¹Dermatology Research Institute, Calgary, AB, Canada
²Faculty of Medicine, University of Western Ontario, London, ON, Canada
³Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
⁴Department of Dermatology, McMaster University, Hamilton, ON, Canada
⁵Dermatrials Research Inc. & Venderm Consulting, Hamilton, ON, Canada
⁶Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁷Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁸Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁹Probity Medical Research, Waterloo, ON, Canada
¹⁰Skin Health & Wellness Centre, Calgary, AB, Canada
¹¹Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹²Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ronald Vender has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, Aralez, Arcutis, Astellas, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Centocor, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Innovaderm, Janssen, Kabi-Care, LEO Pharma, Merck, Novartis, Palladin, Pfizer, Regeneron, Sandoz, Sun Pharma, Takeda, UCB, and Viatris-Mylan. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Alim R. Devani has been an advisor, consultant, speaker, and/ or investigator for AbbVie, Amgen, AnaptysBio, Arcutis, Arena, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, Tribute, UCB, and Valeant. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Apogee Therapeutics, Aralez, Arcutis, Arena, Asana, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, RAPT Therapeutics, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, Tribute, UCB, and Valeant. Tuba Bukhari, Mariya Markovina, Abrahim Abduelmula, and Brian D. Rankin have no relevant disclosures. Funding sources: None.

Abstract: Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

Keywords: spesolimab, generalized pustular psoriasis, clinical trial, biologics, interleukin-36

Introduction

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations, which, if left untreated, can be life-threatening in certain instances.^1,2 According to the European Rare and Severe Psoriasis Expert Network (ERASPEN) criteria, GPP is defined by the presence of “primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques)”, with 3 subclassifications, including “with or without systemic inflammation”, “with or without psoriasis vulgaris”, and “either relapsing (>1 episode) or persistent (>3 months)”.³ The prevalence of GPP varies with geographic location, where it was reported to be higher in Italy, impacting 180 cases per million, but lower in Japan, Germany, and France with 7.5, 5.0, and 1.8 cases per million, respectively.^4,5 GPP can have a pediatric- or adult-onset, and there is a slight female predilection.³ GPP adversely affects patient quality of life (QoL) and can also have a profound negative impact on families.⁶

Homozygous, heterozygous, and compound heterozygous lossof- function mutations in the interleukin (IL)-36 (IL-36) receptor antagonist gene (IL36RN), as well as mutations in other genes involved in the IL-36 signaling pathway, including, CARD14, AP1S3, and SERPINA3, have been identified in a proportion of patients with GPP.^7-9 Moreover, genotype-phenotype studies revealed that 24% of patients with GPP had IL36RN gene variants. The latter was associated with earlier age of onset/diagnosis, a greater degree of inflammation, and more severe disease.^10,11

Presently, there are no universally-accepted international consensus guidelines regarding the management of GPP. In the majority of countries, current first-line systemic therapies are being used offlabel. These include non-biologics, such as acitretin, cyclosporine, methotrexate, and apremilast, as well as biologics, including inhibitors of tumor necrosis factor-alpha, IL-12/23, IL-23, and IL-17.^12-14 Thus, there remains a significant unmet need for an advanced targeted systemic therapy that effectively treats acute GPP flares. Recently, Health Canada and the US FDA approved spesolimab, a novel IL-36 inhibitor, for the latter indication in adults.1 This biologic is the first commercially available IL-36 inhibitor for any indication.

Background

Spesolimab (Spevigo®) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively inhibits the IL-36 receptor (IL-36R), thereby preventing activation of the IL-36 signaling pathway which leads to release of the pro-inflammatory cytokines (IL-36A, IL-36B, and IL-36G) that cause GPP.¹ By inhibiting the overexpression of IL-36 cytokines, clinical resolution of acute flares can be observed.¹⁵

Available as single-use vials containing 450 mg of spesolimab in a 7.5 mL solution (60 mg/mL), spesolimab is administered as an intravenous (IV) infusion.⁶ The recommended dosage for adult patients is a single 900 mg IV dose over 90 minutes.¹

Non-medicinal ingredients of the spesolimab product include arginine hydrochloride, glacial acetic acid, polysorbate 20, sodium acetate, sucrose, and water. No data is currently available for its use in pediatric or pregnant patients; therefore, spesolimab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended in pregnant or nursing women.¹

Supporting Evidence from Clinical Trials

Results from Phase 1 Studies

In a phase 1, multicenter, single-arm, open-label, proof-of-concept clinical trial, a single 10 mg/kg IV dose of spesolimab (formerly named BI 555130) was evaluated in adult patients (n=7) with a GPP flare.² The latter was defined as adult patients with an overall Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 3 or greater (GPPGA total score ≥3) and a GPPGA pustulation subscore of 2 or greater (GPPGA pustulation subscore ≥2). Safety and tolerability were the primary endpoints, with efficacy, including improvements in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) and GPPGA, as the secondary endpoints.

At week 2, improvements in GPPASI were achieved by all patients, with 73.2% of patients achieving a score of clear (GPPASI 0) and pustules being completely cleared (GPPGA pustulation subscore of 0) in 85.7% of patients. In addition, the proportion of patients achieving a GPPGA total score of clear or almost clear (GPPGA 0/1) was achieved by 71.4% of patients by week 1 and 100% of patients by week 4. There were also improvements seen in patient-reported outcomes (PROs) at week 2, with the mean (standard deviation [SD]) change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F) being 12.3 (10.1) and mean (SD) change from baseline in the Visual Analog Scale for pain (Pain-VAS) being -45.9 (32.3). Safety evaluation revealed that by week 20, four patients experienced treatment-emergent adverse events (TEAEs), all of which were mild or moderate in intensity. The most commonly reported TEAEs included eosinophilia and upper respiratory tract infection in two patients each. There were no serious AEs or deaths.²

In this study, patients underwent screening for mutations in genes thought to be involved in the pathogenesis of GPP, including IL36RN, CARD14, and AP1S3. Genetic testing revealed that two patients had homozygous loss-of-function mutations in IL36RN, and one patient had a homozygous mutation in IL36RN as well as a heterozygous mutation in CARD14. Treatment responses were consistent across all patients, irrespective of genetic mutation status.²

Table 1: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 1 clinical trial.

Results from Phase 2 Studies

In a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial (Effisayil™ 1), the efficacy and safety of a single 900 mg IV dose of spesolimab (n=35) versus placebo (n=18) were evaluated in adult patients with a GPP flare.¹⁶ The latter was defined as a GPPGA total score ≥3, GPPGA pustulation subscore ≥2, and affected body surface area (BSA) ≥5%. All patients were followed for 12 weeks.

At week 1, the primary efficacy endpoint of GPPGA pustulation subscore of 0 (clearance of pustules) was achieved by 54% and 6% of patients treated with spesolimab and placebo, respectively (p<0.001); in addition, the GPPGA total score 0/1 was achieved by 43% and 11% of patients treated with spesolimab and placebo, respectively (p=0.02). On day 8, in addition to patients who received spesolimab on day 1 (n= 35), including those who received a second, optional dose of spesolimab on day 8 (n=12), a proportion of placebo-treated patients also received open-label spesolimab (n=15). The secondary efficacy endpoint of 75% improvement in GPPASI (GPPASI75) was achieved by 51.4% of patients by week 4 and 57% of patients by week 12.¹⁶ PROs also improved by week 4, with a median (interquartile range [IQR]) change from baseline in Pain-VAS score of -53.4 (-77.9, -20.2), a median (IQR) change from baseline in the Psoriasis Symptom Scale (PSS) score of -7.0 (-10.0, -3.0), and a median (IQR) change from baseline in FACIT-F score of -22.0 (1.0, 31.0). In addition, patients from the placebo group who received open-label spesolimab on day 8 had comparable positive outcomes in physician-rated outcomes and PROs to those who received spesolimab at the start of the study.¹⁶

After one week, safety evaluations revealed similar rates of AEs between the treatment groups (spesolimab: 66%; placebo: 56%). In addition, TEAEs were similar between the spesolimab (29%) and placebo (28%) treatment groups. Among AEs in the spesolimab-treated group, infections (17%) were the most common AE reported after week 1, with the incidences increasing by week 12 (47.1%). After week 1, infections included: urinary tract infection (n=2), bacteremia (n=1), bacteriuria (n=1), cellulitis (n=1), herpes dermatitis (n=1), oral herpes (n=1), pustule (n=1), and upper respiratory tract infection (n=1). Serious AEs were reported in 6% and 12% of spesolimab-treated patients by week 1 and week 12, respectively. Two patients receiving spesolimab reported drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome; however, based on the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring criteria (score <2: no DRESS; score of 2 or 3: possible DRESS; score of 4 or 5: probable DRESS; score >5: definite DRESS), these diagnoses and casual associations are not certain. In the first patient, the RegiSCAR score was 1, suggesting that the diagnosis was not compatible with DRESS. In the second patient, the RegiSCAR score was 3, indicating possible DRESS; yet, in addition to spesolimab, the patient received concomitant spiramycin and paracetamol (acetaminophen), then experienced a recurrence of the same signs/symptoms with a spiramycin rechallenge months after resolution of the first episode, suggesting spiramycin as a potential causative agent. No AEs led to treatment or study discontinuation.¹⁶

Table 2: Summary of the efficacy and patient-reported outcomes data for spesolimab from phase 2 clinical trial.

