance of their scalp psoriasis following once-daily use for up to 8 weeks.¹⁴
• The gel vehicle improves cosmetic acceptability, minimizes irritation, facilitates ease of use, is odourless, and may encourage patient adherence with a once-daily regimen.
• To avoid the potential effects of calcium metabolism, usage should be limited to 15g daily, or 100g weekly.

Improving Long-term Quality of Life

• Topical corticosteroids are a useful intermittent therapy for managing stable disease affecting relatively small areas of the body, leading to an improved quality of life over a longterm period.
• In general, a gradual reduction in the frequency of corticosteroid use following clinical response is recommended.⁴
• Therapy should be monitored by physicians to limit the risk of cutaneous or systemic side-effects, especially if it is to be used for a prolonged duration.
• Controlling these adverse side-effects will improve patient adherence and outcomes. Hence, the addition of newer vitamin D analogs to the topical armamentarium for psoriasis will no doubt widen therapeutic options and improve adherence.
• Additionally, in quality of life questionnaires administered to psoriatic patients, psychological distress appears to be a selfreported trigger for flare periods in up to 60% of patients.¹⁵
• Psychological interpersonal difficulties can impinge on all aspects of the patient’s daily life. As such, it is important to assess how the patient’s life is affected by the psoriasis, what the patient perceives as the most bothersome aspects of their psoriasis, and what their hopes and expectations of treatment are.¹⁶
• It should also remain a priority to provide treatment that addresses these psychological fears and concerns of patients.
• In order for the treatment to be successful, appropriate therapeutic regimes for patients should take into consideration long-term self-reported assessments for quality of life improvements.

Conclusion

Establishing an effective therapeutic regimen is crucial in managing not only the psoriasis, but also patient adherence to treatment and satisfaction with outcomes. Understanding both patient-specific needs and the available topical therapies are essential in order to successfully treat the majority of psoriatic patients. However, primary care physicians should continually review with patients the therapeutic options and elicit their feedback to optimize long-term management of this chronic condition.

References

1. Bhalerao J, et al. Hum Mol Genet 7(10):1537-45 (1998).
2. Prinz JC. J Eur Acad Dermatol Venereol 24(Suppl 6):1-4 (2010 Oct).
3. Mitra A, et al. Expert Opin Drug Deliv 7(8):977-92 (2010 Aug).
4. Menter A, et al. J Am Acad Dermatol 60(4):643-59 (2009 Apr).
5. Laws PM, et al. Expert Opin Pharmacother 11(12):1999-2009 (2010 Aug).
6. Afifi T, et al. Can Fam Physician 51:519-25 (2005 Apr).
7. Menter A, et al. J Am Acad Dermatol 60(4):643-59 (2009 Apr).
8. Sigmon JR, et al. J Dermatolog Treat 20(4):208-12 (2009).
9. Kircik L. J Drugs Dermatol 8(8 Suppl):s9-16 (2009 Aug).
10. Lebwohl M, et al. Cutis 83(4):205-12 (2009 Apr).
11. Guenther LC. Skin Therapy Lett 14(4):1-4 (2009 May).
12. Luger TA, et al. Dermatology 217(4):321-8 (2008).
13. Jemec GB, et al. J Am Acad Dermatol 59(3):455-63 (2008 Sep).
14. Buckley C, et al. Dermatology 217(2):107-13 (2008).
15. Kirby B, et al. Br J Dermatol 144(Suppl 58):37-43 (2001 Apr).
16. de Arruda LHF, et al. Br J Dermatol 144(Suppl 58):33-6 (2001 Apr).

¹ McMaster University, Hamilton, ON, Canada
² Toronto Dermatology Centre, Toronto, ON, Canada

Introduction

For decades, physicians have relied on conventional delivery vehicles, such as creams and ointments, for the topical treatment of cutaneous skin conditions. However, patient dissatisfaction with older topical therapy delivery methods can result in reduced patient compliance and ultimately poor control of their skin condition. As such, newer delivery vehicles in dermatology are being developed to improve clinical efficacy, reduce side-effects, and ultimately improve patient adherence. Newer vehicles include gel, foam, and spray preparations. The newer topical delivery agents have the potential to limit the progression of cutaneous disorders requiring oral systemic therapy, which can expose the patient to greater risk for adverse side-effects than topical therapy alone.

Vehicle Selection

In determining the most appropriate topical treatment regime for various skin disorders, physicians must undertake patient-specific assessments, including disease severity, patient preference, skin type, formulation availability, and delivery vehicle considerations. Active agents are formulated in a variety of vehicles (Table 1) to address the possible combinations. In general, patients with drier skin may favour creams for their moisturizing effect, while those with oilier skin may prefer gels or solutions. In addition to ease of spreadability, the use of foams may be particularly well suited for application over larger areas and hair bearing sites.

