Skin Therapy Letter uses reasonable efforts to include accurate and up-to-date information, we make no warranties or representations as to the accuracy, completeness, timeliness or reliability of the content and assume no liability or responsibility for any error or omission in the content.

¹Department of Dermatology and Skin Science, The University of British Columbia, Vancouver, BC, Canada
²Vancouver Coastal Health Research Institute, The University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology, New York University, New York, NY, USA

Introduction

Hair loss is a common dermatological problem that affects a large segment of the population both physically and psychologically. There are many causes of hair loss, such as telogen effluvium (thinning of hair as a result of hair follicles perpetually in a resting phase, as opposed to growth phase) and alopecia areata (an inherited autoimmune condition); androgenetic alopecia (AGA) also called male pattern hair loss (MPHL), is the most common. Hair loss can start anytime at or after puberty: many people have hair loss beginning in the late teens due to the effects of androgen hormones on hair follicles.¹ Its occurrence and severity increases with age, with at least 80% of Caucasian men displaying signs of MPHL by age 70.² Because of its considerable psychological impact, many patients seek treatment.³ Currently, only one topical agent is approved for treatment of hair loss in men, although other treatments are being clinically investigated.

Pathogenesis

• The pathophysiology of AGA remains to be fully determined however, as the name implies, androgens and a genetic predisposition appear to be involved.⁴
• Inherited AGA is polygenic with input from either or both parents.
• The androgenic hormones testosterone (T) and dihydrotestosterone (DHT) are the most important in regulating the growth phase duration and hair matrix volume.
  • In men, testosterone is the precursor to DHT. The conversion of T to DHT at the hair follicles is mediated by Type II 5! reductase enzyme.
• DHT, a potent metabolite of testosterone, enlarges follicles in the beard, chest and limbs and miniaturizes follicles in the bitemporal region. In genetically susceptible patients, DHT can cause miniaturisation in the vertex and frontal hairline leading to AGA-patterned thinning.

Clinical Presentation & Diagnosis

• AGA presents with fronto-temporal recession and over the vertex: the occipital scalp is preserved.
• Diagnosis is made based on the clinical history; however a scalp biopsy may be needed in situations where the cause of hair loss is uncertain.
• Telogen effluvium may present like early phase AGA.

Current Topical Treatments

Minoxidil

• Minoxidil is the current topical standard treatment of hair loss. Initially used as an oral antihypertensive medication, its association with hypertrichosis led to its development as a topical therapy for AGA.
• Minoxidil 2% solution was approved by the US FDA for the treatment of MPHL in 1988, and was subsequently approved in 5% strength in a solution format in 1997 and in a foam format in 2006. The 2% solution formulation alone was approved in the US for female pattern hair loss in 1996. Minoxidil 2% solution became available in Canada for the treatment of MPHL in 1986, and the 5% foam in November 2012.⁴
• The content discussed here relates to the branded formulation of minoxidil only and not the compounded or generic formulations.
• The precise mechanism of action of minoxidil is unknown; however it is associated with vasodilation, angiogenesis and enhanced cell proliferation, probably mediated via potassium channel opening.^5,6 Further, it has been seen to prolong duration of anagen of the hair cycle, increase miniaturized hair follicle size, and preserve and thicken preexisting hair.
• Data from a 16-week, randomized, double-blind, placebo controlled (RCT) study of the newly approved minoxidil 5% foam application showed at weeks 8, 12 and 16 the mean increase in target area hair count was significantly greater than placebo (p<0.0001).⁷ At week 16 the percentage change in target area hair count was 13.4% in men treated with minoxidil 5% foam compared with 3% for the placebo arm (21.0 hairs/cm2 vs. 4.3 hairs/cm2, respectively).^7,8 Further, 38.3% of patients in the minoxidil arm demonstrated increased hair growth at week 16, compared with 5.2% in the placebo group (p<0.0001), as rated by an expert panel.⁷
• Data from a 48-week RCT also showed an increase in target area hair count in men treated with minoxidil solution, and that the product reversed hair loss as well as slowed its progression.⁹
• The same study also showed that target area hair counts were greater with the 5% solution compared with the 2% minoxidil solution.
• Minoxidil treatment is life-long: stopping treatment will result in a shedding of all minoxidil-dependent hair growth within 4-6 months after cessation of therapy.⁴
• The recommended dosing of minoxidil 2% solution is twice daily topical application of 1 ml spread evenly over the top of the dry scalp in the hair loss area.
• With minoxidil 5% foam, half a capful is applied twice daily on the dry scalp and left in place for at least four hours. To avoid the drug coming into contact with the face and limit the risk of hypertrichosis in non-scalp body areas, patients should wash their hands with warm water after application.
• Minoxidil has a well-established safety profile. The most frequently reported adverse drug reaction following the short-term, 16-week treatment with minoxidil 5% foam was headache.⁸ The most frequently reported dermatological adverse events were erythema, rash, acne and pruritis. In long-term treatment, the most frequently reported nonserious adverse events were infection and accidental injury.⁸
• The most frequently reported adverse events in the minoxidil 2% solution clinical trials were minor respiratory events, including colds and respiratory infections, rhinitis, sinusitis and coughing. Dermatologic adverse reactions were the next most frequent and included scaling, itching and rash.⁸
• Increased hair shedding is possible in the first 2-6 weeks of treatment, which likely results from inducing anagen from the resting phase.⁸ This may be an indication that minoxidil is effective; patients should be advised not to stop treatment if they experience hair loss for two weeks or less. However, if hair loss continues for longer than two weeks, patients should be advised to stop using the product and talk to their doctor.⁸
• Careful evaluation of the risks and benefits of minoxidil treatment should be considered in patients with pre-existing cardiac, renal or hepatic disease or scalp abnormalities and those receiving potentially interacting drugs concomitantly (e.g., hypotensive agents, such as guanethidine). If minoxidil therapy is initiated in these scenarios, patients should be closely monitored.¹⁰
• Allergic reaction to minoxidil is rare. Constituents of the vehicles may cause skin irritation. Irritant dermatitis to propylene glycol (a component of minoxidil 2% solution vehicle) may occur. Patch testing for propylene glycol can be performed as a precaution. If contact dermatitis results from minoxidil use, treatment should be stopped.
• Minoxidil 5% foam is propylene glycol free. Further, it is aesthetically more pleasing to patients compared to the solution, and thus likely increases compliance.
• Data show patients using the foam product rated it significantly higher compared with the minoxidil solution, finding it easy to apply, quick to absorb and non-drip.¹⁰
• Systemic absorption of minoxidil is weak with only 0.3-4.5% reaching the circulation. It is excreted within four days.

Other Topical Agents

Prostoglandins

• The prostaglandin F2α< analogues latanoprost and bimatoprost are widely used to treat glaucoma.
• Bimatoprost topical solution 0.03% is approved for treating hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.
• Topical latanoprost is under investigation for the treatment of AGA.¹¹

Ketoconazole

• Ketoconazole is an imidazole antifungal agent known to be effective for treatment of seborrheic dermatitis and dandruff. It is available as an over-the-counter topical shampoo at a 2% strength.
• Ketaconazole’s action on scalp microflora may benefit patients with AGA-associated follicular inflammation.^12,13
• While the mechanism by which ketoconazole may improve hair growth is unclear, it is known to have anti-inflammatory effects against T-cells which are found in the balding area in patients with AGA.¹⁴
• Further, ketoconazole decreases colonization of the skin by Malassezia.
• Ketoconaole also inhibits steroid synthesis and decreases DHT levels at the hair follicle by affecting androgen receptor activity.¹⁴

Conclusion

AGA is a common issue among men and can significantly affect self-esteem and quality of life, such that they may seek treatment. While different topical agents are currently being investigated for safety and efficacy, only one topical treatment, minoxidil, is currently approved for hair regrowth. The newly approved 5% foam solution has demonstrated patient preference, which in turn may improve compliance. Given its established efficacy and safety profile, minoxidil may be useful in the topical management of AGA in male patients.

References

1. Pray J. et al. US Pharmacist. 2003; 28(8)1.
2. Gan DC, et al. J Investig Dermatol Symp Proc. 2005;10(3):184-9.
3. Budd D. Eur J Dermatol. 2000 Mar;10(2):122-7.
4. Banka N, Dermatol Clin. 2013 Jan;31(1):129-40.
5. Alsantali A, et al. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):246-53.
6. Messenger AG, et al. Br J Dermatol. 2004 Feb;150(2):186-94.
7. Olsen EA, et al. J Am Acad Dermatol. 2007 Nov; 57(5):767–74.
8. ROGAINE® Canadian Product Monograph
9. Olsen EA, et al. J Am Acad Dermatol. 2002 Sep; 47(3):377-85.10.McEvoy, GK. American Hospital Formulary Service-Drug Information 2002.
10. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements).
11. Blume-Peytavi U, et al. J Am Acad Dermatol. 2012 May;66(5):794-800.
12. Pierard-Franchimont C, et al. Dermatology. 1998;196(4):474-7.
13. Magro CM. et al. J Drugs Dermatol. 2011 Dec; 10(12):1404-11.
14. Inui S, et al. J Dermatol Sci. 2007 Jan;45(1):66-8.

Department of Dermatology and Skin Science,
University of British Columbia, Vancouver, BC, Canada

Introduction

Acne vulgaris (AV) is among the most common dermatological disorders seen by dermatologists, affecting approximately 85% of people between the ages of 12 and 24 years.¹ Emerging evidence suggests that acne is associated with epidermal barrier impairments, including stratum corneum (SC) barrier permeability.²There is also mounting evidence to demonstrate an association between AV and inherent epidermal barrier dysfunction involving increased filaggrin expression and decreased ceramide levels.² While topical therapy remains a key therapeutic approach in the clinical management of AV, it can be associated with side effects that may compromise the SC and impair patient adherence. The use of adjunctive cleansers and moisturizers can help mitigate treatment side effects and subsequently enhance therapeutic efficacy.