Summary of Results from Phase 1 and Phase 2 Studies

In summary, clinical trial results suggest that IL-36 inhibition with spesolimab leads to rapid and sustained improvements in GPP flares in adult patients with a favorable safety profile. Results from both the phase 1 and phase 2 studies demonstrated rapid clearance of pustules, with many patients experiencing clear or almost clear skin after one dose of spesolimab. The safety profile of spesolimab revealed slightly higher rates of infection compared to placebo. There were also two reports of DRESS in the phase 2 clinical trial, although both cases were determined to be non-definitive. Larger sample sizes are required to confirm the safety risks associated with spesolimab use in GPP; in addition, given that this is a rare condition, long-term efficacy and safety data from clinical trials and real-world studies will be of utmost importance in order to elucidate spesolimab’s place in the therapeutic paradigm for GPP.

Spesolimab was also shown to have a positive impact on PROs in GPP patients, including pain, fatigue, and QoL in both phase 1 and phase 2 studies. In the phase 2 clinical trial, PROs particularly improved after one week in comparison to the placebo, with scores continuing to improve past week 4 and maintained until the end of the study at week 12. Despite the individual differences in the clinical progression of GPP, there were rapid and maintained overall improvements in PROs.

Specific Populations

Data on the treatment of GPP using spesolimab is not yet available in children or adolescents (<18 years of age); however, a phase 2b, multicenter, double-blind, placebo-controlled clinical trial (Effisayil™ 2) evaluating the efficacy and safety of maintenance treatment with subcutaneous spesolimab in patients aged 12-75 years is currently ongoing.¹⁷ Although 6% of patients were aged 64-75 years in the phase 2 clinical trial, due to insufficient sample size, efficacy and safety have not been determined in elderly populations.¹

Counselling: Practical Tips to Optimize Use

In preparation for injection, spesolimab must be diluted with 15 mL of sterile 0.9% sodium chloride solution and promptly used. Spesolimab is administered as a single 900 mg dose by continuous IV infusion over a period of 90 minutes in an outpatient setting by a healthcare provider. If the infusion is slowed or interrupted, the total infusion time should not exceed 180 minutes. Pre-existing IV lines may be used as long as they are flushed with a sterile 0.9% sodium chloride solution prior to and after spesolimab administration. If GPP flare signs/symptoms continue, this dosing regimen can be repeated one week after the initial dose.¹

Patients must be informed about the importance of disclosing their complete history of chronic and recurrent infections to their healthcare provider, as spesolimab can increase the risk of infection. Patients should be advised to seek immediate medical attention if they develop new signs/symptoms of infection or infusion-related hypersensitivity reactions, such as anaphylaxis or DRESS after spesolimab use. Patients should also be advised against receiving live vaccines after spesolimab treatment has started, as no studies have been conducted in spesolimab-treated patients that have previously received live bacterial or viral vaccines.¹

Conclusions

A single IV dose of spesolimab is an effective and safe treatment for adult patients presenting with GPP flares. Results of clinical trials using spesolimab indicate that medications targeting the IL-36 pathway can be successful therapeutic interventions to improve the clinical signs and symptoms of GPP. Further long-term studies with larger sample sizes, the inclusion of more pediatric and elderly patients, and the exploration of various dosing regimens for maintenance treatment are required to more accurately assess the efficacy and safety of spesolimab.

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Introduction

Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy.  The aim of this document is to summarize current Canadian guidelines on NMSC management to provide guidance for primary care physicians. Based on a literature review conducted by the NMSC Guidelines Committee, the 2015 recommendations (five chapters) for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas and actinic keratoses were condensed for a family physician audience. This practical summary includes a brief review on epidemiology and pathophysiology of NMSCs, recommendations on primary prevention of NMSCs, and management of actinic keratoses, basal cell carcinomas, and squamous cell carcinomas. The importance of education in primary prevention is highlighted, and an overview of treatment options including topical, cryotherapy, photodynamic, surgical, and radiation therapies are discussed.

NMSC Chapter 1: Introduction to the Guidelines

Introduction

• Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer among Canadians,¹ with basal cell carcinomas (BCC) and squamous cell carcinoma (SCC) accounting for approximately 95% of these cancers.²
• Actinic keratoses (AKs) are precancerous lesions that have the potential to develop into SCCs³ and are therefore regarded as a marker of chronic skin photodamage.⁴

Epidemiology

• 1 in 6 Canadians will develop some form of skin cancer in their lifetime. In 2013, 81,700 Canadians were diagnosed with NMSCs.⁵

Risk Factors

• UV radiation
  • The major environmental risk factor^6-8
  • Proximity to equator and increase in altitude are associated with greater UV exposure and accordingly higher rates of NMSCs.^9,10
• Age
  • 70-80% of cases occur in people aged ≥60^2,11
• Male sex
  • Male to female ratio of 1.7:1 for SCC and 1.2:1 for BCC⁵
• Personal history
  • Personal history of NMSC increases risk¹²
• Ethnicity
  • Caucasians are at greatest risk, followed by Asians and Hispanics; risk is lower in African Canadians.¹³
• Special patient populations
  • Organ transplant recipients, patients with albinism, xeroderma pigmentosum, HIV/AIDS.^14-17

Pathophysiology

• UV radiation (including short wavelength UVB and long wavelength UVA) is the primary causative agent in NMSCs, via three main mechanisms:
  1. Direct mutagenic effects in the tumour suppressor genes P53^18,19 and CDKN2A^20-22, as well as the Hedgehog signalling pathway, specifically in the PTCH1 and SMO genes. The first molecularly targeted therapy in NMSC, vismodegib, is an inhibitor of SMO.²³
  2. Proliferation of malignant and premalignant cells by stimulating production of cytokines.¹⁹
  3. Alteration of cutaneous immune responses. The immunomodulator imiquimod helps target this.²⁴

Diagnosis

• Basal cell carcinomas (BCC)
  • BCCs are found predominantly on the head and neck (80%), followed by the trunk (15%), arms, and legs.⁸
  • Histologic subtypes (figure 1)
    • Nodular (most common) – translucent or waxy nodule with raised telangiectatic edges, with or without central ulceration/crusting.
    • Superficial – frequently occur on the trunk, presenting as scaly erythematous patches. Can be difficult to distinguish from psoriasis, eczema or SCC in situ (Bowen’s disease).⁶
    • Morpheaform – sclerosing or fibrosing
    • Pigmented
    • Infiltrative
  • 40% of patients present with mixed patterns of 2 or more of these subtypes.²⁵

• Squamous cell carcinoma (SCC) (figure 2)
  • Unlike BCCs, which are thought to develop de novo, invasive SCCs have known precursor lesions e.g. AKs and SCC in situ.⁴
  • AKs – 80% occur on face, bald scalp, ears, neck and dorsal arms/hands.⁴
    • Typically red, scaly macules and patches.
  • SCC in situ – slowly growing scaly erythematous macule or patch, similar to superficial BCC.
    • 3-5% risk for progressing to invasive SCC.²⁷
  • SCC – typically thicker than AK, with an erythematous, raised base and irregular borders prone to bleeding. Indurated with or without central ulceration. The edges have a fleshy, rather than clear, appearance.²⁸
  • Keratoacanthomas (KAs) – develop primarily on face, neck, hands.
    • Etiology unclear but lesions believed to originate from hair follicles. Rapid onset, growth and spontaneous regression (usually lasting 4-6 months in total).^29-31
    • Difficult to distinguish from SCC on clinical and histological basis, thus management is essentially similar.⁶

Prognosis and Staging

• Prognosis depends strongly on the lesion’s histologic grade, tumour location, size, thickness and perineural or perivascular invasion, as well as host immune function and prior treatment history.
• SCC metastasis occurs in 2-6% of cases,³² with a much lower rate for BCC (0.0028-0.55%).⁸ Metastatic NMSC has about 44% survival within 5 years.³³

Prevention and Management

• Photoprotection should be started in childhood.
• Biopsies should always be considered for lesions suspicious for skin cancer.²⁸
  • Suspicion of melanoma – complete excision.
  • Raised lesions – superficial shave biopsy.
  • Small lesions with distinct borders can be completely excised with a 2-10mm punch biopsy
  • Small lesions in areas where tissue loss is acceptable can be excised with 3-4mm margin.
  • Large lesions can be sampled by 1 to 2 small-punch biopsies (2-3mm) of the most suspicious areas; incision or shave biopsies are also appropriate.
• Modalities of treatment (Chapters 3, 4, 5) include:
  • Nonsurgical (topical, photodynamic therapy, radiation).
  • Surgical (excision, electrodessication with curettage, cryosurgery, laser ablation).
• Frequent re-evaluation is paramount as the risk for subsequent SCCs or BCCs among patients with previous diagnosis is increased 10-fold.³⁴

Chapter 2: Primary Prevention of Non-Melanoma Skin Cancer

Introduction

• UV radiation, as described previously, is the major modifiable risk factor for NMSC.
• In Canada and elsewhere, much effort has gone into educating the public on the hazards of unprotected exposure. However, various myths and misunderstandings about skin cancer risk continue to impede public education efforts.