Some Newer Therapeutics with Advanced Delivery

Foams for Dermatoses

• Steroid foam preparations are newer formulations that provide commonly prescribed topical steroids in a low residue vehicle1 for the treatment of steroid-responsive dermatoses (e.g., allergic reactions, atopic dermatitis, and psoriasis).
• In Canada, desonide foam 0.05% is indicated for the treatment of mild to moderate atopic dermatitis in patients =1 year of age.
• Foam formulations of corticosteroids offer cosmetic advantages over traditional topical vehicles (ointments and creams), including quality of life variables such as minimal residue after application, quick drying, ease of application, and no odour.
• Other findings included that patients using foam preparations spent less time applying medication as compared with other forms of topicals, and that no significant difference in cost was found between foam and cream/solution after controlling for body surface area.²
• In preliminary studies, steroid foams have also been shown to be more efficacious treatment vehicles by demonstrating more rapid penetration and greater total absorption than conventional delivery modes (i.e., lotions and creams).¹
• Additionally, foam formulations are also considered to have a better acceptability profile in patients, with a greater positive effect on quality of life, than traditional topical formulations.
• These advantages may lead to improved compliance and efficacy of treatment. The most frequently reported adverse events with steroid foam preparations are application-site reactions, such as burning, stinging, or itching.
• However, ethanol-free steroid foam formulations are also being developed to minimize side-effects.²

Gel for Acne

• Many new topical acne formulations have aqueous-based gel vehicle delivery systems that do not contain alcohol and are suitable for use in all skin types.
• A once-daily formulation of clindamycin 1% + benzoyl peroxide (BP) 5% in a gel vehicle improves absorption and cosmetic acceptability, and facilitates ease of use, especially over larger or hair-bearing areas.³
• Recent study findings demonstrate that this fix-dose combination not only has the potential to inhibit antimicrobial resistance,4 but also to improve both treatment tolerability and safety.⁵
• The nonmedicinal constituents in this anti-acne compound include both glycerin (humectant) and dimethicone (emollient) to reduce both epidermal barrier impairment and cutaneous irritation, and increase hydration.

Gel for Scalp Psoriasis

• Calcipotriol 0.005% + betamethasone dipropionate 0.05% in a lipophilic gel is specially formulated for the treatment of scalp psoriasis.⁶
• A study comparing this two-compound gel with calcipotriol alone was conducted and the proportion of patients with ‘clear’ or ‘minimal’ disease at week 8 was significantly greater in the gel group (68.6%) as compared to the group receiving calcipotriol monotherapy (31.4%).⁷ Additionally, the rate of improvement was more rapid and adverse events were less with the two-compound gel.
• The results further showed that the two-compound scalp formulation demonstrated significant efficacy after only a 1 week period, with a faster onset of effect than either of the individual components in the same vehicle.

Spray for Psoriasis

• All of the newer topical clobetasol propionate (CP) formulations produce clearing or near-clearing of psoriasis for a large proportion of patients within 2-4 weeks, with response, safety, and tolerability rates that are at least comparable to those observed with older topical CP ointments and creams.⁸
• CP spray is the only CP 0.05% formulation currently approved for treatment up to 4 weeks for those moderate-to-severe plaque psoriasis patients whose benefit/risk ratio supports the additional 2 weeks of treatment.
• Previous studies have indicated that the additional 2 weeks of therapy with CP spray greatly increased efficacy without adversely affecting the safety profile of the drug.⁹
• The CP spray may have an important role in the treatment of large areas of affected skin (up to 15-20% body surface area), expanding the range of topical treatment in psoriasis patients and improving quality of life scores at the end of treatment when compared with other formulations.⁹

Conclusion

Patient dissatisfaction with traditional topical modes of delivery in dermatology have led to the recent introduction of newer delivery vehicle formulations to improve clinical efficacy, reduce side-effects, and better address and promote patient adherence. Newer therapeutic options formulated as gels, foams, sprays, and shampoos have shown to be clinically efficacious, while exhibiting a high degree of patient satisfaction associated with their use. The newer topical delivery agents will also likely reduce the number of patients prematurely progressing to oral systemic therapies to control their cutaneous conditions, which can pose a more adverse side-effect profile than topical therapy alone.

References

1. Reid DC, et al. Expert Opin Pharmacother 6(10):1735-40 (2005 Aug).
2. Stein L. J Am Acad Dermatol 53(1 Suppl 1):S39-49 (2005 Jul).
3. Tan JK. Skin Therapy Lett 7(5):1-2 (2002 May).
4. Jackson JM, et al. J Drugs Dermatol 9(2):131-6 (2010 Feb).
5. Zouboulis CC, et al. Cutis 84(4):223-9 (2009 Oct).
6. Guenther LC. Skin Therapy Lett 14(4):1-4 (2009 May).
7. Kragballe K, et al. Br J Dermatol 161(1):159-66 (2009 Jul).
8. Feldman SR, et al. Am J Clin Dermatol 10(6):397-406 (2009).
9. Mraz S, et al. J Dermatolog Treat 19(6):354-9 (2008).