Pathophysiology & Clinical Presentation

• The four main pathophysiologic features of AV are:³
  1. Androgen-mediated stimulation of sebaceous gland activity
  2. Abnormal keratinization leading to follicular plugging (comedone formation)
  3. Proliferation of Propionibacterium acnes (P. acnes) within the follicle
  4. Inflammation
• Genetic factors, stress and diet may also influence the development of acne.
• Some data suggest that patients with AV suffer from inherently compromised facial SC barrier permeability, and that the severity of AV may correlate with the degree of SC barrier impairment and decreased levels of free sphingosine and total ceramides, suggesting a deficiency of the intercellular lipid membrane.²
• Some medications used to treat AV can alter SC integrity and function, either via the active ingredient, the vehicle, or both. This can result in signs and symptoms of cutaneous irritation such as erythema, scaling and a burning or stinging sensation.²
• Recent data show that the experience of just one treatment-related side effect (e.g., irritation, dryness, redness) significantly, negatively impacts adherence to acne treatment.⁴

Topical Therapy

Topical therapy is used for mild to moderate acne and also for maintenance therapy in all severity levels (Table 1).

• Evidence-based treatment guidelines recommend fixed-dose combination topical BPO+adapalene (dose: BPO 2.5% + adapalene 0.1%) or BPO + clindamycin (available doses: clindamycin 1% + BPO 5%) for treatment of mild-moderate papulopustular acne.⁵
• Fixed-dose combination products reduce the number of medications and applications; therefore have potential to improve adherence.⁶
• Retinoids prevent and break down blackheads and also have anti-inflammatory activity.
• BPO is an antimicrobial agent that has some keratolytic effects and does not contribute to antibiotic resistance as it is bactericidal through an oxidative mechanism.
• Antibiotics have antimicrobial and anti-inflammatory effects. They can be used in conjunction with BPO lotion, gel or wash to limit antibiotic resistance. They should not be used for maintenance therapy.
• Topical dapsone gel is antimicrobial and antineutrophilic.
• New fixed-dose retinoid-based combination therapies are available (e.g., tretinoin and clindamycin).
• Combining a topical retinoid with a topical antimicrobial (BPO or topical/oral antibiotic) targets three pathogenic factors; trials show combination therapy results in significantly improved clearing as opposed to antimicrobial therapy alone.⁶

Cleansers & Moisturizers

• The goal of cleansing for patients with acne or acne-prone skin is to remove surface dirt, sweat, excess oil, exfoliated cells and micro-organisms without irritating or disrupting the skin’s protective barrier.
• Regular use of mild cleansers is an important component of effective acne management as a hydrated SC absorbs medication more readily and is less prone to irritation.
• Routine cleansing may enhance antimicrobial activity and decrease the risk of infection.
• Simplified treatment and skin care regimes should be recommended, including the use of an appropriate moisturizer and washing with a mild, soap-free cleanser twice daily.⁴

Types of Cleansers

• To date, limited published data exist to inform the clinical management of AV with regard to cleansers and moisturizers. Recommendations are based largely on general knowledge (e.g., non-soap based cleansers).
• Ideally, cleansers for acne skin should be: non-comedogenic, non-acnegenic, non-irritating, and non-allergenic.⁷
• A wide spectrum of skin cleansing agents exist for acne ranging from lipid free cleansers, syndets and astringents to exfoliants and abrasives.⁸
• Anionic detergents (i.e., soaps) can alter the natural pH of skin, which is normally between 5.3 and 5.9.
• An increase in pH can result in increased transepidermal water loss (TEWL), which causes dryness. Further, an increase in pH may facilitate microbial growth, which can exacerbate AV.⁹
• Abrasive cleansers can promote SC barrier dysfunction and contribute to signs and symptoms of irritation: these should be avoided.
• Suitable cleansers for acne-prone skin are generally based on mild synthetic surfactants that minimize the potential for skin barrier disturbances.
• Non-ionic surface-acting agents (e.g., silicone and polysorbate) are less likely to cause irritation and are formulated to the same pH as the skin (5.5).
• Silicone surfactants (e.g., dimethicone) such as Spectro®, are effective at eliminating surface debris without completely stripping away protective oils.
• Cleansers that contain zinc coceth and zinc gluconate, such as Cetaphil® DermaControl, also provide astringent properties without irritation or alteration to the pH level of the skin, and the zinc complex absorbs excess oil for a matte appearance of the skin.
• Cleansers containing emollients, such as Cetaphil® DermaControl, Effaclar, Spectro® and Cetaphil® Gentle Skin Cleanser can minimize damage to the SC barrier by emulsifying dirt and oil for easy removal. Additionally, Cetaphil® DermaControl contains humectants, which attract moisture to the skin in order to alleviate the drying effects of cleansing.

Types of Moisturizers

• Effective moisturizers combine humectants and emollients to prevent or reduce water evaporation, draw moisture up from deeper layers, alleviate xerosis and maintain skin barrier integrity.
• Moisturizers should also prevent primary irritation.
• Broad spectrum UVA/UVB sun protection is also important for patients with AV, particularly for those on topical and systemic retinoid therapy.¹⁰
• The different types of moisturizers include (Table 2):
  1. Occlusives
  2. Humectants
  3. Emollients
  4. Protein rejuvenators¹¹
  5. Ceramides
• Moisturizers containing ceramides have recently entered the market and work to replace naturally occurring lipids in the SC.
• The only published clinical trial data studying an adjunctive moisturizer in AV patients concerns Cetaphil® DermaControl. It contains ceramides and an oil-absorbing zinc complex. It is non-comedogenic, non-irritating, nonacnegenic and non-greasy.
• The recent development of oleosome technology, which is also present in Cetaphil® DermaControl, enables the delivery of broad spectrum UVA/UVB sun protection (SPF 30). This technology effectively reduces the concentration of filters being applied to the skin, decreasing the potential for skin sensitivity reactions.¹⁰

Acne Therapy & Adherence

• Treatment adherence in patients with AV is a significant problem and is documented at approximately 50%.⁴
• An estimated 30-40% of patients using topical acne treatment formulations do not comply with their prescribed regimen.¹²
• Clinical variables that have been shown to negatively impact adherence include age, patient satisfaction with treatment, and knowledge about acne treatment.⁴
• Irritation resulting from topical medications and the emergence of bacterial resistance to both topical and oral antibiotics remain significant barriers to good treatment adherence.
• Recent advances in vehicle technology have improved efficacy, local tolerance and adherence.¹³
• Additionally, novel delivery mechanisms and vehicles, such as pumps and foams, are convenient and preferred by patients, which may also improve adherence.¹⁴
• The appropriate selection and use of moisturizers has positive effects on treatment adherence.⁴
• Patient satisfaction with treatment and clinical improvement as evaluated by a dermatologist have been shown to improve treatment adherence and may also improve patient self-esteem.⁴
• Discuss realistic treatment expectations with patients and consider dosing strategies that can enhance adherence (Table 3).

Adjunctive Skin Care in Acne: Clinical Evidence

• Alleviating dryness and improving skin comfort by using a moisturizer concomitantly with retinoid therapy could enhance treatment efficacy. Data from a randomized, splitface study showed the application of a moisturizing cream applied twice daily for 15 days by patients taking either oral isotretinoin (10-20 mg) for two months or topical tretinoin 0.05% for one month provided significant improvements, compared with baseline, in the levels of skin dryness, roughness and desquamation induced by either drug.¹⁵ As well, skin properties and discomfort were substantially improved.
• Results from a study evaluating a facial moisturizer with SPF 30 and ceramide precursor formulated for blemish prone skin with 0.05% tretinoin found a patient preference for the moisturizer.¹⁰ It was a randomized, investigator-blinded, split-face study assessing erythema, scaling and dryness in patients with blemish prone skin. While both sides developed skin irritation, it worsened in the non-moisturized sides. Notably, all five parameters, namely erythema, scaling, dryness, stinging/burning and pruritus were improved on the sides treated with moisturizer.
• Adjunctive use of moisturizer with a topical tretinoin cream improved tolerance of the treatment.⁹

Conclusion

Skin barrier impairment in patients with AV can negatively impact acne treatment. Therefore, providing patient-specific skin care recommendations, including product selection and proper use, is an important part of the clinical management of AV and may improve patient tolerance to treatment.² The adjunctive use of appropriate gentle soap-free cleansers and non-comedogenic moisturizers, ideally products that also restore SC barrier function, provide SPF protection and reduce side effects of topical acne therapy, are recommended. Moreover, they are preferred by patients and will likely improve treatment adherence.