Some Misguided Notions

• “I rarely bother with sunscreen”
  • Skin damage from UV exposure accumulates in a roughly linear fashion over time, underscoring the importance of early and lifelong sun protection.³⁵
  • Only 56% of Caucasian North Americans report moderate or frequent use of sunscreen when outside on a sunny day.³⁶
  • In organ transplant recipients, who experience long term immunosuppression and are particularly susceptible to NMSCs, regular sunscreen use was associated with significant reductions in new SCC and AK occurrences.³⁷

• “A tan will protect me from skin cancer”
  • The protective effect tanning (facultative pigmentation) yields only modest protection, the equivalent of using a sunscreen with a sun protection factor (SPF) of 2-3.³⁸
  • UVB (but not UVA) does induce a small amount of melanin biosynthesis, but the dose of UV radiation required to achieve this is mutagenic in itself³⁹ (as previously described in Chapter 1 – Pathophysiology).

• “Indoor tanning is safer than the sun”
  • UVA emissions from tanning beds can exceed that from the sun by as much as 10-fold.⁴⁰
  • Tanning devices increase the risk of BCC and SCC by 1.5 and 2.5-fold, respectively.⁴¹
• “With sunscreen, I can stay out all day”
  • In one study, use of sunscreen was associated with sun exposure that was 13-39% longer than if no sunscreen was applied.⁴²
  • Over-reliance on sunscreen can offset or eliminate the benefits of this protective measure.
  • The most basic photoprotective tools are avoidance of midday sun (when UV index, based on intensity of UVB radiation, is highest) and wearing UV-blocking clothing.
• “I choose a sunscreen by its SPF”

• • SPF is a measure of how much longer it takes sunscreen-protected skin (applied at 2 mg/cm²) to produce a minimal erythema (redness) response to UVB exposure, compared with unprotected skin.
  • The relationship with UVB deflection is not linear. A product with an SPF of 15, under laboratory-controlled conditions, blocks 93% of UVB rays, while another with an SPF of 30 will block 97% of UVB rays.
  • SPF provides only a crude estimate of how much protection a sunscreen product can provide against UVB-induced damage, since the strength of UV rays can alter with environmental changes.
  • SPF does not indicate efficacy in blocking UVA, which can also be damaging and carcinogenic to the skin.

  Figure 3. An explanation of Sun Protection Factor (SPF)⁴³

  • SPF value has traditionally been synonymous with the efficacy of a sunscreen product; however, SPF measures only UVB protection.
  • Newer UV absorbers cover the entire UV spectrum and can be divided into two groups: organic filters and inorganic blockers.
  • Organic filters are chromophores that absorb UV radiation.⁴⁴
  • Inorganic blockers (zinc oxide and titanium dioxide) can both absorb and reflect or scatter UV radiation.⁴⁵
  • The implication of reactive oxygen species in UV-induced lesions has also inspired the inclusion of antioxidants such as vitamin C and E.⁴⁶
  • Sunscreen products are labelled “broad spectrum” if they protect against both UVA and UVB.
  • Only broad-spectrum products with an SPF of ≥15 can claim to retard/reduce the incidence of skin aging and skin cancer.⁴⁷
• “Everyone knows how to use sunscreen”
• • Manufacturers recommend that sunscreens be applied at an even thickness of 2mg/cm², because SPF values are determined under those laboratory conditions.
  • However, the amount of sunscreen used is typically less than half that recommended,⁴⁸ decreasing UV protection by 2-4 fold.⁴⁹
  • Sunscreen application is also not homogenous, with some commonly neglected areas (e.g. ears, neck, back of hands, temples).^50,51 With normal bathing, physical activity and towelling, the SPF of a single application of sunscreen is also reduced by 40% and 55% after 4 and 8 hours, respectively.⁵²

Recommendations⁴³

• Physicians should regularly counsel patients that:
  • They should protect their skin from the sun by wearing appropriate clothing, avoiding exposure to midday sun, and using sunscreen.
  • They should use broad-spectrum sunscreen products with a SPF ≥30 or equivalent.
  • They should apply sunscreen liberally and evenly (2mg/cm²; about 35mL or 2 tablespoons for an average-sized adult), ideally at least 15 minutes before going outside.
  • They should reapply sunscreen, ideally, at least once during the day and more frequently if swimming or sweating and after towelling.
  • Use of sunscreen should not be a reason for extending the duration of sun exposure.
  • Indoor tanning should be avoided at all times.

Chapter 3: Management of Actinic Keratoses

Introduction

• These lesions are keratinocyte intra-epidermal neoplasias,⁵³ and are by definition confined to the epidermal layer of the skin.
• They are typically small (3-6mm), flat, pink or nonpigmented, and painless.⁵⁴
• However, hyperkeratotic/thickened and pigmented AKs can also occur.
• Sometimes better detected by palpation as a result of their sandpaper-like texture.
• Precursors in the evolution of SCC.⁵⁵

Occurrence and Natural History

• AKs are common in older, fair-skinned individuals.⁵⁶
• AKs often present in clusters on sun-exposed areas of the arms, head and neck.^57,58
• In one study, 0.6% of lesions progressed to in situ or invasive SCC over 1 year, whereas 55% spontaneously regressed clinically.⁵⁹ However, unless the areas has been surgically excised, there are high rates of recurrence.^60,61

Treatment Options

• Surgical Removal
  • AKs are not routinely surgically excised, and a biopsy is generally unnecessary unless lesions are recurrent or diagnosis is unclear.
  • Shave excision is commonly used for removal of hypertrophic AKs.
  • Curettage may be used alone or in conjunction with shave excision, electrodessication, or cryosurgery.
• Cryosurgery
  • Local treatment with liquid nitrogen (LN2/cryosurgery) is the most common approach to AK management.
  • Outcomes are operator-dependent and vary depending on freeze time, number of LN2 applications, and other parameters.⁶²
  • Because of these variables, as well as the fact that cryosurgery only targets clinically evident lesions, only 4% of patients remained free of AKs in the treated area.⁶³
• 5% 5-FU (Fluorouracil) Cream
  • 5% 5-FU cream was first used as treatment for discrete AKs, but may be also used as field therapy.^63-65
  • Generally applied twice daily for up to 4 weeks.
  • Leads to local inflammation, erosion and pain, which may be tolerated poorly and reduce compliance.⁶⁶
  • About half of patients achieve complete clearance, and >90% experience some reduction in lesion number.⁶⁵
• 5% Imiquimod Cream
  • Used primarily as field therapy
  • The most commonly used regimen is three-times-weekly dosing, applied in 4-week treatment cycles
  • Transient increase in the number of visible AKs in the treated field, thought to arise from subclinical lesions. These eventually regress and should be regarded as evidence of efficacy^67,68
  • With the above regimen, 73% of patients maintained clearance in the treated field for at least a year, which is significantly greater than that of patients using 5% 5-FU (33%) or receiving 2 sessions of cryosurgery (4%)⁶³