¹Department of Medicine, McMaster University, Hamilton, ON, Canada
²Toronto Dermatology Centre, Toronto, ON, Canada

ABSTRACT
Topical therapy forms the cornerstone of treatment in the management of psoriasis. It plays a significant role as monotherapy in mild to moderate psoriasis, and it is used predominantly as adjunctive therapy in moderate to severe forms of the disease. Over the past decade, the topical treatment of psoriasis has evolved from the age-old applications, such as coal tar, to the more cosmetically acceptable and efficacious options containing topical corticosteroids, vitamin D analogues, and combined agents. With the advent of topical therapies in tailored vehicles and sophisticated delivery modes, the outlook for effectively managing psoriasis with topical approaches appears promising. To ensure therapeutic success, patient education about the disease, treatment options, proper administration, and adverse effects is essential, which will alleviate the common problem of poor patient adherence and promote more optimal clinical outcomes.

Key Words:
psoriasis, topical therapies, corticosteroids, vitamin D analogues, steroid foams

Psoriasis is a chronic, recurring inflammatory disease that affects the skin, scalp, and joints.1 The typical lesions are pruritic, erythematous, and exhibit well-demarcated papules and plaques with silvery-white scales.² Psoriasis affects 2% of the population and ranges in severity from mild to severe; patients with moderate to severe disease experience significant deterioration in quality of life. It affects men and women equally. The age of onset of psoriasis follows a bimodal distribution (peaks between ages 20 to 30 years and again between the ages of 50 to 60).³ Both genetic and environmental factors have been implicated in the pathophysiology of psoriasis. About 35% of patients with psoriasis have a family history of the disease. Several environmental factors can trigger psoriasis in susceptible individuals: infection (most commonly streptococcal infection); trauma to the skin (Koebner phenomenon); drug reaction (e.g., lithium, beta blockers, anti-malarial drugs, non-steroidal anti- inflammatory drugs, and glucocorticoids); and stress.²

The clinical presentation of psoriasis varies depending on the morphologic subclass. Plaque psoriasis is the most common subtype and is usually concentrated on the extensor surfaces (i.e., elbows, knees, and lumbar back), scalp, genital areas, palms, soles, joints, and nails.³ Removal of scale causes sites of punctate bleeding (Auspitz’ sign), a sign of historic note. Therapy varies depending on disease severity and the degree of body surface area involvement. However, the vast majority of patients (approximately 80-90%) present with relatively mild disease and have only limited involvement of the skin, which can be well- controlled with topical therapy.⁴

Topical Treatment Options

Corticosteroids

For decades, topical cor t icosteroids, par t icularly hig h-potency steroids, have been the mainstay in the topical treatment of psoriasis. Their efficacy can be attributed to multiple mechanisms of action, including anti-inflammatory, immunosuppressive, and antiproliferative effects.⁵ In choosing an appropriate corticosteroid potency and its vehicle, the disease severity, location being treated, and patient preference should be considered.⁶ Psoriatic patients with thick, chronic plaques often require treatment with the highest potency corticosteroids. Steroids are also excellent constituents to compound with other effective antipsoriatic agents, such as salicylic acid and liquor carbonis detergens (LCD).

Vitamin D3 Derivatives

Vitamin D analogs are known to play an important role in the
treatment of chronic plaque psoriasis through the stimulation of cellular differentiation, inhibition of proliferation, and immunomodulation.⁷ Their discovery was prompted by the realization that oral vitamin D had a therapeutic effect on psoriatic plaques. However, parent vitamin D3 might not be suitable for treating psoriasis owing to the potential for hypercalcemia.⁵ Hence, several vitamin D3 analogues have been developed for the treatment of psoriasis. Vitamin D analogues, such as calcipotriol and calcitriol, inhibit corneocyte proliferation and stimulate corneocyte differentiation in vitro.⁷ In addition, these analogues have only minimal effects on calcium levels and calcium excretion.

Tar

Coal tar has been used since ancient times for the treatment of
various skin diseases, and its utility for the treatment of psoriasis dates back approximately 100 years.⁶ Although the mechanism of action of coal tar is not well understood, it is known to suppress DNA synthesis by lessening the mitotic labeling index of keratinocytes.6 Many formulations of coal tar exist, however, these products lack patient acceptance due to cosmetic inelegance, including staining of clothes and a potent tar odor that is present in almost all products. Additional potential adverse effects include irritant contact dermatitis, folliculitis, and photosensitivity to ultraviolet A light.