References

1. Leyden JJ. J Am Acad Dermatol. 2003 Sep;49(3 Suppl):S200-10.
2. Thiboutot D, et al. J Clin Aesthet Dermatol. 2013 Feb;6(2):18-24.
3. Haider A, et al. JAMA. 2004 Aug;292(6):726-35.
4. Dreno B, et al. Int J Dermatol. 2010 Apr;49(4):448-56.
5. European Dermatology Forum Guideline on Treatment of Acne
6. Zaenglein AL, et al. Pediatrics 2006 Sep; 118(3);1188-99)
7. Solomon BA, et al. Clin Dermatol.1996 Jan-Feb;14:95-9.
8. Mukhopadhyay P. Indian J. Dermatol.2011 Jan-Feb;56(1): 2-6.
9. Decker A, et al. J Clin Aesthet Dermatol. 2012 May;5(5): 32-40.
10. Schorr E, et al. J.Drugs in Dermatol. 2012 Sep;11(9) 957-60.
11. Lynde CW. Skin Therapy Lett. 2001. Dec;6(13):3-5.
12. Finlay AY. J Eur Acad Dermatol Venereol. 1999 Sep;12(Suppl 2):S77.
13. Koo J. Skinmed. 2003 Jul-Aug;2(4):229-33.
14. Vender R, et al. Patient preferences in acne: a point-of-care educational initiative. Poster presentation.
15. Laquieze S, et al. J Drugs Dermatol. 2006 Nov-Dec;5(10):985-90

Division of Dermatology, University of Toronto, Toronto, ON, Canada
Women’s College Hospital, Toronto, ON, Canada

Introduction

Acne vulgaris is a disease of the pilosebaceous follicle characterized by non-inflammatory (open and closed comedones) and inflammatory lesions (papules, pustules, and nodules). Its pathogenesis is multifactorial – the interplay of hormonal, bacterial, and immunological (inflammatory) factors results in the formation of acne lesions. Although acne is not a life-threatening condition, it can have detrimental effects on the quality of life of affected individuals. Fortunately, acne is readily responsive to the wide-range of available medications, with the goals of therapy being to clear the lesions, prevent scarring, and limit any treatment-related side-effects and psychosocial sequelae. Newer fixed-dose combination products target multiple acne pathogenic factors and offer simplified dosing regimens, which may potentially enhance both efficacy and patient adherence when compared with single agent therapy.

Acne Overview

Pathogenesis

• All forms of acne involve one or more of these pathophysiologic factors:
  • hyperkeratinization of the follicular epithelium with comedo formation
  • increased sebum production
  • bacterial proliferation of Propionibacterium acnes (P. acnes)
  • local immune activity causing inflammation
• Hormones are known to affect sebum production, but may also play a role in follicular hyperkeratinization independent of the effect on the sebaceous gland. During adrenarche, an increase in adrenal androgens leads to:
  • enlargement of sebaceous glands that results in increased sebum production.
  • abnormal desquamation and greater adhesion of the exfoliated keratinocytes in the sebaceous follicle, leading to obstruction in the follicle, and resulting in production of the microcomedo (a plug of keratin and sebum – the precursor of all acne lesions).
• Colonization of the pilosebaceous apparatus by P. acnes occurs in this anaerobic environment where sebum provides the nutrition for its survival. This gram-positive bacterium contributes to the inflammation by:
  • releasing enzymes
  • inducing cytokine release from other cells
  • triggering an immune response (e.g., antibody production)

Prevalence and Disease Features

• Acne affects about 85% of individuals between the ages of 12-24 years.¹ Persistent acne (beyond the teenage years) and adultonset are increasingly common.²
• Grading to determine acne severity is inherently subjective, as the process is largely based on clinical observation. Many grading systems have been developed that take into account lesion type and extent of involvement for measuring severity. Depending on the chosen technique, the measurement spectrum can range from Grades 1 to 4 all the way up to Grades 1 to 12. Acne may be classified according to predominance of specific skin lesions and the number of each lesion determines classification from mild to severe:
  • Comedonal (non-inflammatory) – mild, moderate, or severe
  • Papular (inflammatory) – mild, moderate, or severe
  • Pustular (inflammatory) – mild, moderate, or severe
  • Nodular – mild, moderate, or severe
• Acne can be physically and emotionally scarring, causing significant psychosocial morbidity and reduced self-esteem independent of acne severity.

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Treatment Overview

• The majority of patients present with mild-to-moderate comedonal or papulopustular acne that can be treated with topical agents (Table 1).
• Severe cases with nodules, cysts, or scarring will require the addition of systemic therapy.
• Available topical anti-acne compounds have a direct or indirect influence on the above mentioned pathogenetic factors.
• Treatment selection is guided by the predominant acne lesion type.

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Rationale for BP/Antibiotic Combination

Effective treatment considers all pathogenic factors and single-agent therapy does not address all four major pathophysiologic features of acne.

• Topical antibiotics have been used to treat acne for more than 40 years and are still widely used. The efficacy of antibiotics is attributable to their inhibitory effects on both the proliferation of P. acnes and inflammatory mediators.
• The emergence of resistant strains has, in some cases, been associated with a failure to respond to antibiotic therapy, which was first reported with the topical antibiotics clindamycin and erythromycin.³
• The use of BP reduces the occurrence of resistance and can be effective in the treatment of both nonresistant and resistant P. acnes strains.⁴
• BP does not promote antimicrobial resistance and has been shown to prevent such resistance when used concomitantly with topical erythromycin or topical clindamycin.
• A number of clinical studies have demonstrated improved efficacy and safety of combinational BP/antibiotic approach to acne management (Table 2).

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Combination Treatment Considerations

• Mild-to-moderate inflammatory acne can usually be managed with two topical drugs. Typically one is applied in the morning and the other at bedtime.
• A retinoid is used to deal with the precursor of all acne lesions (i.e., the microcomedo) and an antibacterial agent for its effects on P. acnes. Topical antibacterial options include BP or a BP/antibiotic combination.
• BP is extremely effective against P. acnes, but can be irritating. The irritation can be minimized by using the lowest concentration of BP in a water-based vehicle that does not reduce its efficacy. Another way to reduce the irritation induced by BP is to combine it with an antibiotic.
• BP/antibiotic combinations also reduce the irritation that can be induced by a topical retinoid. Only if a patient is allergic to BP (estimates range from 1%-2% of the population⁸) should a topical retinoid be used with a topical antibiotic alone. The topical antibiotic should be discontinued as soon as possible and the retinoid can be used for maintenance alone.

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Prescribing Recommendations to Minimize Bacterial Resistance

• Antibiotics should not be used as monotherapy, nor should they be used to treat mild acne.
• Avoid topical antibiotics if non-antibiotic topical preparations will suffice.
• Use alternatives to antibiotics for maintenance.
• Stop antibiotic treatment when the skin clears or if no further improvement is noted.
• If there is a failure to respond to oral antibiotics or a rapid relapse after discontinuation, consider other therapy (e.g., systemic retinoid, anti-androgens in women).
• If the antibiotic is needed again, use the same antibiotic.
• Use full doses of antibiotics and do not taper.
• Avoid concomitant topical and systemic use of different antibiotics to reduce the risk of developing resistance to both agents.
• Do not switch or rotate antibiotics in non-responding patients.
• Use BP during antibiotic therapy.
• BP bleaches clothing and hair, and thus, patients should be warned when prescribed.
• Limit the use of BP on the chest and back to night-time due to its bleaching effect on clothing or recommend that patients wear a white T-shirt under clothing for daytime application.

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Non-Adherence

• Patient non-adherence to treatment can influence outcomes, which is of particular concern with topical medications (e.g., proper application and accurate dosing).
• Some clinical strategies to promote treatment adherence include:
  • advocating patient involvement in therapeutic decision-making
  • devoting time to patient education on acne and the selected treatments, instructions for use, potential side-effects, and expected rate of improvement
  • selecting treatments that facilitate ease of use (i.e., once-daily dosing)
  • modifying current treatment if patient dissatisfaction is encountered

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Conclusion

Since multiple factors are involved in acne pathogenesis, treatment that targets the majority of these elements can be expected to achieve optimal results. When considering the options for reducing the P. acnes population, it is best to choose therapeutic agents that do not encourage resistance patterns. Evidence for improved efficacy, safety, and onset of action, as well as longer remission, has been noted with combination therapies. Advances in dual agent fixed-dose compounds offer simpler dosing regimes that can promote patient adherence. Furthermore, the cumulative benefits of these advances may lead to improved therapeutic outcomes and overall improvements in quality of life for acne patients.

References

1. Krowchuk DP, et al. Adolesc Med 12(2):vii, 355-74 (2001 Jun).
2. Tan JK. Skin Therapy Lett Pharm 4(2):1-3 (2009 Jul-Aug).
3. Crawford WW, et al. J Invest Dermatol 72(4):187-90 (1979 Apr).
4. Dutil M. Skin Therapy Lett 15(10):5-7 (2010 Nov-Dec).
5. Eady EA, et al. Br J Dermatol 134(1):107-13 (1996 Jan).
6. Lookingbill DP, et al. J Am Acad Dermatol 37(4):590-5 (1997 Oct).
7. Leyden JJ, et al. J Cutan Med Surg 5(1):37-42 (2001 Jan-Feb).
8. Lindemayr H, et al. Contact Dermatitis 7(3):137-40 (1981 May).

¹Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada

Introduction

Psoriasis is a chronic, recurrent, immune-mediated, papulosquamous skin condition characterized by rapid proliferation of keratinocytes. Worldwide prevalence is reported to be 2%¹ and incidence rates in the US and Canada have been reported to be as high as 4.6% and 4.7%, respectively.² Psoriasis is commonly manifested as well-defined erythematous plaques with silvery white scale on the elbows, knees, intergluteal cleft, and trunk. Between 50-80% of all psoriasis patients also develop scalp involvement at some stage.^3,4 Approximately 80% of patients affected with psoriasis have mild to moderate disease that can be managed with topical agents.¹ Various available topical therapies will be briefly discussed. The focus of this review will be on vitamin D3 analogues, including evidence from clinical trials investigating these agents.

Rationale for Treatment of Psoriasis

Although, in a vast majority of cases, psoriasis is not life threatening, it is associated with significant physical, psychological, social and economic burdens. Effective interventions are available that can dramatically improve disease symptoms and quality of life.

Patient-centered Care

The chronicity of psoriasis requires a long-term, patientspecific approach to management. From a pharmacologic perspective, factors that can influence treatment decisions include safety and efficacy, onset of action, product characteristics, and cost. As well, important considerations unique to each patient include medical history, disease severity, lifestyle, preferences, tolerability, and adherence.