• 75% Imiquimod Cream
  • Used as field therapy, applied daily to face or scalp for two 2-week cycles, separated by a 2-week rest period.
  • Trials reported fewer withdrawals due to adverse effects, compared to 5% imiquimod.⁵⁴
  • Eight weeks after treatment, complete clearance occurred in about 36% of patients;⁶⁹ however, within one year further AKs developed in half of these patients.⁷⁰
• Ingenol Mebutate Gel
  • Available in two concentrations – one (0.015%) for the face and scalp, and the other (0.05%) for the trunk and extremities.
  • Dosing is once daily for 3 days for the facial and scalp areas, and 2 days for the trunk and extremities – shorter than the other topical agents and potentially advantageous in terms of compliance.⁷¹
  • After 12 months about half of the patients remained clear and overall lesion count was reduced >85% in the treated area.⁷²
• 5% 5-Fluorouracil +10.0% Salicylic Acid Solution
  • A dual-action topical indicated to treat hyperkeratotic AKs.
  • Salicylic Acid (SA) is a keratolytic, and the theory behind its use is to improve penetration in hyperkeratotic AKs.⁷³
  • Dosing is once daily to affected lesions, until lesions have cleared or for a maximum of 12 weeks.
  • At 8 weeks post-treatment, complete histological clearance of a single pre-defined AK lesion was achieved in 70% of patients. 50% of lesions were cleared at end of treatment.⁷³
• PDT and Daylight PDT
  • Two PDT systems available for AK treatment.
    • Blue light + photosensitizer 5-aminolevulinic acid (ALA)
    • Red light + methyl aminolevulinate (MAL)
  • Reasonable option for AKs disseminated over large areas.
  • In hyperkeratotic AKs, curettage is generally required before PDT.
  • PDT causes a burning sensation while the treated area is being illuminated.⁷⁴
  • Daylight PDT is currently being explored, in which MAL cream is applied to the photodamaged skin and patients sit in bright sunlight for 2 hours, wearing sunscreen as usual for UV protection. Pain is reported to be significantly reduced.^75,76
• Combined Treatment Modalities
  • One option is the combination of cryosurgery followed with an adjunctive field-directed therapy (e.g. imiquimod, 5-FU) 1-2 weeks after.^77,78
• Treatment Options for Actinic Cheilits (AC)
  • An AK occurring on photodamaged lips, or AC, presents as a white lesion with interspersed red areas.
  • Histologic analysis of the vermillion surrounding ACs commonly identifies foci of SCC;⁷⁹ because SCCs in this area have an elevated rate of metastasis,⁸⁰ field-directed therapy may be preferred over cryosurgery.
  • Surgical vermilionectomy allows for long-term clearance but poses risk of cosmetic damage or functional impairment.⁸¹
  • Less invasive approaches include field therapy with 5% FU, ALA-PDT, and MAL-PDT. Imiquimod is also commonly used, although Canadian labelling restricts use on the lips.⁸²

AKs in Organ Transplant Recipients

• Rate of SCC development increased by ~100-fold.^83,84
• AKs may be morphologically different from typical AKs, appearing more prominent (wartlike) and hyperkeratotic, and their SCCs are at elevated risk of local recurrence and metastasis.⁸²
• Field treatment with topical therapy or PDT is recommended.⁸⁵

Treatment Recommendations Summary⁸⁶

1. AKs with atypical morphology or presentation or resistant to treatment should be biopsied/excised.
2. Isolated AKs should generally be treated with cryosurgery or a surgical procedure. Curettage or direct surgical excision are preferred options, if the lesions are hyperkeratotic.
3. Areas with clustered AKs and those with histologic evidence of field cancerization should be treated with field-directed therapies.
4. If cryosurgery or surgery is used in patients with solar elastosis or other evidence of extensive photodamage, field-directed therapy may be applied once healing is complete.
5. Patients with evidence of photodamage or history of AKs should be regularly monitored for new lesions, with increased monitoring with any of the following – history of NMSC, history of nonresponsive AKs, ongoing systemic immunosuppression.
6. Actinic cheilitis may be treated with any of the following modalities: cryosurgery, field-directed therapy, PDT, complete or partial vermillionectomy, laser resurfacing, ED&C.
7. Organ transplant recipients and others with long-term systemic immunosuppression and clinical evidence of AKs may receive field-directed therapies to prevent the emergence of AKs and NMSC in areas of photodamage.
8. In organ transplant recipients, a high level of suspicion for malignant transformation should be noted. Lesions that do not respond to treatment should be biopsied/excised.

Chapter 4: Management of Basal Cell Carcinoma (BCC)

Introduction

• BCC is the most commonly diagnosed skin cancer in Canada.²
• It is a slow-growing malignant tumour originating in the basal layer of the epidermis.
• It rarely metastasizes, but growth leads to local destruction of neighbouring skin and underlying tissue.^8,87
• It most commonly affects sun-exposed surfaces – head and neck predominantly, followed by trunk and extremities.
• Subtypes:
  • Nodular (60%) – most common on face. Nodular/popular appearance, with pearly quality, and often surface telangiectasias and ulceration.
  • Superficial (30%) – most common on trunk. Red, scaly macule or patch.
  • Morpheaform/scleorsing (5%) – atrophic plaques or papules with ill-defined margins. Aggressive growth pattern
  • Less common, aggressive
    • Infiltrative
    • Micronodular
    • Mixed

• Risk associated with age (incidences increase ≥60 years of age) and sex (male).⁸⁸
• UV radiation is the most significant risk factor. Additional risk factors – fair skin, immunosuppression, environmental exposure to ionizing radiation, arsenic, UV radiation, psoralen plus UVA (PUVA), and a past history of BCC.^89-99
• Basal cell nevus syndrome (BCNS) is an autosomal dominant condition characterized by a mutation in the PTCH gene (important in the Hedgehog signalling pathway), leading to development of multiple BCCs.¹⁰⁰
• With timely detection and treatment, prognosis of BCC is usually excellent.
• Features used to stratify risk include site, size, histologic subtype, tumour margins, perineural or perivascular invasion, prior treatments, and immune status (table 2).
• Metastasis is rare (0.028% to 0.5%), usually to regional lymph nodes, lung, bone.⁸

Treatment Overview

• Goal of treatment – complete removal with optimal preservation of function and cosmesis.
• Surgical
  • Surgical excision with postoperative margin assessment, Mohs micrographic surgery (MMS), cryosurgery, and electrodessication and curettage (ED&C).
• Nonsurgical
  • Photodynamic therapy (PDT), radiotherapy (RT), and topical therapy.

Surgical Treatment

• Surgical Excision with Predetermined Margins
  • For well-defined, low-risk BCC <2cm, excising a 3-4mm peripheral margin results in a 95% tumour clearance rate.^102,103
  • For high-risk subtypes and large BCCs, 6-10mm margin recommended.¹⁰²
• Mohs Micrographic Surgery
  • MMS is a technique used on high-risk skin cancers to maximize tissue sparing and maximize cure rates.
  • MMS begins with narrow margin (0.5-1mm) excision, then the tissue is immediately processed using horizontal frozen sections. The physician examines the sections, and accordingly removes more tissue where any residual tumour is located. This process is continued until the tissue section(s) show no histologic evidence of residual tumour.¹⁰⁴
  • Cure rates as high as 99% and 96% for primary and recurrent tumours, respectively.^105-107
• Electrodessication and Curettage (ED&C)
  • Higher cure rates for smaller lesions.^108,109
  • Advantages – inexpensive, tissue-sparing, generally well tolerated.
  • Disadvantaged – potential hypopigmented scars, need for specialized training, lack of histologic confirmation of clearance.
• Cryosurgery
  • Most effective for treating low-risk BCC on trunk and limbs.^110,111
  • Not generally indicated for head and neck lesions or high-risk BCC due to poorer outcomes.^112,113
  • Curettage often combined with cryosurgery, which may improve cure rates.¹¹⁴

Nonsurgical Treatment

• Photodynamic therapy (PDT)
  • A topical photosensitizing agent (generally methyl aminolevulinate [MAL]) is applied to the lesion and irradiated with light, causing tumour cell death.
  • Adverse reactions – local pain, pruritus, erythema, edema.¹¹⁵
  • A systematic review reported a 1 year clearance rate of 84%.¹¹⁶
  • Good evidence for use of PDT in treatment of small lesions for patients contraindicated for surgery who can tolerate higher risk of recurrence and for whom cosmetic outcome is important, or possibly for patients with multiple small, low-risk BCCs.
• Radiation therapy (RT)
  • Primary surgical alternative for high-risk BCC, with long-term cure rates ≥90% for both primary and recurrent high-risk lesions.⁸
  • RCTs have compared RT with surgically alternatives; for primary facial BCC <4cm, 4-year tumour clearance rates were 99.3% and 92.5% for surgical excision and RT, respectively.¹¹⁷
  • Main advantages – tissue-sparing, non-invasive.¹¹⁸
  • Risks – local erythema, edema, ulceration, infection.
  • Potential long-term sequelae – chronic dermatitis, radio-necrosis, radiation-induced malignancies.¹¹⁹
• Topical therapy
  • Imiquimod, an immune response modifier, is the main topical therapy used in treating superficial BCCs.^120,121
  • Approved for treatment of superficial BCCs on trunk, extremities, neck
  • Clearance rates over 80%.^122,123
  • Nodular BCC does not appear to respond as well to topical imiquimod.¹²⁴

Locally Advanced or Metastatic BCC

• No standard therapy exists, in large part due to the rarity of such progression.
• Combination of surgery, radiation, chemotherapy.
• Newer research examines genetic targets of BCC.
• The oral agent vismodegib (inhibitor of Smoothened gene) is approved in Canada for treatment of metastatic BCC or locally advanced BCC that is inappropriate for surgery or radiotherapy.^124,125
• Disadvantages – high cost and toxicity (hair loss, muscle cramps, taste disturbance).¹²⁶

Follow-up

• A meta-analysis assessing the risk of developing a second BCC reported a 3-year risk ranging from 33-70%, with a mean of around 44%.³⁴
• Patients who received surgical treatment of low-risk tumours and confirmed histological clearance of high-risk tumours are at very low risk of recurrence and could safely be followed annually.¹¹⁹
• For patients at higher risk of recurrence (no histological confirmation of clearance, or nonsurgical treatment), biannual skin checks are recommended for the first 3 years, then yearly thereafter.