Retinoids

Retinoids are a unique drug class within the armamentarium
of antipsoriatic treatments, which is largely dominated by immunomodulator y therapies. The mechanism of action of retinoids in psoriasis may include direct suppression of inflammation, as well as inhibition of proliferation and normalization of differentiation in the epidermal layer.⁵ The topical retinoid approved for psoriasis is tazarotene, and it is available as a gel or cream in 0.05% and 0.1% formulations.

Calcineurin Inhibitors

There are two topical preparations of calcineurin inhibitors:
tacrolimus ointment (0.03% and 0.1%) and pimecrolimus cream (1.0%). The initial trials indicated treatment efficacy in patients with psoriasis when used under occlusion. Hence, it led to the belief that the penetration of topical calcineurin inhibitors into thick psoriatic plaques was limited. Consequently, tacrolimus and pimecrolimus have been used in areas of skin where greater topical penetration is improved, such as in flexural or facial skin.⁷

The main side-effects of calcineurin inhibitors in some patients are a burning sensation and pruritus with initial treatments; however, the discomfort generally diminishes with ongoing use.⁷

Newer Topical Treatment Options

Calcipotriol + Betamethasone Dipropionate Gel (Xamiol®/Taclonex® Scalp)

Xamiol® is a lipophilic gel that is specially formulated for the
scalp and contains the active ingredients calcipotriol 0.005% and betamethasone dipropionate 0.05%.⁸ Calcipotriol binds to the intracellular vitamin D receptor, forming a heterodimer unit. These units migrate to the nucleus, where they bind the vitamin D response element, which directly regulates the genes involved in epidermal proliferation, inflammation, and keratinization.⁷

Betamethasone dipropionate is a potent topical steroid that binds to glucocorticoid receptors in the cytoplasm, then rapidly translocates to the nucleus where they inhibit or stimulate genes that regulate inflammation.⁸ As a result, the production of cytokines (such as interleukin-1 and interleukin-8, tumor necrosis factor-alpha, and gamma-interferon) are inhibited; and nitric oxide, prostaglandins, and levels of leukotrienes are reduced. Both vitamin D and corticosteroids can increase the number of T regulatory cells that are diminished in psoriatic skin.

A study comparing Xamiol® w ith Dovonex®/Daivonex® (calcipotriol/calcipotriene alone) demonstrated that the proportion of patients with ‘clear’ or ‘minimal’ disease at week 8 was significantly greater in the Xamiol® group (68.6%) as compared with the Dovonex® group (31.4%; P < 0.001).⁹

Additionally, the rate of improvement was more rapid and adverse events were less with Xamiol®.

A second study investigated the clinical efficacy of the two- compound scalp therapy (Xamiol®) after only 1 week of treatment.10 The percentage of patients who had ‘absent’ or ‘very mild’ disease (according to Investigator’s Global Assessment) after 1 week of treatment was significantly higher with the two-compound scalp formulation (30.6%) compared with betamethasone (24.1%; P < 0.001), calcipotriol (10.0%; P < 0.001), or vehicle (6.9%; P < 0.001).10 The results showed that the two-compound formulation demonstrated significant efficacy in treating scalp psoriasis after a 1 week period, with a faster onset of effect, than either of the individual components in the same vehicle.

Calcitriol Ointment (Silkis®/Vectical®)

Topical vitamin D modulators are among the most widely used
medications for the treatment of psoriasis. Calcitriol 3 µg/g ointment is a synthetic topical vitamin D analog considered to be as effective as other vitamin D analogs, but calcitriol has the advantage of increased tolerability in sensitive regions, such as the face, hairline, and postauricular and flexural areas.11 The use of a tolerable vitamin D3 analog in sensitive skin areas may minimize the need for corticosteroids and allow for better individualization in developing a psoriasis management regimen.

Calcitriol ointment has been extensively evaluated for the treatment of chronic plaque-type psoriasis and has been shown to be effective, safe, and well-tolerated in a number of short-term and long-term clinical trials.12 Pharmacokinetic studies in patients with psoriasis and healthy control subjects have demonstrated that topical calcitriol ointment produces little systemic drug absorption and does not result in systemic hypercalcemia even when applied to approximately one-third of the body surface area.¹²

In two randomized, double-blind clinical trials, twice-daily application of calcitriol ointment for 8 weeks resulted in clearing or minimal residual psoriasis in approximately 34% of patients, compared with 12% to 22.5% of patients treated with the vehicle ointment.12 The calcitriol ointment was shown to have a local safety profile comparable to its vehicle. Treatment-related side- effects were relatively minor and included erythema, pruritus, and general skin discomfort.