The dominating factor for improving adherence to prescribed therapy is time invested by the physician, where clinical knowledge and experience are translated into patient care and treatment satisfaction. Strategies to build this interface include:

• Establishing good doctor-patient communications
• Modifying or adapting regimens based on response to therapy and patient feedback
• Selecting simple and effective therapeutic regimens
• Encouraging patient self-management (e.g. nonpharmacologic and lifestyle interventions)

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Topical Treatments for Psoriasis

Corticosteroids

• Corticosteroids have anti-inflammatory, anti-pruritic, vasoconstrictive, and immunosuppressive properties.¹
• They are available in an array of formulations and strengths, which make them suitable for treating different areas.¹ In general, ointments have the highest potency (due to occlusion and moisturization), and lotions, foams or gels are preferred for hair-bearing areas (due to ease of spreadability and minimal residue).¹
• The most efficacious topicals for treating psoriasis are highest potency steroids, followed by vitamin D3 analogues.¹
• Use is limited by potential side-effects (e.g., skin atrophy, striae, telangiectasia, tachyphylaxis).¹ Overuse or misuse are associated with hypothalamic-pituitary-adrenal (HPA) axis suppression.⁵
• Generally, treatment should continue until the skin is clear, then tapered. Therapy may be limited to 2-4 weeks in certain areas.¹
• Adverse effects may be minimized by once daily use; longterm remission may be maintained by application on alternate days.²

Other Agents

• Calcineurin inhibitors (tacrolimus and pimecrolimus) are immunomodulating compounds that act through T-cell modulation. They are particularly effective for treating psoriasis of the face and intertriginous areas.¹
• Retinoids (e.g., tazarotene) modulate cell differentiation and proliferation.¹ Tazarotene is available in cream or gel formulations, applied once daily. It is particularly useful for palmoplantar psoriasis as it does not leave a greasy residue.
• Anthralin and coal tar have a long history of use for psoriasis, but they have largely been replaced by newer agents with superior efficacy and better patient acceptability.¹
• Combination therapy is generally more efficacious than monotherapy¹ and can have a lower incidence of adverse effects. Common combinations include two topical agents or a topical agent with phototherapy.

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Vitamin D3 Analogues

Background

• In the 1990’s, the introduction of vitamin D3 analogues revolutionized the topical treatment for psoriasis. Due to their therapeutic efficacy and limited toxicity, vitamin D3 analogues have become a first-line option for psoriasis.¹
• Vitamin D3 analogues exert their effect by binding to nuclear vitamin D receptors, inhibiting keratinocyte proliferation and promoting differentiation. A recent study also showed calcipotriol induced apoptosis in psoriatic keratinocytes.⁶
• They can induce a steroid-sparing effect, thereby reducing side-effects such as skin atrophy, tachyphylaxis, and other adverse reactions related to corticosteroid use.
• Available vitamin D3 analogues in Canada include:
  • Calcipotriol ointment, cream, and scalp solution;
  • Calcitriol ointment; and
  • Calcipotriol + betamethasone dipropionate ointment and scalp gel.

Calcipotriol

• Calcipotriol 50 mcg/g ointment or cream (Dovonex®) is available for use on the body and 50 mcg/mL scalp solution is used on the scalp and other hair-bearing areas. It is used twice daily on affected areas and application can be reduced to once daily maintenance therapy when appropriate, and then discontinued after satisfactory improvement.
• In mild to moderate chronic plaque psoriasis, a systematic review showed calcipotriol was as effective as moderately potent topical steroids (e.g., betamethasone valerate ointment). It was also more effective when compared to calcitriol, coal tar, and short-contact dithranol.⁷
• Calcipotriol cream is also a highly efficacious maintenance treatment used alone or in an alternating regimen with calcipotriol/betamethasone dipropionate ointment.⁸
• Irritation can occur on sensitive areas (e.g., flexures, face and hairline). Up to 35% of patients can experience redness, burning, scaling, and pruritus in lesional / perilesional skin.¹
• Hypercalcemia is a rare concern; doses should be limited to 100 g/week of calcipotriol cream or ointment.¹
• Calcipotriol is clinically effective in children with very little risk of local or systemic side-effects.⁹ Maximum doses are calculated based on body surface area (BSA) and age.

Calcitriol

• Calcitriol ointment 3 mcg/g (Silkis™) is indicated for topical treatment of mild to moderate plaque-type psoriasis with up to 35% BSA involvement. Applied twice daily, no more than 30 g of ointment should be used daily, or 200 g per week.
• In two identically designed, randomized, double-blind, placebo-controlled trials of twice daily calcitriol ointment on mild to moderate psoriasis over 8 weeks, efficacy was seen as early as 2 weeks. At the end of 8 weeks, efficacy was sustained and significantly higher than placebo.¹⁰
• In two long-term studies over 52 weeks, no major safety concerns were reported. Adverse events (e.g., erythema, pruritus and skin discomfort) were mild.¹⁰ Calcitriol is less irritating than other vitamin D analogues, making it more suitable for use on the face and flexural areas.¹¹
• Treatment is approved for patients ≥18 years of age. Safety and efficacy in children have not yet been studied.

Calcipotriol and Betamethasone Dipropionate

• Calcipotriol/betamethasone dipropionate in ointment (Dovobet®) or scalp gel (Xamiol®) has a more rapid onset of action, greater efficacy, and comparable safety vs. either agent alone.^12-14
• It promotes normal keratinization, inhibits inflammation, and modulates epidermal proliferation and differentiation.
• When combined, the different modes of action of the two molecules become synergistic, enhancing efficacy and reducing side-effects.¹⁵
• It is an appropriate first-line therapy that is effective and well tolerated across all grades of disease severity.⁹
• Treatment is indicated for once daily application for 4 weeks, but long-term studies of both the ointment¹⁶ and scalp gel¹⁷ formulations have shown good tolerability and safety with as-needed use over 52 weeks.¹⁴
• Avoid use on the face, intertriginous or sensitive areas (e.g., flexural and genital regions).
• Up to 30% of BSA may be treated.
• Calcipotriol/betamethasone dipropionate therapy showed improvements in health-related quality of life measures and cost effectiveness through pharmacoeconomic analyses.¹⁴
• Treatment was well tolerated, the most common side-effects were mild to moderate lesional or perilesional irritation.¹⁴
• A 4-week, double-blind study in 24 patients with extensive psoriasis did not show HPA axis suppression. Furthermore, a follow-up study involving a subset of 19 patients over 52 weeks, some of who alternated with calcipotriol every 4 weeks, also did not demonstrate HPA axis suppression.¹⁴
• Calcipotriol/betamethasone dipropionate ointment cannot be compounded from its two individual ingredients, as this will result in a mixture that is both unstable and ineffective. However, the commercially available combination product is a stable preparation.

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Role of Family Physicians in Psoriasis Management

Even though the majority of psoriasis patients may be managed with topical medication, nonadherence rates for topical treatment is estimated at 40%,¹⁸ including up to 50% for unfilled prescriptions.¹⁹

As the primary contact for people seeking healthcare, family physicians play a crucial role in promoting treatment adherence among psoriasis patients. This may be achieved by adopting a more patient-specific approach to management, through engaging in ongoing discussions with patients about treatment expectations, choice of therapy, including offering simplified dosing regimens, as well as regularly assessing tolerability and side-effects from medications.

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Conclusion

Vitamin D3 analogues offer a form of topical treatment for plaque-type psoriasis that is effective, safe, and in the long run, cost-effective. Single product, fixed-dose, combination therapy is an important, once daily, topical option for the symptomatic treatment of psoriasis that yields comparable safety, increased efficacy, and improved cosmetic acceptance, resulting in higher patient adherence and optimized outcomes.

References

1. Menter A, et al. J Am Acad Dermatol 60(4):643-59 (2009 Apr).
2. van de Kerkhof PC. In: Bolognia J, et al. Dermatology. Philadelphia: Elsevier Limited, USA, p125-49 (2003).
3. van de Kerkhof PC, et al. Am J Clin Dermatol 2(3):159-65 (2001).
4. Papp K, et al. J Eur Acad Dermatol Venereol 21(9):1151-60 (2007 Oct).
5. Staughton RC, et al. Br Med J 2(5968):419-21 (1975 May 24).
6. Tiberio R, et al. Clin Exp Dermatol 34(8):e972-4 (2009 Dec).
7. Ashcroft DM, et al. BMJ 320(7240):963-7 (2000 Apr 8).
8. Segaert S, et al. J Dermatolog Treat 17(6):327-37 (2006).
9. Canadian Psoriasis Guidelines Committee. Canadian Guidelines for the Management of Plaque Psoriasis, 1st edition. June 2009.
10. Scott LJ, et al. Am J Clin Dermatol 2(2):95-120 (2001).
11. Del Rosso JQ, et al. J Clin Aesthet Dermatol 3(8):46-53 (2010).
12. Jemec GB, et al. J Am Acad Dermatol 59(3):455-63 (2008 Sep).
13. van de Kerkhof PC, et al. Br J Dermatol 160(1):170-6 (2009 Jan).
14. McCormack PL. Drugs 71(6):709-30 (2011 Apr 16).
15. Kircik L, et al. Skin Therapy Lett FP 4(2):4-5 (2008 May).
16. Kragballe K, et al. Br J Dermatol 154(6):1155-60 (2006 Jun).
17. Luger TA, et al. Dermatology 217(4):321-8 (2008).
18. Zaghloul SS, et al. Arch Dermatol 140(4):408-14 (2004 Apr).
19. Storm A, et al. J Am Acad Dermatol 59(1):27-33 (2008 Jul).