Recommendations

Chapter 5: Management of Squamous Cell Carcinoma

Introduction

• Second to BCC, squamous cell carcinoma (SCC) is the most common form of non-melanoma skin cancer, accounting for ~20% of all cases in Canada.²
• Although less common than BCC, SCC has a great potential for metastasis and is associated with a higher risk of mortality.^32,33
• Chronic exposure to UV radiation is the most important risk factor.^6-8
• SCCs arise from the superficial layers of keratinocytes and commonly appear on sun-exposed surfaces, such as the head and neck.
• SCC has varied presentations – it can be scaly, centrally ulcerated, or erythematous, and may have irregular borders prone to bleeding. It may arise from actinic keratosis.
• It is sometimes confined to epidermis (SCC in situ or Bowen disease), but can also invade nearby tissues and metastasize to regional lymph nodes and more distant sites.¹³⁶

Staging And Prognosis

Sentinel Lymph Node Biopsies

• Although SCC metastasis is rare, region lymph nodes (usually head and neck) are the most common site of disease spread.¹³⁸
• Prognosis of metastatic SCC is poor – 34.4% survival rate beyond 5 years.³⁸
• Thus, early detection of nodal involvement is important.
• Sentinel lymph node biopsy is commonly used in breast cancer and cutaneous melanoma but its value in high risk SCC is not well established.

Surgical Treatments with Margin Control: The cornerstone of SCC management

• Fixed-Margin Surgical Excision
  • Widely regarded as the treatment of choice for most cutaneous SCCs.¹³⁹
  • Advantages – histologic verification of tumour margins, rapid healing, good cosmesis.¹⁴⁰
  • SCC recurrence rates following surgical excision of primary invasive cutaneous SCC tumours: 5.7% for short term (follow up <5 years) and 8.1% for long term (follow up >5 years).³⁸
  • Higher recurrence rates for recurrent tumours: 17.3% and 23.3% for short- and long-term, respectively.³⁸
  • No consensus for acceptable surgical margin.¹⁴¹
    • 4-5mm for low-risk SCCs
    • 6-13mm for high-risk SCCs

• Mohs Micrographic Surgery
  • Highest clearance rates, and allows normal tissue to be spared by offering complete control of the surgical margin.^142-150
  • Thus, MMS should always be considered for SCC lesions with poorly defined borders, especially for cosmetically sensitive areas such as the face, hands, feet.

Destructive Treatments Without Margin Control

• Electrodessication and Curettage (ED&C)
  • Generally, 1-3 cycles of ED&C are performed during a single visit.¹⁴⁰
  • Cure rates for SCC in situ are 93-98%.^151,152
  • Since reliable margin control is not achieved, the effectiveness is highly dependent on the skill and experience of the physician.
  • Because the tumour margin is lost, ED&C should not be used for recurrent or high-risk tumours, or for deeper lesions that extend to soft, subcutaneous fat.^139,142
• Cryosurgery
  • In low-risk SCC lesions, including SCC in situ and KAs, high short-term clearance (follow up <5 years; 96.8-100%) and 5 year cure rates (96.1%) have been reported following cryosurgery.^63,113,114
  • May be inferior to ED&C in terms of patient pain, speed of healing, recurrent rate.¹⁵³
  • Disadvantages – scarring, hypopigmentation,¹⁵⁴ no established standards for optimal temperature, duration of treatment.

Radiation Therapy

• Can be used to treat inoperable primary cutaneous SCC lesions.
• High rates of short-term clearance (93.3%) and long-term cure (90-92.5%) are comparable to those achieved with surgical excision.^38,155
• Often suggested as an adjuvant to surgical management of high-risk SCC lesions, especially those with perineural involvement and positive surgical margins.^141,142

Photodynamic Therapy

• Currently, use of PDT in Canada is restricted to treatment of superficial BCCs and AKs.
• May be effective for SCC in situ, especially in the lower leg (which generally has poorer healing in response to other therapies).¹⁵⁶

Topical Regimens

• No topical therapies approved by Health Canada for treating SCC.
• Topical agents, such as 5-FU and imiquimod, have shown efficacy in the treatment of SCC in situ;¹⁵⁷ short-term cure rates of 27-85% with 5FU and 73-88% with imiquimod.¹⁵⁸
• Adverse effects of 5FU – erythema, pain, dermatitis, pruritus.¹⁵⁷
• Adverse effects of imiquimod – erythema, edema, weeping, pruritus, hypopigmentation, erosion, burning, pain.¹⁵⁷
• 5-year cure rates are unknown so cannot be recommended, but anecdotal evidence suggests they may be used off-label to manage low-risk SCC.

Other Approaches

• Laser
  • Argon, CO2 and Nd:YAG lasers have been studied in the treatment of SCC in situ in case reports and small series.
  • Mostly focusing on anogenital lesions, as well as SCC in situ of the digits.¹⁵⁹
  • High cost and need for specialized equipment.

• Intralesional therapy
  • Intralesional therapy with alpha-interferon or chemotherapeutics such as methotrexate, 5-FU, and bleomycin has produced cure rates of 91-100% for keratoacanthomas.¹⁵¹
  • Currently rarely used in practice.¹⁶⁰

Treatment Recommendations¹³⁷

1. Suspected SCCs should be biopsied according to the criteria outlined in Chapter 1.
2. Risk of recurrence should be established using the criteria in Table 4.
3. Selected patients with high-risk SCCs may be considered for sentinel lymph node biopsy in consultation with a multidisciplinary skin cancer clinic.
4. Primary low-risk SCC lesions of the skin, including SCC in situ and keratoacanthomas, may be treated with the following options:
   1. Surgical excision with 4-5mm margin (first line)
   2. ED&C
   3. Cryosurgery
   4. Radiation therapy
5. The following off-label modalities can be also considered in the treatment of SCC in situ:
   1. Photodynamic therapy
   2. 5-FU
   3. Imiquimod
6. Treatment options for recurrent or otherwise high-risk SCC lesions include the following:
   1. MMS
   2. Surgical excision with 6-13mm margin
   3. Radiation therapy
7. Adjuvant radiation therapy may be added to the surgical treatment of high-risk SCCs, such as those with perineural invasion.
8. Patients with select, high-risk SCCs may be considered for a referral to a multidisciplinary clinic.

Conclusion

• Complete removal of SCC along with preservation of function and cosmesis is best achieved through surgical methods allowing tumour margin assessment.
  • Fixed-margin surgical excision and MMS are the cornerstone treatments.
• Treatment options for high-risk lesions are limited to MMS, fixed-margin surgical excision, and radiation therapy.
• There are a number of second-line options for management of low-risk SCCs; while not currently approved, PDT and topical therapy may be especially useful for lesions in lower leg.

Introduction

Hand dermatitis (HD) can have a significant impact on quality of life of those affected. It may interfere with activities both at work and in the home and can be associated with social and psychological distress.^1,2 The chronic form, chronic hand dermatitis (CHD) affects up to 10% of the population, which can have a considerable societal impact.² Canadian Guidelines for the management of chronic hand dermatitis have been published to help guide management of this burdensome condition.³ This article provides helpful practical guidance for the general practitioner in the management of patients with HD.

Abbreviations: CHD – chronic hand dermatitis; ENT – ear, nose, and throat; HD – hand dermatitis; KOH – potassium hydroxide; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroid(s)

Diagnosing HD – Important points to cover:

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposure to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum as needed.

Figure 1.
Examples of hand dermatitis(HD)

Determining if HD is Acute or Chronic

Figure 2.
Establish diagnosis of acute hand dermatitis and chronic hand dermatitis (CHD). HD – hand dermatitis

• It is important to first differentiate between acute and chronic forms of HD, as the treatment options may vary.
• Acute HD lasts less than 3 months or occurs only once in a calendar year.
• CHD lasts for at least 3 months and/or patients experience at least 2 relapses in a calendar year.

TIP: Could This Be Tinea?