In another study, patients who received calcitriol ointment exhibited improvement in psoriasis symptoms that was similar to the corticosteroid betamethasone propionate, but were much less likely to have relapsed 8 weeks after treatment discontinuation.¹³

Clobetasol Proprionate 0.05% Spray and Shampoo (Clobex®)

Ultrapotent topical corticosteroids are the most widely used
psoriasis treatments and new formulations provide efficacious, safe, and tolerable options that may increase patient satisfaction and adherence to therapy. Although skin moisturizing is often described as an important benefit of ointments, the available evidence suggests that reduction of inflammation achieved with the anti-inflammator y agent is the key factor driving improvement outcomes, such that the newer clobetasol propionate (CP) formulations are roughly equal in efficacy to conventional ointments and cream formulations in clinical trial settings.¹⁴

All of the newer topical clobetasol propionate formulations produce clearing or near-clearing of psoriasis for a large proportion of patients within 2-4 weeks, with response, safety, and tolerability rates that are at least comparable to those observed with older topical clobetasol propionate ointments and creams.14 CP spray is the only clobetasol propionate 0.05% formulation currently approved for up to 4 weeks of treatment in moderate to severe plaque psoriasis patients whose benefit/risk ratio supports the additional 2 weeks of therapy. Previous studies have indicated that the additional 2 weeks of treatment with CP spray greatly increased efficacy without adversely affecting the safety profile of the drug.¹⁵

The CP spray may have an important role in the treatment of large areas of affected skin (up to 15-20% of body surface area), expanding the range of topical therapies for psoriasis patients. CP spray also resulted in greater improvements in quality of life (DLQI) scores at the end of treatment when compared with other formulations.¹⁵

CP 0.05% shampoo is also efficacious and safe for the management of moderate scalp psoriasis.¹⁶ CP shampoo effectively helps to prevent the relapse of scalp psoriasis and the short-contact shampoo formulation of clobetasol propionate can be utilized for extended periods without leading to notable side- effects.¹⁶ This treatment also leads to high patient satisfaction, which may increase adherence and result in even greater overall treatment efficacy.

Steroid Foams

Steroid foam preparations are newer formulations that provide
commonly prescribed topical steroids in a low residue vehicle.¹⁷

Despite the availability of numerous topical agents for the treatment of relatively localized psoriasis, patients are frequently dissatisfied due to the lack of efficacy and difficulty in using prescribed treatments. Patient compliance is reported to be low in the psoriatic population (approximately 40% non-compliance), the reason most often given by patients is that the treatments interfere with their lifestyle or require significant behavioral changes.¹⁸

Foam formulations of corticosteroids offer cosmetic advantages over traditional topical vehicles (ointments and creams), including quality of life variables such as minimal residue after application, quick drying, ease of application, and lack of fragrance. Other findings included that patients using foam preparations spent less time applying medication as compared with other topical medications. Furthermore, no significant difference in cost was found between foam and cream/solution after controlling for body surface area.¹⁸

In preliminary studies, steroid foams have also been shown to be more efficacious treatment vehicles by demonstrating more rapid penetration and greater total absorption than conventional delivery modes (i.e., lotions and creams).¹⁷ These advantages may lead to improved compliance and efficacy of treatment. The most frequently reported adverse events with steroid foam preparations are application-site reactions, such as burning, stinging, or itching. However, ethanol-free steroid foam formulations are also being developed to minimize these side-effects.¹⁸

Conclusion

With the advent of new topical treatments and varying vehicle delivery advances, the outlook for effectively managing psoriasis with topical therapies looks positive. To ensure therapeutic success, proper patient education about the disease, available treatment options, vehicle selection, and adverse effects is essential. Focusing on these areas will help to adequately address the primary reasons for poor patient adherence to topical therapy and inevitably result in more optimal clinical outcomes.