Section of Dermatology, University of Manitoba, Faculty of Medicine, Winnipeg, MB
CancerCare Manitoba, Winnipeg, MB

Introduction

External genital warts (EGW) are a common infection caused primarily by human papillomavirus (HPV) types 6 and 11. EGW negatively impacts upon patient psychosocial function and is a co-factor for infection with other sexually transmitted infections (STI), by allowing an easier portal of entry into the skin. Both patient and provider-applied therapies can be utilized in tandem to effectively treat EGW. More recently, prophylactic strategies using vaccines have been instituted to prevent HPV acquisition and resultant disease. As well, the recent introduction of a new formulation topical immunomodulator has further widened the spectrum of available therapies.

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Pathogenesis

• EGW is caused by human papillomavirus (HPV)
• An HPV viron is small and non-enveloped; its protein coat (capsid) is composed of two structural proteins
• The viral genome consists of single, supercoiled double-stranded circular DNA of approximately 8000 base pairs in size¹
• >200 types of HPV have been identified, approximately 40 infect the anogenital tract²
• HPV infections are categorized as low risk or high risk based upon oncogenic potential^3,4
• High risk-types include HPV 16, 18
  • Responsible for 100% cases of cervical cancer and 80% cases of anogenital cancers
• Low risk types include HPV 6, 11⁴
  • Responsible for 95% EGW cases
  • HPV 6: 74.4%
  • HPV 11: 14.2 %
  • HPV 6 and 11: 3.7%
• Low risk HPV types are also responsible for 10% of cervical intraepithelial neoplasia grade 1, 42% of related low-grade vulvar intraepithelial neoplasia, and 100% of recurrent respiratory papillomatosis

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Disease Overview

Epidemiology

• The World Health Organization estimated 300 million cases worldwide of HPV infection without any detectable abnormality; 30 million cases worldwide of active EGW
• Approximately 1 million new cases annually of EGW in the US⁵
• Prevalence in Manitoba (2004): 165.2 per 100,000 for men; 128.4 per 100,000 for women⁶
• Incidence in British Columbia (2004): 1.54 per 1000 males; 1.23 per 1000 females⁷
• In Canada, the incidence of genital warts was estimated to be 107 per 100,000 person-years in 1999, increasing to 126 per 100,000 person-years in 2006.⁷
• Incidence highest in women between the ages of 20-24 years (3.38 per 1000 women)
• Incidence highest in men aged 25-29 years (3.03 per 1000 men)

Burden of Disease

• Psychosocial impact⁸
  • Feelings of anger, disgust, embarrassment
  • Fear of cervical cancer
  • Concern over recurrence, transmission, and treatment
    efficacy
  • Change in lifestyle
• Socioeconomic burden
  • 60% increase in office visits (US) in last decade⁹
  • $220 million in health care costs (US 2004, private insurance)¹⁰
  • A population-based study of EGW treatment in British Columbia confirmed its significant burden on the health care system:⁷
    • Between 1998 to 2006, 39,493 patients were diagnosed with EGW, with 43,586 episodes
    • Overall incidence was 1.26 per 1000 population, at an average cost of $190 per episode for treatment, which translates into about $1 million annually in direct medical costs.
    • The incidence and prevalence of EGW are comparable across Canada.

Natural History

• EGW noted by patient in 65% of cases (52% females; 79% males)⁸
• EGW noted at physician visit in 16% of cases (30% females; 1% males)⁸
• Transmitted most commonly through sexual contact (i.e., genital-genital, oral-genital, genital-anal)
• Infection may also rarely occur due to perinatal transmission (laryngeal papillomatosis) or fomites¹¹
• HPV gains access to basal epithelium via abrasions or microabrasions
• Incubation (1-8 months)
• Individual patient immune response results in active growth or host containment (6-9 months)
• Clinical course of EGW include remission or persistent infection with recurrences
• 30% spontaneously resolve within 4 months, 50% at 6 months¹²

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Treatment Options (Table 1)

• Patients may prefer self-applied therapies for initial treatment
• Combination therapy may be more effective than monotherapy
• Inadequate responders may improve with transition to or addition of other therapies or modification of the existing approach
• According to Canadian STI Guidelines¹³ therapies are broadly grouped as patient-applied or office-based treatments:
  • Office-based treatments
    • Podophyllin resin (when no other treatment is available)
    • Surgical excision
    • Cryotherapy
    • Bichloracetic acid or trichloroacetic acid
  • Patient-applied treatments
    • Podophyllotoxin
    • Imiquimod
• Cytodestructive therapies involve the physical removal or chemical destruction of EGW:
  • Cryotherapy (liquid nitrogen)
  • Surgical/ablative techniques (surgical excision, carbon dioxide laser, electocautery)
  • Trichloroacetic or bichloroacetic acid
  • Podophyllin resin
  • Podophyllotoxin (0.5%) – standardized concentration of purified podophyllin
• Immunomodulatory therapy with topical imiquimod
  • Immune response modifier
  • Antiviral and antitumor effects
  • TLR-7 agonist
  • Induces Th1-type immune response and the generation of cytokines such as IFN-alpha
  • Pregnancy Category C
  • Due to its favourable efficacy, safety, and tolerability profiles, as well as lowest recurrence rate, Canadian Consensus Guidelines on HPV¹⁴ recommends the use of imiquimod prior to initiating more invasive strategies, such as destructive/excision or laser therapies.
  • Imiquimod 5% cream (Aldara™)
    • Approved by Health Canada in 1999
    • Officially indicated for the treatment of external genital and perianal warts in immunocompetent adults
    • Applied 3 times weekly for up to 16 weeks to a specific treatment area
    • In a Phase 3 clinical trial, 72% of women and 33% of men had complete clearance of baseline target warts (analyses did not include non-target or new warts)¹⁵
    • Side-effects include erythema (67%), erosion (32%), excoriation/flaking (25%), edema (16%)¹⁵
  • Imiquimod 3.75% cream (Vyloma™)
    • Approved by Health Canada in March 2011 for the topical treatment of external genital warts and perianal warts (whether present at the start of therapy or emerging during therapy) in immunocompetent adults.
    • Developed with the goal to shorten treatment duration, simplify dosing regimen, and improve tolerability, thereby encouraging adherence.
    • Two recent identical, gender stratified, randomized, placebo-controlled clinical studies involving 981 patients >12 years of age with 2-30 lesions in the inguinal area, perineal region, perianal area, penile shaft/glans/foreskin, scrotum, or vulva demonstrated imiquimod 3.75% applied once-daily for up to 8 weeks was well tolerated and efficacious in the treatment of EGW (Table 2 and Figure 1).^16,17
    • Efficacy was measured in terms of number of EGW (baseline and new).
    • In patients achieving complete clearance, almost 70% maintained clearance at 12 weeks post-treatment.¹⁷
    • Common side-effects included pain, irritation, and pruritus at the treatment site.

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Figure 1: Change in wart count compared with baseline (left axis, circle) compared with local skin reaction (LSR) sum score (right axis, square) for imiquimod 3.75% in women. Modified from Baker et al.¹⁶

Prevention

Two vaccines available for the prevention of HPV acquisition:

• Quadrivalent (HPV types 6, 11, 16, 18) vaccine (Gardasil®)²¹
  • Prevention of EGW caused by HPV 6, 11 and cervical cancer and other cancers caused by HPV 16, 18 including vulva and vaginal cancers, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, and vaginal intraepithelial neoplasia
  • Indicated in females aged 9-45 years
  • Indicated in males aged 9-26 years
• Bivalent (HPV types 16, 18) vaccine (Cervarix®)^22,23
  • Adjuvant results in very high serum antibody levels against HPV, excellent subtype cross-protection
  • Excellent for prevention of cervical cancer and other cancers caused by HPV 16, 18
  • Does not protect against EGW acquisition
  • Indicated in females aged 10-25 years

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Conclusion

EGW is a worldwide problem. The scope of diseases, both oncogenic and nononcogenic, caused by HPV is broad. EGW is a manifestation of nononcogenic HPV subtypes 6 and 11. Therapeutic strategies to eradicate EGW have been developed and preventative vaccines are now widely available. Hopefully, the development of novel therapeutic molecules targeting EGW will supplement current tools in the treatment armamentarium against HPV and facilitate the eradication of this prevalent disease.

References

1. Phelps WC, et al. Ann Intern Med 123(5):368-82 (1995 Sep 1).
2. Wiley D, et al. Obstet Gynecol Surv 61(6 Suppl 1):S3-14 (2006 Jun).
3. Munoz N, et al. N Engl J Med 348(6):518-27 (2003 Feb 6).
4. Garland SM, et al. Cancer Epidemiol Biomarkers Prev 18(6):1777-84 (2009 Jun).
5. Fleischer AB, Jr., et al. Sex Transm Dis 28(11):643-7 (2001 Nov).
6. Kliewer EV, et al. Sex Transm Dis 36(6):380-6 (2009 Jun).
7. Marra F, et al. Sex Transm Infect 85(2):111-5 (2009 Apr).
8. Maw RD, et al. Int J STD AIDS 9(10):571-8 (1998 Oct).
9. Centers for Disease Control and Prevention. STD Surveillance 2008. Table 43. Selected STDs and complications – initial visits to physicians’ offices, National Disease and Therapeutic Index: United States, 1966-2008.
10. Hoy T, et al. Curr Med Res Opin 25(10):2343-51 (2009 Oct).
11. Handsfield HH. Am J Med 102(5A):16-20 (1997 May 5).
12. Winer RL, et al. J Infect Dis 191(5):731-8 (2005 Mar 1).
13. Genital human papillomavirus (HPV) infections. Canadian guidelines on sexually transmitted infections. Public Health Agency of Canada (January 2008).
14. Roy M, et al. J Obstet Gynaecol Can 29(8 Suppl 3):S37-41 (2007 Aug).
15. Edwards L, et al. Arch Dermatol 134(1):25-30 (1998 Jan).
16. Baker DA, et al. Infect Dis Obstet Gynecol 2011:806105 (2011). Available at: http://www.hindawi.com/journals/idog/2011/806105/cta/
17. Ferris D, et al. Imiquimod 2.5% and 3.75% applied daily for up to 8 weeks to treat external genital warts. Poster (P-544) presented at The 26th International Papillomavirus Conference, Montreal, QC, July 3-8, 2010.
18. Gunter J. Am J Obstet Gynecol 189(3 Suppl):S3-11 (2003 Sep).
19. Scheinfeld N, et al. Dermatol Online J 12(3):5 (2006).
20. Gooderham M. Skin Therapy Lett FP 5(2):1-4 (2009 Jun).
21. Gardasil product monograph. Kirkland, QC: Merck Canada Inc.; August 26, 2011.
22. Cervarix product monograph. Mississauga, ON: GlaxoSmithKline Inc.; July 12, 2010.
23. Hsueh PR. J Microbiol Immunol Infect 42(2):101-6 (2009 Apr).