• Check the feet for signs of tinea pedis and onychomycosis.
• Look for an active border suggestive of tinea.
• Take a skin scraping for KOH microscopy and culture.

TIP: Could This Be Psoriasis?

• Check the feet, scalp, elbows, knees, gluteal cleft and umbilicus for signs of psoriasis.
• Check the nails for signs of psoriasis: pitting, onycholysis, subungual hyperkeratosis, splinter hemorrhages, salmon patches (oil drops).

Prevention, Avoidance and Patient Education

• Every patient with HD, whether acute or chronic, should protect their hands and avoid irritants and exacerbating factors.
• Avoid wet work, frequent hand washing and alcohol-based hand sanitizers.
• Gloves should be worn to protect the hands: cotton gloves at home, or during the night; gel padded gloves for friction and protective gloves for wet work and irritant exposure.
• The following tips are provided for patients on what to use, what to avoid and helpful common practices.

Assessing and Encouraging Patient Adherence

• Ask patients to bring products and prescriptions to follow up appointments to assess usage.
• More frequent patient follow up visits improve adherence.
• Provide education on the disease, treatment options and potential side effects of therapy.
• Choose treatment in agreement with the patient.
• Suggest joining a support group or organization, such as the Eczema society of Canada ( https://eczemahelp.ca/).

Emollient Therapy

• All patients with HD should use a bland, rich emollient to help restore the skin barrier, and apply frequently throughout the day.
• Regular application may prevent itching and reduce the number of flares.
• For hyperkeratotic eczema, patients should use an emollient with keratolytic agent (salicylic acid 10-20% or urea 5-10%).
• Unscented petroleum jelly is inexpensive and helpful for many patients.

Management of Acute HD

• It is important to make a diagnosis of acute HD so that treatment can be started as quickly as possible to maximize the outcome and prevent chronic involvement.
• Patients with HD should be adequately counselled on prevention and avoidance strategies.
• Avoidance of irritants, potential allergens and regular use of emollients is essential.
• Early treatment includes control of flares with a potent or super-potent topical corticosteroid (TCS) applied twice daily. For example, clobetasol propionate 0.05% ointment applied twice daily is generally effective in acute flares.
• For less severe flares, consider betamethasone valerate 0.1% ointment applied twice daily until controlled.
• In more severe cases, systemic steroids (prednisone, intramuscular triamcinolone) should be considered. Prednisone starting at 40-50 mg orally once a day and tapering over three weeks is an effective treatment course.
• Avoid short courses of prednisone as the condition may flare again, so a tapering dose is advised.
• Look for signs of infection and treat concomitantly.
• Try to identify any allergen exposures and recommend avoidance. If allergy is suspected, the patient should be referred for patch testing.
• Once controlled, consider maintenance therapy with topical calcineurin inhibitors (TCIs), such as tacrolimus 0.1% ointment twice daily when necessary, or twice weekly as maintenance therapy.

Figure 3.
Severity-based treatment algorithm for the management of hand dermatitis (HD). CS – corticosteroid; TCS – topical corticosteroid

QoL Consideration

• Patients with mild or moderate CHD who have a significant impact on QoL should be managed as severe CHD.

Did You Know?

• Hydrocortisone topical agents should not be recommended for most cases of HD because it is rarely effective and patients may become sensitized.
• Hydrocortisone is responsible for the majority of allergies to topical steroid products.

Management of Chronic HD

• The treatment plan for CHD depends on whether it is mild, moderate or severe.

Management of Mild CHD

• Patients with mild CHD should be educated on proper prevention and avoidance strategies as outlined earlier.
• Regular emollient therapy should be used to restore and maintain the skin barrier.
• TCS therapy should be initiated with betamethasone valerate 0.1% ointment twice daily for 4-8 weeks.
• If not responding, adherence to the treatment plan should be assessed. Ask the patient to bring medication to follow up appointment to assess amount of product actually used.
• The patient can then be counselled on proper use of the product and provide support for ongoing management.
• If not responding with an adequate trial, a higher potency TCS, such as clobetasol priopionate 0.05% ointment should be prescribed as next line therapy. Reassess after 2 weeks. If not responding to an adequate trial of a potent or super potent TCS, the patient should be considered to have moderate CHD.

Figure 4.
Treatment algorithm for the management of mild chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

TIP: Always assess adherence, reconsider the diagnosis and rule out contact allergens, concomitant infection or colonization when patients do not respond to therapy.

Management of Moderate CHD

• In addition to regular use of emollients, patients with a diagnosis of moderate CHD should be given a 4-8 week trial of a moderate TCS, such as betamethasone valerate 0.1% ointment, or a super potent TCS, clobetasol propionate 0.05% ointment for a 2-week trial. If improved, the patient can continue this as necessary, for control of the condition.
• Another option is maintenance with a TCI, such as tacrolimus 0.1% ointment twice a day as needed, or twice weekly for maintenance. If not improved, reconsider the diagnosis and assess the patient for adherence.
• If a diagnosis of moderate CHD is confirmed, consider treating the patient with a course of phototherapy, if accessible. If unavailable or the patient does not respond, consider treating as severe CHD.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 5.
Treatment algorithm for the management of moderate chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Safety Tip

When patients show signs of adverse effects to TCS, including
atrophy or telangiectasias or they cannot tolerate topical steroid
use, consider TCI (tacrolimus ointment 0.1%) as a non-steroid
topical therapy option for treatment and maintenance.

When to Refer

• Patients with CHD should be referred to a dermatologist when:
  • They may require patch testing
  • They are not responding to therapy
  • Condition is worsening instead of improving
  • Require phototherapy

Management of Severe CHD

• Patients who are diagnosed with severe CHD, patients with mild to moderate CHD who have failed an adequate trial on therapy, or patients who have a significant impact on the QoL, should be treated as having severe CHD.
• Treatment should be initiated with a potent or super-potent TCS, such as clobetasol propionate 0.05% ointment twice a day for 4-8 weeks (2 weeks on dorsal hands if super potent). If improved, patients may continue to use on an as needed basis, or switch to a TCI for ongoing maintenance therapy.
• Patients should be reassessed at 4-8 weeks. If they are not responding to therapy, consider adherence and review proper care.
• A course of phototherapy may also be considered if available.
• Treatment with oral alitretinoin (30 mg orally, once a day) is the next line of therapy based on best available evidence.⁴ Alitretinoin should be prescribed by those who are comfortable with prescribing retinoids.
• As with all retinoids, caution should be used in females of child bearing potential due to teratogenic potential. Monitoring of therapy with regular blood tests for hepatotoxicity and alterations in lipid profile is also recommended.
• If the patient responds to therapy, it should be continued for 3-6 months and reassessed at that time. Patients may discontinue therapy at this point, and continue with ongoing maintenance with topical therapy. If, in the future, they experience a flare, they can be retreated with alitretinoin.⁵
• If a patient does not respond to 12 weeks of alitretinoin, they should be referred for confirmation of diagnosis and other treatment options, which would include treatment with immunosuppressive therapy such as cyclosporine, methotrexate, mycophenolate mofetil or azathioprine.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 6.
Treatment algorithm for the management of severe chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Conclusion

HD can have a significant burden on the patient with an impact on
QoL. Early diagnosis of acute or chronic HD is important for optimal
management. Other conditions such as tinea manuum and psoriasis
need to be ruled out and managed appropriately. Once a diagnosis of
HD is confirmed, treatment depends on the severity of the disease.
A treatment algorithm has been developed to assist the general
practitioner to make a diagnosis and either refer or treat accordingly.
Whichever treatment option is prescribed, all patients should be
educated on emollient therapy, hand protection and avoidance of
irritants or allergens, which may be contributing to their disease.

References

1. Diepgen TL, Agner T, Aberer W, et al. Management of chronic hand eczema. Contact Dermatitis 2007;57:203-10, doi:10.1111/j.1600- 0536.2007.01179.x.
2. Agner T. Hand eczema. In: Johansen JD, Frosch PJ, Lepoittevin J-P, editors. Contact dermatitis. 5th ed. Berlin: Springer-Verlag; 2011. p. 395-406
3. Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, Agner T, Barber K, Bissonnette R, Ho V, Shear NH, and Toole J. Canadian Hand Dermatitis Management Guidelines. J Cut Med Surg 2010; 14(6): 267-284
4. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. Br J Dermatol 2008;158:808-17, doi:10.1111/j.1365- 2133.2008.08487.x.
5. Bissonnette R, Worm M, Gerlach B, et al. Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol 2009;162:420-6, doi:10.1111/j.1365-2133.2009.09572.x.
6. Veien NK, Larsen P, Thestrup-Pedersen K, and Schou G. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate British Journal of Dermatology Volume 140( 5): 882-886, May 1999
7. Krejci-Manwaring J, McCarty MA, Camacho F, Manuel J, Hartle J, Fleischer A Jr and Feldman SR: Topical tacrolimus 0.1% improves symptoms of hand dermatitis in patients treated with a prednisone taper. J Drugs Dermatol. 7:643-646. 2008. PubMed/NCBI
8. Thestrup-Pedersen K, Andersen KE, Menne T, and Veien NK. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single blind placebo controlled study. Acta Derm Venereol 2001; 81: 353-355
9. Granlund H, Erkko P , Eriksson E , and Reitamo S. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema. Acta Dermato-venereologica [1996, 76(5):371-376]

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

ABSTRACT

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 (BPO) 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 allows for progressive follicle penetration and decreased irritation, resulting in increased efficacy. Furthermore, adapalene or clindamycin with BPO 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.