References

1. Lebwohl M. A clinician’s paradigm in the treatment of psoriasis. J Am Acad Dermatol 53(1 Suppl 1):S59-69 (2005 Jul).
2. Luba KM, Stulburg DL. Chronic plaque psoriasis. Am Fam Physician 73(4):636-44 (2006 Feb).
3. Turchin I, Adams SP. Dermacase: psoriasis. Can Fam Physician 52(9):1073, 1080 (2006 Sep).
4. Langley RGB. Psoriasis. 2nd ed. Toronto (ON): Key Porter Books (2010).
5. Mitra A, Wu Y. Topical delivery for the treatment of psoriasis. Expert Opin Drug Deliv 7(8):977-92 (2010 Aug).
6. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol 60(4):643-59 (2009 Apr).
7. Laws PM, Young HS. Topical treatment of psoriasis. Expert Opin Pharmacother 11(12):1999-2009 (2010 Aug).
8. Guenther LC. Treatments for scalp psoriasis with emphasis on calcipotriol plus betamethasone diproprionate gel (Xamiol). Skin Therapy Lett 14(4):1-4 (2009 May).
9. Kragballe K, Hoffman V, Ortonne JP, et al. Efficacy and safety of calcipotriol plus betamethasone diproprionate scalp formulation compared with calcipotriol scalp solution in the treatment of scalp psoriasis: A randomized controlled trial. Br J Dermatol 161(1):159-66 (2009 Jul).
10. Jemec GBE, van de Kerkhof PCM, Enevold A, et al. Significant one week efficacy of a calcipotriol plus betamethasone diproprionate scalp formulation. J Eur Acad Dermatol Venereol [Epub ahead of print] (2010 Apr 28).
11. Sigmon JR, Yentzer BA, Feldman SR. Calcitriol ointment: a review of topical vitamin D analog for psoriasis. J Dermatolog Treat 20(4):208-12 (2009).
12. Kircik L. Efficacy and safety of topical calcitriol 3 microg/g ointment, a new topical therapy for chronic plaque psoriasis. J Drugs Dermatol 8(8 Suppl):s9-16 (2009 Aug).
13. Abramovits W. Calcitriol 3 microg/g ointment: An effective and safe addition to the armamentarium in topical psoriasis therapy. J Drugs Dermatol 8(8 Suppl):s17-22 (2009 Aug).
14. Feldman SR, Yentzer BA. Topical clobetasol propionate in the treatment of psoriasis: a review of newer formulations. Am J Clin Dermatol 10(6):397-406 (2009).
15. Mraz S, Leonardi C, Colon LE, et al. Different treatment outcomes with different formulations of clobetasol propionate 0.05% for the treatment of plaque psoriasis. J Dermatolog Treat 19(6):354-9 (2008).
16. Poulin Y, Papp K, Bissonnette R, et al. Clobetasol propionate shampoo 0.05% is efficacious and safe for long-term control of moderate scalp psoriasis. J Dermatolog Treat 21(3):185-92 (2010 May).
17. Reid DC, Kimball AB. Clobetasol propionate foam in the treatment of psoriasis. Expert Opin Pharmacother 6(10):1735-40 (2005 Aug).
18. Stein L. Clinical studies of a new vehicle formulation for topical corticosteroids in the treatment of psoriasis. J Am Acad Dermatol 53(1 Suppl 1):S39-49 (2005 Jul).

¹ McMaster University, Hamilton, ON, Canada
² Toronto Dermatology Centre, Toronto, ON, Canada

Introduction

Eczema is a chronic relapsing dermatitis and, as such, it is imperative to maintain the hydration and barrier function of the skin in these patients with daily moisturizer use. Emollients have long been used to maintain the skin barrier function in patients with eczema (atopic dermatitis). Ceramide and urea-based moisturizers have been shown to be beneficial in reducing transepidermal water loss (TEWL), improving barrier function, and maintaining hydration of the stratum corneum layer of the epidermis; thus, they should be considered a mainstay of treatment in patients with xerosis (dry skin) and eczema.

Overview of Eczema

Eczema is a chronic, pruritic, inflammatory skin disease with wide ranging severity; it is usually the first manifestation of atopic disease. Eczema is a major public health problem worldwide that commonly presents during early infancy and childhood, but can persist or start in adulthood (prevalence in children is 10-20% and 1-3% in adults).¹ Prevalence has increased by two to threefold during the past 30 years in urban areas and industrialized countries, but it remains much lower in rural and less industrialized regions.²

• The causes of eczema are not completely understood, but dysfunction of the skin barrier, likely the result of both genetic and environmental factors, and immune dysregulation are important in its pathophysiology.³
• Acute eczema presents as erythematous patches, papules, plaques, and excoriations secondary to scratching; there may also be weeping of serous exudate. Chronic lesions have the same characteristics, with the addition of lichenification, fissures, and occasional alopecia.⁴
• Partly due to the ease of accessibility for scratching, infantile eczema predominantly involves extensor surfaces of the arms and legs, face, and trunk. Scaling, exudate, and fissures are also common findings in infants.
• In adults, flexural areas, face and neck, wrists, and the dorsal areas of the hands and feet are the most commonly affected regions.