Department of Medicine, McMaster University, Hamilton, ON, Canada

Introduction

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Its pathophysiology is multifactorial and complex, including obstruction of the pilosebaceous unit due to increased sebum production, abnormal keratinization, proliferation of Propionibacterium acnes (P. acnes), and inflammation.

Topical agents are the most commonly used therapy for acne. First generation topicals mainly consist of single agent retinoids, benzoyl peroxide (BP), and antibacterials that target comedones, P. acnes, and inflammation. Novel topical therapies include combination products with advanced vehicle formulations that target multiple acne pathophysiologies and offer simplified treatment regimes. For example, the combination of clindamycin and tretinoin in a unique vehicle formulation of suspended crystalline tretinoin allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BP combinations target comedones, inflammation, and P. acnes synergistically. These newer combination products have the potential to increase both efficacy and patient adherence when compared with single agent treatment.

Disease Overview

Diagnostic Features and Grading (Table 1)

• Acne vulgaris has distinguishing comedones (open and closed) and inflammatory lesions in the form of papules, pustules, or nodules and cysts.^1,2
• The presence of comedones confirms the diagnosis of acne vulgaris.³

Differential Diagnosis Include:

• Rosacea
• Perioral dermatitis
• Bacterial folliculitis
• Drug induced acneiform eruptions

Prevalence, Pathophysiology and Psychosocial Impacts

• Acne is a common worldwide skin disease that affects about 85% of individuals between the ages of 12-24 years.⁴
• The four main pathophysiologic features include:³
  1. androgen-mediated stimulation of sebaceous gland activity,
  2. abnormal keratinization leading to follicular plugging (comedone formation),
  3. proliferation of P. acnes within the follicle, and
  4. inflammation.
• Genetic factors, stress, and possibly diet may influence the development of acne.³
• Acne can cause a considerable amount of emotional distress and physical discomfort, thus, medical treatment must be accompanied by patient counseling and education, which can contribute to improved self-esteem and adherence to therapy.

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Topical Treatment Overview and Options

Topical therapy (Tables 2 and 3) is used for mild to moderate acne and also for maintenance therapy in all levels of disease severity.

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Newer Novel Topical Agents

Clindamycin Phosphate 1.2% + Tretinoin 0.025% Gel (Biacna™)

• This fixed-dose combination gel was approved by Health Canada in December 2010 for the topical treatment of acne vulgaris in patients ≥12 years of age.⁷
• It combines the anti-inflammatory and antibacterial actions of clindamycin with the comedolytic and anticomedogenic actions of tretinoin⁷ to target several mechanisms in the pathogenesis of acne.
• Multiple studies have demonstrated significantly greater reductions in comedones and inflammatory lesions by 12 weeks compared with either agent alone or vehicle.^8-10
• A more rapid reduction in acne lesions was observed by 8 weeks compared with either agent alone or vehicle.⁸
• Application is recommended once-daily at bedtime (preferred) or morning (as the vehicle delivery formulation provides for the photostability of tretinoin).⁷
  • Patients should be instructed to use only a pea-sized amount.
• Vehicle characteristics
  • It is available as an aqueous gel that is alcohol free with a unique formulation.¹¹
  • It contains solubilized clindamycin phosphate and a stable combination of both solubilized and crystalline tretinoin.¹¹
  • The crystalline suspension allows for tretinoin to be released in a rate-controlled manner, thereby resulting in slower and progressive follicular penetration and increased tolerability.¹¹
  • Long-term efficacy and a favourable safety profile was shown in a 52 week study.¹²
• Side-effects and contraindications
  • Crohn’s disease, ulcerative colitis, colitis with previous antibiotic therapy, use of concomitant erythromycincontaining products, pregnancy (category C)⁷
  • Side-effects from topical retinoids may include peeling, redness, dryness, itching, and photosensitivity
  • Because tretinoin increases the skin’s sensitivity to UV light, patients should be reminded to avoid excessive or unnecessary sun exposure and wear sunscreen and protective clothing daily.

Adapalene 0.1% + Benzoyl Peroxide 2.5% Gel (Tactuo™)

• This combination treatment was Health Canada approved in May 2011.
• Proposed mechanism of action: adapalene has comedolytic, anticomedogenic, and anti-inflammatory effects and BP is a highly lipophilic oxidizing agent with bacteriocidal and keratolytic effects.¹³
• BP lowers the incidence of bacterial resistance compared with other topical antibiotics and can be used for the longterm management of acne.
• The complementary modes of action address 3 out of the 4 pathophysiologic processes of acne:
  1. abnormal keratinization leading to follicular plugging (comedone formation),
  2. proliferation of the bacterium P. acnes within the follicle, and
  3. inflammation.
• Large double-blinded randomized controlled trials showed that this combination gel was significantly more effective than the respective monotherapies, producing marked differences in total lesion counts.^14,15
• Studies demonstrated a comparable safety profile to adapalene.¹⁵
• Adapalene is stable when combined with BP in the presence or absence of light.¹³
• Once-daily dosing provides regime simplicity.

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Bacterial Resistance in Acne

• Antibiotics are recommended for use with BP (available in gel, lotion, and wash).
• BP is an efficient bactericidal agent that will minimize the development of bacterial resistance at skin sites where topical antibiotic (i.e., clindamycin and erythromycin) therapy is applied.
• BP is effective against both nonresistant and resistant P. acnes strains.¹⁶
• A 4-week randomized study of patients with mild to moderate acne explored the safety and tolerability of fixed combination clindamycin phosphate and tretinoin gel (CT) once-daily in conjunction with morning use of a BP wash, targeting several pathologic factors and limiting the potential for clindamycin-induced P. acnes resistant strains.¹⁷
  • Side-effects were mild and included transient dryness, scaling, erythema, burning, stinging, and itching during the first week of therapy, then improving within 1-2 weeks.
  • CT gel + BP wash was shown to be a safe and welltolerated therapeutic regimen to effectively treat acne while mitigating the potential for bacterial resistance.

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Patient Adherence

Acne is a chronic disease and poor medication adherence is a major contributor to treatment unresponsiveness.¹⁸ Factors that can impact treatment follow-through include:

• Convenience and decreased complexity of treatment encourage patient adherence.
• Treatment regimens that are effective and well-tolerated, as well as simple and easy to incorporate into the patient’s lifestyle, are more likely to increase adherence.
• Patients most commonly attribute frustration with the therapeutic regimen and forgetfulness as reasons for failure to use prescribed medications.¹⁹

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Conclusion

The successful topical treatment of acne depends on appropriate agent selection based on patient-specific acne severity, tolerance, adherence, and adequate follow-up. The advent of combinational therapeutic products provide increased efficacy by targeting multiple pathophysiologic processes. Additional advantages of using combination therapy include reduced complexity of treatment regimen and convenient once-daily dosing. The future of topical acne treatment holds the promise of more novel uses of conventional anti-acne agents formulated with advanced vehicle delivery systems that offer less side-effects, increased tolerance, dosing simplicity, and improved efficacy.

References

1. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol 56(4):651-63 (2007 Apr).
2. Witkowski JA, Parish LC. The assessment of acne: an evaluation of grading and lesion counting in the measurement of acne. Clin Dermatol 22(5):394-7 (2004 Sep-Oct).
3. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 292(6):726-35 (2004 Aug).
4. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 49(3 Suppl):S200-10 (2003 Sep).
5. Tan JK. Topical acne therapy: current and advanced options for optimizing adherence. Skin Therapy Lett Pharm 4(2):1-3 (2009 Jul-Aug).
6. Alexis AF. Clinical considerations on the use of concomitant therapy in the treatment of acne. J Dermatolog Treat 19(4):199-209 (2008).
7. Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/tretinoin gel formulation in the treatment of acne vulgaris. Expert Opin Pharmacother 9(16):2931-7 (2008 Nov).
8. Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/ tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris. J Am Acad Dermatol 54(1):73-81 (2006 Jan).
9. Eichenfield LF, Wortzman M. A novel gel formulation of 0.25% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Pediatr Dermatol 26(3):257-61 (2009 May-Jun).
10. Schlessinger J, Menter A, Gold M, et al. Clinical safety and efficacy studies of a novel formulation combining 1.2% clindamycin phosphate and 0.025% tretinoin for the treatment of acne vulgaris. J Drugs Dermatol 6(6):607-15 (2007 Jun).
11. Del Rosso JQ, Jitpraphai W, Bhambri S, et al. Clindamycin phosphate 1.2%-tretinoin 0.025% gel: vehicle characteristics, stability, and tolerability. Cutis 81(5):405-8 (2008 May).
12. Kircik LH, Peredo MI, Bucko AD, et al. Safety of a novel gel formulation of clindamycin phosphate 1.2%-tretinoin 0.025%: results from a 52-week openlabel study. Cutis 82(5):358-66 (2008 Nov).
13. Tan JK. Adapalene 0.1% and benzoyl peroxide 2.5%: a novel combination for treatment of acne vulgaris. Skin Therapy Lett 14(6):4-5 (2009 Jul-Aug).
14. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixeddose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 57(5):791-9 (2007 Nov).
15. Gold LS, Tan J, Cruz-Santana A, et al. A North American study of adapalenebenzoyl peroxide combination gel in the treatment of acne. Cutis 84(2):110-6 (2009 Aug).
16. Dutil M. Benzoyl peroxide: enhancing antibiotic efficacy in acne management. Skin Therapy Lett 15(10):5-7 (2010 Nov-Dec).
17. Draelos ZD, Potts A, Alio Saenz AB. Randomized tolerability analysis of clindamycin phosphate 1.2%-tretinoin 0.025% gel used with benzoyl peroxide wash 4% for acne vulgaris. Cutis 86(6):310-8 (2010 Dec).
18. Yentzer BA, Ade RA, Fountain JM, et al. Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. Cutis 86(2):103-8 (2010 Aug).
19. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol 152(5):1015-21 (2005 May).