Key Words:
acne vulgaris, adapalene, benzoyl peroxide, clindamycin, retinoid, topical combination therapies, tretinoin

Introduction

Acne vulgaris is a common chronic inflammatory cutaneous disease involving the pilosebaceous unit. Acne is a common worldwide skin disease that affects about 85% of individuals between the ages of 12-24 years.¹ The pathophysiology includes androgen-mediated stimulation of sebaceous gland activity, abnormal keratinization leading to follicular plugging (comedo formation), proliferation of P. acnes within the follicle, and inflammation.² Genetic factors, stress, and possibly diet may influence the development of acne.² 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.

Treatment of Acne Vulgaris

Treatment is targeted to one or multiple pathogenic element(s). Topical therapies remain the most common and effective treatment option for mild to moderate acne and also for maintenance therapy for all levels of acne severity.¹ Retinoids (e.g., adapalene, tazarotene, tretinoin) act to reduce dyskeratosis at the pilosebaceous unit, inhibit the formation of microcomedones, and have mild anti-inflammatory effects.³ Advanced vehicle formulations in the form of emollient cream and microsphere gel reduce irritation and enhance efficacy.⁴ Antimicrobials (e.g., benzoyl peroxide (BPO), clindamycin, erythromycin, sodium sulfacetamide) have bactericidal or bacteriostatic action against P. acnes. Anti-inflammatory agents such as dapsone act through direct inhibition of leukocyte trafficking and the generation of chemical mediators of inflammation by leukocytes and/or potential interference with bacterial synthesis, thereby altering the levels and activity of P. acnes.⁵

Combination products (e.g., BPO + antibiotic, retinoid + antibiotic) target multiple pathogenic factors, which are complementary and synergistic in mechanisms of action. It also simplifies the treatment regimen and reduces dosing frequency.³ BPO + clindamycin combination products have been widely studied, a recent meta-analysis showed that BPO 2.5% + clindamycin is comparable to BPO 5%+ clindamycin in reducing acne lesion counts.⁶ Investigators suggest that BPO 2.5% + clindamycin may in fact be more effective in treating non-inflammatory acne lesions possibly because of decreased irritation, thereby encouraging treatment follow-through by patients.⁶ Furthermore, combination preparations were found to be superior in treating acne lesions compared with using either agent alone.⁶

The addition of BPO to topical antibiotics and retinoids in managing mild to moderate acne reduces the incidence of bacterial resistance. This bacteriostatic agent is efficacious against both nonresistant and resistant P. acnes strains. BPO acts by producing free-radical oxygen that oxidizes bacterial proteins and exerting a mild keratolytic effect on comedones. In more severe acne, when oral antibiotics are necessary, BPO may contribute to suppressing the emergence of resistant P. acnes strains.⁷

Newer Fixed-dose Dual-agent Therapies

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

This fixed-dose combination gel was approved by the US FDA in November 2006 and sanctioned by Health Canada in December 2010 for the once-daily treatment of acne vulgaris in patients ≥12 years of age.⁸ It combines the anti-inflammatory and antibacterial actions of clindamycin with the comedolytic and anticomedogenic actions of tretinoin⁵ 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 (Table 1).

Recommended application is once-daily at bedtime (preferred) or morning (as the vehicle delivery formulation provides for the photostability of tretinoin).⁸ Patients should be instructed to use only a pea-sized amount. The vehicle is an alcohol free aqueous gel containing a unique formulation of solubilized clindamycin phosphate and stable combinations of both solubilized and crystalline tretinoin.¹⁴ 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.¹⁴ The long-term efficacy and favorable safety profile was shown in a 52-week study, with the vast majority of participants not experiencing certain local cutaneous reactions, such as no itching (92%), no burning (91%), and no stinging (94%).¹⁵ The most frequent adverse events were acne (29/442; 7%, usually a flare), sunburn (12/442; 3%), hypersensitivity (7/442; 2%), contact dermatitis (5/442; 1%), and application-site desquamation (3/442; 1%).¹⁵ Common class-wide side-effects from topical retinoids can include peeling, redness, dryness, itching, and photosensitivity. Tretinoin increases the skin’s sensitivity to UV light, therefore patients should be reminded to avoid excessive or unnecessary sun exposure and wear sunscreen and protective clothing daily. The contraindications include Crohn’s, ulcerative colitis, colitis with previous antibiotic use, and use of concomitant erythromycin containing products; it has a US FDA pregnancy category C classification.⁸

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

This combination gel was approved by the US FDA in January 2009 and approved by Health Canada in May 2011. It is the first fixed-dose retinoid-BPO treatment that has been developed as a convenient once-daily formulation. Adapalene has comedolytic, anticomedogenic, and anti-inflammatory properties and BPO is a highly lipophilic oxidizing agent with bactericidal and keratolytic effects.¹⁶ BPO lowers the incidence of bacterial resistance compared with other topical antibiotics and can be used for the long-term management of acne. The complementary modes of action address three pathophysiologic processes of acne: abnormal keratinization leading to follicular plugging (comedo
formation), proliferation of the bacterium P. acnes within the follicle, and inflammation. Multiple studies have demonstrated significantly greater reductions in comedones and inflammatory lesion by 12 weeks compared with either agent alone or vehicle (Table 2).

Studies have shown that this adapalene + BPO combination has a comparable safety profile to adapalene monotherapy.¹⁸ The long-term tolerability and safety of adapalene 0.1% + BPO 2.5% gel was evaluated in 452 acne subjects over 12 months, with 327 patients completing the study (72%).²¹ No subjects discontinued due to lack of efficacy, while 2% discontinued due to adverse events. Overall, treatment was well tolerated with mean scores for local intolerance (comprising erythema, dryness, scaling, and burning/stinging) reported as mild or less in all study visits. The most common adverse event was dry skin (17%). The highest irritation scores were recorded in the first week and subsequently declined thereafter. Adapalene is stable when combined with BPO in the presence or absence of light.¹⁵ It has been assigned a pregnancy category C rating.

Patient Adherence

Acne is a chronic disease and poor medication adherence is a major contributor to treatment unresponsiveness.¹⁰ Convenience and decreased complexity of treatment encourage patient adherence. Effective yet well tolerated treatment regimens offering simplified dosing suited to a patient’s lifestyle are more likely to optimize adherence and outcomes. Patients most commonly attribute frustration with the therapeutic regimen and forgetfulness as reasons for failure to use prescribed medication.²²

Conclusion

Successful topical treatment of acne depends on appropriate agent selection based on patient-specific acne severity and 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. 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).
2. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 292(6):726-35 (2004 Aug).
3. Alexis AF. Clinical considerations on the use of concomitant therapy in the treatment of acne. J Dermatolog Treat 19(4):199-209 (Epub 2008 Jul 09).
4. Tan JK. Topical acne therapy: current and advanced options for optimizing adherence. Skin Therapy Lett 4(2):1-3 (2009 Jul-Aug).
5. Katsambas A, Dessinioti C. New and emerging treatments in dermatology: acne. Dermatol Ther 21(2):86-95 (2008 Mar-Apr).
6. Seidler EM, Kimball AB. Meta-analysis of randomized controlled trials using 5% benzoyl peroxide and clindamycin versus 2.5% benzoyl peroxide and clindamycin topical treatments in acne. J Am Acad Dermatol (Epub 2011 Aug 06).
7. Dutil M. Benzoyl peroxide: enhancing antibiotic efficacy in acne management. Skin Therapy Lett 15(10):5-7 (2010 Nov-Dec).
8. 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).
9. 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).
10. 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).
11. Richter JR, Forstrom LR, Kiistala UO, et al. Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical con- trol of facial acne. J Eur Acad Dermatol Venereol 11(3):227-33 (1998 Nov).
12. Zouboulis CC, Derumeaux L, Decroix J, et al. A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily, in the topical treatment of acne vulgaris. Br J Dermatol 143(3):498-505 (2000 Sep).
13. Feneran AN, Kaufman WS, Dabade TS, et al. Retinoid plus antimicrobial combination treatments for acne. Clin Cosmet Investig Dermatol 4:79-92 (Epub 2011 Jul 16).
14. 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).
15. 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).
16. 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).
17. Gollnick HP, Draelos Z, Glenn MJ, et al. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol 161(5):1180-9 (2009 Nov).
18. Gold LS, Tan J, Cruz-Santana A, et al. Adapalene-BPO Study Group. A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis 84(2):110-6 (2009 Aug).
19. 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).
20. Poulin Y, Sanchez NP, Bucko A, et al. A 6-month maintenance therapy with adapalene-benzoyl peroxide gel prevents relapse and continuously improves efficacy among severe acne vulgaris patients: results of a randomized controlled trial. Br J Dermatol 164(6):1376-82 (2011 Jun).
21. Pariser D, Westmoreland P, Morris A, et al. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1%. J Drugs Dermatol 6(9):899-905 (2007 Sep).
22. Zaghloul SS, Cunliffe WJ, Goodfield MJ. Objective assessment of compliance with treatments in acne. Br J Dermatol 152(5):1015-21 (2005 May).