Top

Treatment Rationale

The major goal of disease management is to reduce the frequency and severity of flares, and prolong periods of remission. Comprehensive long-term management addresses both skin barrier dysfunction and immune dysregulation, but also includes patient and caregiver education, flare prevention through trigger avoidance and hydration, as well as pharmacologic and non-pharmacologic therapies.³

• Non-pharmacologic patient-specific strategies include removal of allergens (e.g., foods, pet dander, pollen), identification of trigger factors (e.g., stress, low humidity), and a balanced intake of dietary nutrients.⁵
• Short (5-10 minutes) tepid baths or showers can help to hydrate the skin. A soft towel should be used to pat dry without rubbing, a moisturizer is applied within 3 minutes.
• Particularly during infancy, a higher intake of vitamin A may reduce the incidence of eczema seen in children with a positive family history of atopy. The use of Lactobacillus during pregnancy and while nursing may postpone the onset of eczema in infants and children.⁵
• Pharmacologic therapy includes the use of emollients, topical corticosteroids, and topical calcineurin inhibitors.
• For mild eczema, over-the-counter (OTC) emollients and topical corticosteroids, e.g., hydrocortisone 0.5% (low potency) and clobetasone 0.05% (mid potency) are available for self-treatment.
• Physicians can emphasize to patients that the goals of selftreatment are to stop the itch-scratch cycle, maintain skin hydration, and avoid or minimize factors that can trigger or aggravate eczema.
• An ideal moisturizer is one that performs four functions:⁶
  1. repair the skin barrier,
  2. maintain skin integrity and appearance,
  3. reduce transepidermal water loss (TEWL),
  4. restore the lipid barrier’s ability to attract, hold, and redistribute water.
• It is appropriate for patients or caregivers to consult a physician if OTC treatments are not providing adequate relief, eczematous lesions appear to be infected, or the patient’s sleep is frequently disturbed by pruritus.⁵

Top

Available Therapeutic Moisturizers

Ceramide-based Moisturizers

• Recent biochemical findings indicate that disturbances of epidermal lipid compartment structures (particularly of ceramides) account for the defects in barrier function of atopic dry skin.⁷
• Optimal barrier function requires the presence of sufficient extracellular lipids to form a competent lamellar bilayer system of the stratum corneum.⁷
• Ceramides, which consist of different sub-fractions of lipids, represent one of the major lipid constituents of the extracellular lipids and are functionally important for the stability of the multilamellar bilayer system.
• Studies have revealed that ceramides are reduced in the whole atopic population, but particularly in those individuals in an active phase of the disease.⁸
• A reduction of ceramides has been inversely correlated with TEWL, which can result in chronically dry skin.
• Topical ceramide supplementation controls ceramide deficiency and improves the overall skin condition.⁶
• Their benefits are derived from prophylactic and regular use, which may reduce the need for topical corticosteroids and calcineurin inhibitors, and possibly mitigate the side-effects from these medications.
• OTC ceramide-based moisturizers include Impruv® cream and Cetaphil Restoraderm™ lotion. CeraVe® and TriCeram® are currently available in the U.S. only, however, CeraVe® is due to be launched in Canada soon.

Prescription Ceramide-based Moisturizers

• These consist of a higher percentage (compared to OTC brands) combination of ceramides, cholesterol, and fatty acids that mimic those naturally found in the skin.9
• EpiCeram® was approved by Health Canada in September 2009 as a Class 2 medical device for use as a non-steroidal lipid barrier emulsion to manage burning and itching symptoms associated with dry skin conditions, such as eczema.
  • In a study involving 113 children with moderate to severe atopic dermatitis, similar efficacy to a mid-strength topical corticosteroid was demonstrated.⁹
  • This multi-lipid emulsion has a favourable safety profile and does not appear to have substantial restrictions for use, such as treatment duration or patient age.
• Prescription ceramide-dominant formulations include EpiCeram® cream (available in Canada and the U.S.) as well as Atopiclair® and MimyX® (available in the U.S. only).

Urea-based Moisturizers without Hydrocortisone

• Urea-based moisturizers are OTC formulations that are indicated for xerotic skin with or without pruritus.
• Urea works by enhancing the water-binding capacity of the stratum corneum and long-term treatment with urea has been demonstrated to decrease TEWL.¹⁰
• Application of these moisturizers is recommended shortly after bathing, while the skin is still wet.
• The short-term therapeutic effects of urea-based moisturizers are apparent in patients even after 1 week of daily application in those with dry skin and eczema.¹¹
• It has also been shown that long-term urea application reduces the susceptibility to skin irritation from sodium lauryl sulfate, a surfactant commonly used in many soaps, shampoos, detergents, and toothpastes.
• The protective effect (after prolonged application) of urea-containing moisturizers has promising clinical ramifications, such as reduction of contact dermatitis from irritating stimuli.¹⁰
• Higher concentration urea-based formulations induce more prominent keratolytic (softening/shedding) activity that can increase skin irritation. A lower concentration is generally used on the face and body, whereas a higher concentration may be applied to thickened skin areas (e.g., feet).
• OTC urea-based moisturizers include various strengths of urea: 5% (e.g., Eucerin® cream); 10% (e.g., Uremol® 10 cream or lotion, Eucerin® lotion or cream, Urisecâ„¢ cream); 12% (e.g., Uresecâ„¢ lotion); 20% (e.g., Uremol® 20 cream); 22% and 40% urea creams.
• Urea 40% cream is a potent keratolytic that is not suitable for use as a regular moisturizer.