Faculty of Medicine, Sherbrooke University, Sherbrook, QC Dermatology Clinic, Moncton, NB

Introduction

Atopic eczema (or atopic dermatitis) is a common inflammatory skin condition that dermatologists, pediatricians, family physicians, and primary-care providers see on a daily basis. It generally presents as a chronically relapsing, highly pruritic, inflammatory skin disease that is associated with significantly reduced quality of life for patients and their families. Irritability, fatigue, sleep disturbances, treatment dependence, mood changes, and other psychological sequelae are frequently reported. Also, the social stigma associated with this visible skin condition should not be neglected.^1-3

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Overview of Atopic Dermatitis

• Eczema is characterized by a chronic course of recurring flares, as it often presents with periods of remission and flare-ups; continuous treatment and skin care are necessary.^1-3
• Eczema can occur at any age, but it typically appears in early childhood (although late-onset disease is possible), with disease flares occurring periodically throughout the patient’s life.¹
• It is estimated that up to 17% of Canadians will develop atopic eczema at some point during their lifetime.⁴
• Atopic eczema has become more prevalent over the past few decades. Approximately half of eczema patients will develop the disease before 1 year of age.² Of these, approximately one-third will continue to suffer from eczema in adulthood.
• Most patients (approximately 85%) have mild to moderate disease.¹

Pathogenic and Other Contributing Factors

• The exact cause of atopic eczema is unknown, however, it is believed to have a multifactorial pathogenesis, with genetics, impaired immune responses, the environment, and skin barrier defects being the most predominant contributing factors.³
• The epidermis is the body’s first line of defense against environmental insults, as it forms a protective layer between the body and exogenous factors.⁵
  • An intact epidermal layer is essential for the skin to function as a physical and chemical barrier against environmental agents.⁵
  • Any breakdown in the epidermis increases skin moisture loss and the penetration of infectious and noxious external agents.⁵
• Several genetic factors are known to contribute to the dysfunction of the epidermal barrier in atopic eczema.
  • In particular, genetic defects associated with increased IgE (antibody) production and protease expression, and decreased levels of structural proteins in the epidermis have been linked to atopic eczema.
  • Gene mutations are believed to engender some of the aforementioned structural abnormalities in the epidermis and induce immune dysregulation.⁴
• The scratching that can result from symptomatic pruritus may additionally cause skin trauma and excoriation, potentially leading to further inflammation, disease exacerbation, and secondary infections.
• Environmental factors may also contribute to skin barrier dysfunction, including washing with harsh soaps and detergents, and exposure to various infectious and noxious agents.
  • Soap or detergent use is one of the most common triggers of atopic eczema flares by adversely affecting the skin barrier. The use of inappropriate cleansing agents increases transepidermal water loss (TEWL), induces the release of pro-inflammatory cytokines, and elevates skin pH – provoking scaling, dryness, tightness and roughness, erythema, and swelling.

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Treatment Rationale

Management of atopic dermatitis is frequently multimodal, incorporating several non-pharmacologic and pharmacologic approaches.

• Basic skin care practices, such as quick daily bathing and gentle cleansing of skin with mild, unscented soaps/cleansers, followed by moisturization (hydration) with emollients can minimize the skin impairment and treat the symptoms of dry skin and itching.⁶
• Additionally, the avoidance of irritants and other triggers known to exacerbate atopic eczema may prove useful in preventing flares.⁶
• However, despite vigilant skin care practices, most patients will continue to experience atopic eczema symptoms and recurrent flares that will require pharmacologic treatment.⁶

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Treatment Options

Topical Corticosteroids

• Topical corticosteroids have been the predominant atopic eczema therapy for more than four decades – they provide flare control through their anti-inflammatory, anti-proliferative, immunosuppressive, and vasoconstrictive actions.
• Common adverse effects of topical corticosteriods include striation, skin thinning and atrophy, and potential systemic effects.³

Topical Calcineurin Inhibitors

• The topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, are alternative topical anti-inflammatory agents in the clinician’s armamentarium.
• These agents may be used on all body parts, including sensitive areas, such as the face, neck, and groin.
• They can also be used in patients who have experienced steroid related side-effects or in those suffering from a chronic disease that is unresponsive to topical steroids, as well as in patients for whom therapy with steroids is inadvisable or has been unsuccessful.²
• The calcineurin inhibitors do not cause the adverse effects on collagen synthesis or skin thickness as compared with topical corticosteroids.⁷
• Long-term treatment with tacrolimus has also been associated with improvements in collagen synthesis and skin thickness.7

Antimicrobials

• Antimicrobials are commonly prescribed for clinically infected eczematous lesions where Staphylococcus aureus colonization is suspected as a contributing factor.
• Short-term combination topical therapy with an antibiotic and corticosteroid is widely used. However, overuse and prolonged treatment increases the risk for developing antibiotic resistance.
• A recent report in Cochrane Database Systematic Review did not find clear evidence of benefit for antimicrobial interventions in atopic dermatitis patients.⁸

Lifestyle/Non-pharmacologic Strategies

• Identify and eliminate triggering factors
• Avoid allergens
• Minimize exposure to irritants (e.g., wool, perfumes, soap, hot baths or showers)
• Use emollients to hydrate and rehydrate
• Ensure that sports equipment is dried completely – sweat is a common irritant
• Encourage patient self-education, suggest visiting reputable websites (e.g., Canadian Skin Patient Alliance, Eczema Society of Canada, and the Canadian Dermatology Association)

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A Paradigm Shift in the Management of Eczema

• Conventional therapeutic approaches have been recently challenged by a newer strategy that takes a preventative long-term approach to treating atopic eczema.^7,9
• The clinical justification for preventative maintenance therapy is that it can improve atopic eczema related skin barrier dysfunction and diminish the immunological inflammatory abnormalities often associated with chronic eczematous flares and disease exacerbation.⁹
• The preventative maintenance approach uses intensive topical anti-inflammatory therapy until visible lesions have nearly cleared.^7,9 This is followed by low dose intermittent application, usually twice-weekly, of anti-inflammatory agents to previously affected skin areas to prevent flares and disease exacerbation.^7,9
• Several clinical trials comparing the preventative to the traditional “reactive” approach using topical corticosteroids have shown that preventative therapy is an effective strategy.¹⁰
• In 2002, Hanifin et al. published a randomized, double-blinded, 20-week clinical trial comparing the preventative application of 0.05% fluticasone cream with vehicle cream.¹¹
  • Patients preventatively receiving 0.05% fluticasone cream were 7.7 times less likely to experience a flare relapse than those receiving vehicle.
• Alternatively, preventative use of 0.1% and 0.03% tacrolimus ointment was recently studied in two large, multicentre, randomized, double-blind, 12-month clinical trials involving adult (n=257) and pediatric (n=125) atopic eczema patients.⁹
  • Patients were randomized to twice-weekly preventative tacrolimus therapy or twice-weekly vehicle after an initial flare treatment with twice-daily tacrolimus ointment.
  • Preventative application of tacrolimus significantly reduced the number of disease exacerbations requiring substantial therapeutic intervention in both treatment populations.
  • Preventative therapy also resulted in significantly fewer treatment days (12.4 vs. 31.5), and increased flare-free time until first relapse (142 days vs. 15 days) in adult patients.^9-14 In addition, preventative therapy in children significantly reduced the number of treatment days (34.0 vs. 59.9), and prolonged the time to first relapse compared with reactive treatment (295 days vs. 56 days).^12-15
  • Similar results have also been shown in trials reporting the use of pimecrolimus cream for flare prevention in children.¹³
• TCIs may offer benefits over corticosteroids in the long-term treatment of atopic eczema given their lack of association with skin atrophy and decrease in collagen synthesis.^3-7,9
• Based on the above studies, in September 2010, Health Canada approved a new indication for the use of tacrolimus ointment as maintenance therapy in moderate to severe atopic dermatitis.¹⁶

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Conclusion

As there is no cure for atopic eczema, a long-term strategy for disease control and management is of significant importance for this chronically relapsing condition. Recent insights into the mechanisms that drive cutaneous inflammation have led to a better understanding of atopic eczema and highlighted the role of the epidermal barrier in its pathogenesis. Targeting the skin barrier and restoring its function may prove an effective treatment strategy for atopic eczema. Preventative treatment with topical steroids or topical calcineurin inhibitors offer a novel therapeutic approach with clinical implications for physicians and their patients. Furthermore, studies have shown that topical tacrolimus may confer additional benefits, as it improves the functionality of the skin barrier and does not cause skin atrophy. As demonstrated in clinical investigations, the substantial reduction in flare-ups among preventatively treated patients may result in fewer atopic eczema-related physician visits and quality of life improvements (e.g., work/school performance).

References

1. Bieber T. Atopic dermatitis. N Engl J Med 358(14):1483-94 (2008 Apr 3).
2. Lynde C, et al. J Cutan Med Surg (Epub: 2005 Jun 30).
3. Ong PY, et al. Prim Care 35(1):105-17, vii (2008 Mar).
4. Barnes KC. J Allergy Clin Immunol 125(1):16-29 e1-11 (2010 Jan).
5. Cork MJ, et al. J Invest Dermatol 129(8):1892-908 (2009 Aug).
6. Darsow U, et al. J Eur Acad Dermatol Venereol 24(3):317-28 (2010 Mar).
7. Rustin MH. Br J Dermatol 157(5):861-73 (2007 Nov).
8. Birnie AJ, et al. Cochrane Database Syst Rev (3):CD003871 (2008).
9. Wollenberg A, et al. Allergy 63(6):742-50 (2008 Jun).
10. Wollenberg A, et al. Allergy 64(2):276-8 (2009 Feb).
11. Hanifin J, et al. Br J Dermatol 147(3):528-37 (2002 Sep).
12. Thaci D, et al. Br J Dermatol 159(6):1348-56 (2008 Dec).
13. Sigurgeirsson B, et al. J Eur Acad Dermatol Venereol 22(11):1290-301 (2008 Nov).
14. Wollenberg A, et al. Br J Dermatol 159(6):1322-30 (2008 Dec).
15. Thaci D, et al. J Eur Acad Dermatol Venereol 24(9):1040-6 (2010 Sep).
16. Tacrolimus ointment (Protopic®) product monograph. Astellas Pharma Canada, Inc., Markham, ON, Canada (2010 Sep).

¹ Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
² Section of Dermatology, University of Manitoba, Winnipeg, MB, Canada

Introduction

Head lice infestations (Pediculosis capitis) are a worldwide problem with prevalence estimates typically ranging between 1-3% in elementary school aged children.^1,2 Although this obligate parasite is a nuisance, infestation does not pose a health risk. Infestations tend to occur more frequently in females,³ and less frequently in black children,⁴ as it may be more difficult for lice to grasp their oval-shaped hair shafts. It is not associated with poor hygiene. Infestation occurs across all levels of society, but occurs more frequently under conditions of overcrowding. Recent evidence suggests increasing frequency of topical treatment failure may be related to a growing resistance to the neurotoxic pediculicides that have been the first-line treatment for the last 40 years.⁵ Herein, we will review the current topical treatment options, including newer non-pediculicidal options.

Overview of Facts on Lice

• Pediculus humanus capitis (the head louse) is a 2-4 mm blood sucking, wingless insect.
• A louse cannot jump, but rather has 6 legs adapted for crawling along hairs at 23 cm per minute.⁶
• A louse will feed every 3-6 hours.
• Prior to feeding, the louse injects saliva into the skin.
• The life span is approximately 4 weeks and the female lays 6-8 eggs per day.
• Eggs hatch in 8 days, leaving their shell (“nit”) cemented to the base of the hair.
• Head lice spread by head contact, shared fabrics, shared combs, and other fomites that are commonly in contact with the scalp and hair.⁷
• A louse can survive 2-3 days away from a human host.
• Pets are not vectors.

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Diagnosis and Symptoms

Many affected individuals report no symptoms, but the most commonly reported symptom is scalp pruritus.⁸ The pruritus is thought to be caused by hypersensitivity to the louse saliva that is injected into the scalp during feeding, but the itching often does not begin until 1-4 weeks after infestation. Although any part of the scalp may be colonized, there seems to be a predilection for the nape of the neck and post-auricular areas.

Skin Findings

• Often there are no significant findings on the skin.
• Pruritic, papular lesions may be found at the nape of the neck.
• There may be excoriations on the scalp.
• Secondary staphylococcal infection is possible.
• Possible enlargement of cervical / nuchal lymph nodes.

Hair Findings

• True infestation is confirmed by the presence of live adult lice or nymphs (hatched immature lice) present on the scalp with nits.
• The presence of nits alone does not confirm infestation, as an empty nit can remain cemented to a hair even after the infestation has cleared.
• The distance of the nit from the scalp can be a clue to the duration of the infestation, as it moves with the hair away from the scalp when hair grows.
• A nit within 0.6 mm of the scalp is usually a viable egg.

Diagnosis is best made by wet or dry combing the scalp with a fine-toothed nit comb with teeth spaced 0.2 mm apart. One study comparing wet combing with visual inspection found that wet combing accurately diagnosed infestation 90.5% of the time, as compared to 28.6% with visual inspection.²

Directions for Detection by Wet Combing⁹

• Saturate hair with a conditioner.
• Remove tangles with a regular comb.
• With the nit comb against the scalp, comb to the end of the hair.
• Check the comb for lice after each pull by visual inspection and by cleaning the comb with a tissue and inspecting the contents.
• Dispose of the tissue in a plastic bag.
• Comb the entire scalp at least 5 times.
• Seal the plastic bag and dispose of it.
• If infestation is confirmed, rinse off all conditioner prior to treatment.

Treatment Options

Management

Traditionally, topical pediculicides have been the mainstay in the initial treatment of pediculosis. They are widely available without a prescription, which has contributed to the difficulty in gathering data on the true prevalence of infestation. Easy access and improper use has likely contributed to the significant resistance that has developed against topical pediculicides. Knockdown resistance (kdr) is a heritable insensitivity to dichlorodiphenyltrichloroethane (DDT), the pyrethrins, and the pyrethroids. A recent study examining lice collected in Quebec, Ontario, and British Columbia found the allele for resistance present in 97.1% of the 274 lice sampled.⁵ These findings suggest that a significant resistance to the traditional first-line treatment options exists within Canada.

In recognition of the developing resistance, there has been an increased interest within Canada to explore effective non-pediculicidal options. A recent study found the efficacy of isopropyl myristate 50% to be significantly higher (57%) than the standard treatment with pyrethrin 0.33% + piperonyl butoxide 4%.¹⁰

While non-pediculicidal therapy may be efficacious against treatment resistant infestations, re-infestation from close contacts and fomite transmission is a common problem. Along with treatment, it is important to decontaminate the environment.

Environmental Decontamination¹⁴

• Family members and close contacts should be examined and be treated for any infestation.
• Any clothing, linens, combs, toys, and fabrics used by the individuals in the 3 days preceding treatment should be decontaminated.
• Fabrics can be washed in high heat and put in a hot dryer for 20 minutes.
• Items that cannot be washed can be sealed in a plastic bag for 14 days or placed in the freezer for 24 hours.
• Brushes can be soaked in rubbing alcohol for 1 hour.
• Floors and furniture can be cleaned by vacuuming.
• Spraying the home with a pediculicide is not recommended.
• No nit policies at schools are unnecessary.

Management Tree

(scalp pruritus, papules at the nape of the neck, or known close contact with another infested individual)

Examine scalp using fine-toothed nit comb (0.2 mm spacing) Wet hair with lubricant, such as hair conditioner (optional), and comb front to back with the comb against the scalp

By wet or dry combing (presence of live adult louse or nymph)

Choose treatment (based on patient preference, age, and local resistance to topical pediculicides)

Take measures to decrease risk of reinfestation and spread (treat all family members, notify school, and decontaminate environment)

Manual Removal

Some patients may prefer to attempt mechanical treatments prior to topical therapy. Wet combing, as described earlier, can be both diagnostic and therapeutic. To attempt this method the patient should wet comb the entire scalp until no more lice are found every 3-4 days for 3 weeks, or at least 2 weeks after the last adult louse was found.¹⁴

Treatment Failure

Treatment failure is commonly a result of inadequate or improper treatment, resistance, or reinfestation. If environmental decontamination was performed and the treatment was properly administered, then immediate retreatment with a different agent is advised.

Conclusion

Head lice infestation is a common problem for children in Canada. The first-line treatment of using topical pediculicides is unfortunately not as effective as it once was because of a heritable resistance that seems to be rising in prevalence. Topical non-pediculicides may be an effective option in the case of failed treatment due to louse resistance to standard treatment.

References

1. Harris J, et al. Commun Dis Public Health 6(3):246-9 (2003 Sep).
2. Jahnke C, et al. Arch Dermatol 145(3):309-13 (2009 Mar).
3. Counahan M, et al. J Paediatr Child Health 40(11):616-9 (2004 Nov).
4. Centers for Disease Control and Prevention. Fact sheet: head lice. Available at: http://www.cdc.gov/lice/head/factsheet.html. Accessed June 28, 2010.
5. Marcoux D, et al. J Cutan Med Surg 14(3):115-8 (2010 May-Jun).
6. Ko CJ, et al. J Am Acad Dermatol 50(1):1-12 (2004 Jan).
7. Burkhart CN, et al. J Am Acad Dermatol 56(6):1044-7 (2007 Jun).
8. Mumcuoglu KY, et al. J Med Entomol 41(4):803-6 (2004 Jul).
9. District Health Authority Public Health Services of Nova Scotia. Guidelines for treatment of pediculosis capitis (head lice), August 2008.
10. Kaul N, et al. J Cutan Med Surg 11(5):161-7 (2007 Sep-Oct).
11. Mumcuoglu KY, et al. Isr Med Assoc J 4(10):790-3 (2002 Oct).
12. US Food and Drug Administration public health advisory on lindane.
13. Position Statement from Infectious Diseases and Immunization Committee, Canadian Paediatric Society. Paediatr Child Health 13(8):692-704 (2008 Oct).
14. Goldstein AO, et al. (2010 Jan). Available at: http://www.uptodate.com/home/index.html. Accessed July 3, 2010.

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.

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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

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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).

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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.

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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).