Urea-based Moisturizers with Hydrocortisone

• Urea-based moisturizers with hydrocortisone are prescription strength formulations and are effective for xerotic skin with inflammation and mild eczema.⁴
• Topical corticosteroids are effectively used for controlling active skin inflammation in eczema. The lowest effective potency of topical corticosteroids is always preferred for the local treatment of lesions.
• Combining an emollient with a corticosteroid has been shown to be effective. A cohort study found that the addition of 10% urea to a commercially prepared steroid cream gave better results in treating subacute atopic eczema than the steroid cream alone.¹²
• Side-effects from topical steroids are directly related to the potency of the compound and the length of use.
• Potential risks from long-term topical steroid use include fungal infections, impetigo, viral warts, and herpes simplex. As well, discontinuation of topical corticosteroids may lead to a flare of symptoms.
• Low-potency hydrocortisone 1% cream has been found to be quite safe for cutaneous use.
• Prescription-based urea moisturizers containing 10% urea with 1% hydrocortisone are available in lotion or cream preparations (e.g., Uremol® HC).

Top

Diabetic Skin Care Management

Xerosis of the feet is a common skin condition; incidence increases with age, exposure to dry winter conditions, and physiological changes that alter circulatory supply to the lower extremities (e.g., diabetes).
People with diabetes have a high incidence of xerosis of the feet, especially on the heels.

While assessing for predictors of foot lesions in diabetic patients, one study found that 82.1% of this cohort had skin with dryness, cracks, or fissures.¹¹ An unpublished survey of 105 consecutive patients with diabetes conducted by one of the authors revealed that 75% had clinical manifestations of dry skin.

Dry skin often leads to cracks and fissures that can act as portals of entry for bacteria. These cracks and fissures are associated with an increased risk of cellulitis and foot ulceration that, if left unchecked, can eventually lead to amputation.
Xerosis of the feet in diabetic individuals can be controlled with the regimented use of moisturizers.¹¹
Healthcare providers should routinely inspect the feet of diabetic patients and encourage daily moisturization.
Urea has been found to be a potent skin humidifier (by decreasing TEWL) and descaling agent.

Studies of diabetic patients revealed that urea is safe and effective in controlling xerosis of the feet and showed longerlasting effect than other emollient creams.¹¹

Urea cream works as a keratinolytic and helps in the treatment of corns and calluses of the feet.¹³ This can be functionally important as these hyperkeratotic papules can be uncomfortable, and even painful, thereby restricting physical activity in affected individuals.

Top

Conclusion

Eczema is a chronic relapsing dermatitis and, as such, it is
imperative to maintain the hydration and barrier function of the
skin in these patients with daily moisturizer use. Ceramide and
urea-based moisturizers have been shown to be beneficial in
reducing TEWL, improving barrier function, and maintaining
hydration of the stratum corneum layer of the epidermis, and
thus, should be a mainstay of treatment in patients with dry
skin and eczema.

Failure to adequately moisturize the skin
can lead to a flare of symptoms or an increased incidence
of infections. However, adherence to a schedule of regular
moisturizer use is associated with improved patient quality of
life outcomes (e.g., reduced pruritus, improved sleep patterns,
less depression) and a reduction in the severity and frequency
of eczematous flares.¹⁴

References

1. Simpson EL. Curr Med Res Opin 26(3):633-40 (2010 Mar).
2. Leung DYM, et al. Lancet 361(9352):151-60 (2003 Jan).
3. Levy ML. Curr Med Res Opin 23(12):3091-103 (2007 Dec).
4. Ahuja A. South Med J 96(11):1068-72 (2003 Nov).
5. Carbone A, et al. Ann Pharmacother 44(9):1448-58 (2010 Sep).
6. Anderson PC, et al. Curr Opin Pediatr 21(4):486-90 (2009 Aug).
7. Chamlin SL, et al. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
8. Di Nardo A. Acta Derm Venereol 78(1):27-30 (1998 Jan).
9. Madaan A. Drugs Today 44(10):751-5 (2008 Oct).
10. Flynn TC, et al. Clin Dermatol 19(4):387-92 (2001 Jul).
11. Trung H, et al. Ostomy Wound Manage 48(5):30-6 (2002 May).
12. Hindson TC. Arch Dermatol 104(3):284-5 (1971 Sep).
13. Hogan DJ, et al. Corns: treatment and medication. Available at: http://emedicine.medscape.com/article/1089807-treatment. Accessed: September 30, 2010.
14. Loden M. J Eur Acad Dermatol Venereol 19(6):672-88 (2005 Nov).