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.

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.

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.

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.

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

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).

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.

Top

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.

Top

Top

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.

Top

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.

Top

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

Top

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).

Dermatrials Research, Hamilton, ON, Canada

Background

Topical acne formulations are the most common treatments used by patients and
prescribed by family physicians and dermatologists. Patients feel more comfortable
using topical therapies because they have milder side-effects, can be easier to use,
are generally less expensive, and are more readily available.

The vast spectrum of topical acne treatments allow for an individualized approach
that can be tailored to meet the needs of each patient. However, even with a wellconceived
treatment plan, when the patient leaves the office with the prescription,
appropriate steps must be taken before the patient actually uses the medication as
intended. Patient adherence is crucial in preventing treatment failure.

Causes of Nonadherence

Two primary reasons directly influence nonadherence1:

1. Difficulties encountered with the patient-physician relationship

• Patients misunderstand the clinician’s instructions.
• The treatment strategy selected is not explained sufficiently.
• The realistic expected rate of improvement and potential treatment outcomes are not effectively conveyed to patients.
• Emphasize that the goal is for management and not to cure their acne.

2. Treatment-related issues

• Patients misunderstand the side-effects of treatment.
• Patients misinterpret the risks and benefits of treatment.
• Treatment regimen and instructions are too difficult to follow.
• Patients forget to apply the medication.
• Patients find that the therapy is intolerable.
• Patients find that the cost of therapy is prohibitive.
• Patients have difficulties storing the medication properly.
• The medication has an unpleasant odor.
• The vehicle is inappropriate.

Improving Adherence

Developing a rapport with acne patients is a crucial component in realizing
treatment success.2 If a comfortable ongoing dialogue can be established, patients
will tend to offer a more thorough account of their treatment experiences and feel
more compelled to adhere to prescribed therapies.

Tips to Improve Adherence

• Gain the trust of your patients by being receptive to their individual needs through eliciting their input and expressing empathy surrounding their unique circumstances.
• Consider organizing a dedicated acne counseling session that is guided by experienced nurses.
• Express concern by following-up with patients who have missed appointments.
• Provide handouts that reinforce the aims of the selected therapies, explain the facts about acne and treatment expectations; such literature can serve as at-home reference material.
• Educate patients about the prevalence of acne and reassure them that they are not alone.
• Address nonadherent issues with the patient.
• If the patient is dissatisfied with the current treatment, be willing to modify the therapeutic approach.
• To improve short-term adherence, it may be necessary to increase the frequency of clinic visits.
• Long-term adherence can usually be achieved once short-term adherence has been established, which usually occurs when patients notice improvement in the signs and symptoms of their acne.
• Recommend the use of gentle non-soap cleansers to avoid compounding irritation and dryness from medication.
• Flexibility for application, i.e., switching morning and night use depending on tolerance, once daily, or prn use.
• Encourage patients to keep checklists and diaries in order to monitor adherence.
• Different topical antibiotics, benzoyl peroxide (BPO), and retinoids may be combined for less frequent usage.
• Adjust the frequency and duration of application to reduce side-effects; increase dosage as tolerated.

Adolescent Patients

• Consider seeing teenaged patients alone, without parents, to explore any sensitive issues that they may be more comfortable expressing one-to-one.
• Be aware that teenaged patients may be especially vulnerable to heightened anxiety about their appearance.
• Encourage patients’ suggestions of medications that friends may have recommended.
• If a parent is present, make sure to address the teenaged patient and not the parent.
• Greet the patient first and then the parent or guardian.
• Offer after school appointments to avoid disrupting their curriculum.

Tips for an Effective Office Visit

• Avoid making the patient feel rushed through the visit.
• Allow adequate time for patients to discuss their concerns and provide feedback about the prescribed treatment.
• Suggest that all acne medication and skin care products be brought to each visit for pharmaceutical editing.
• Minimize waiting room time for patients to reduce frustration.

Considerations for Vehicle Selection

When deciding on suitable treatment options, a thorough assessment of individual needs in terms of acne severity, lifestyle,
and preference of delivery vehicle must all be jointly considered.

• Patients with drier skin may prefer creams for their moisturizing properties.
• Patients with oilier complexions may prefer the lighter feel of gels, lotions, solutions, or foams.
• Less viscous formulations, such as lotions, gels and foams are better suited for application on larger surface areas and regions with greater hair density.
• Minimize irritation by using aqueous vehicles rather than those containing alcohol when possible.
• Product innovations, such as the new pump delivery system that is used for the BPO/ clindamycin combination make application easier and may promote patient adherence.
  • Compounded by the pharmacist for optimal efficacy and low irritation.
  • Results may be visible as early as 2 weeks.
  • Fewer ingredients may lessen the potential for irritation.

Considerations for Treatment Selection

Improved adherence may be achieved by considering the features of anti-acne therapy. Accessibility of the anatomical site
for topical therapy, i.e., the face, chest, and shoulders are more accessible than the back. Other important considerations
include: efficacy, tolerability, cosmetic acceptability, regimen simplicity, convenience, and ease of application.

Suggestions for Prescribing

• Assessment and diagnosis of the patient’s acne as inflammatory or noninflammatory narrows the treatment prospects.
• Limit the use of BPO on the chest and back due to its bleaching effect on clothing; recommend nighttime application and suggest wearing old t-shirts or sleepwear.
• It is important to educate patients about the expected side-effects of all prescription and over the counter products that they are currently using.
• Consider alcohol-based solutions for the chest and back.
• Consider a cotton ball application for topical medications that include dabber applicators.
• Ensure the patient has an adequate supply of medications, i.e., large quantities for larger areas.
• Prescribe multiple tubes or jars of medications for use at different locations, e.g., school, lockers, gym, home.
• As much as possible, use simplified regimens.
• Provide estimates of amounts to apply by using descriptive references that are easily understood by the patient (e.g., apply a pea-size amount of gel to each of the five facial regions: forehead, each cheek, chin, and central face).
• Missed applications and nonadherence to the prescribed regimen are often unreported to the treating physicians; bearing this in mind, the dosage may need to be increased.
• Patients should be assessed every 2-3 months to monitor therapeutic efficacy.

Conclusion

Adopting a comprehensive approach that takes into account individual preferences, properties of available treatments, and
disease severity can encourage patient adherence and lead to improved treatment outcomes. However, often underestimated,
but representing the key to gaining adherence, is the attention devoted by physicians to establishing effective communication
with the patient through:

• patient education on acne and the aims of initial and maintenance treatment.
• patient engagement in treatment selection.
• counseling on aggravating factors, medication use, adverse events, and the importance of adherence.

References

1. Renzi C, et al. Arch Dermatol 138(3):337-42 (2002 Mar).
2. Baldwin HE. Dermatol Ther 19(4):224-36 (2006 Jul-Aug).
3. Del Rosso JQ. Cutis 78 (2 Suppl 1):5-12 (2006 Aug).
4. Date AA, et al. Skin Pharmacol Physiol 19(1):2-16 (2006).
5. Tan J. Skin Therapy Lett FP 3(4):4-5 (2007 Nov).

1. Michael DeGroote School of Medicine McMaster University
2. Dermatrials Research, Hamilton, ON, Canada

ABSTRACT

Pruritus, or itch, is a common sensation that causes a person to want to scratch. It is a complex process that may negatively impact quality of life and commonly occurs with skin disorders such as atopic dermatitis and urticaria. It could also be a symptom related to an underlying disease process such as cholestasis or hyperthyroidism, or simply be caused by dry skin, especially in the cold, winter months. Therapy is often aimed at eliminating the underlying cause first, followed by the management of the itchy sensation. Treatment may include prescription and over-the-counter (OTC) medications, herbal remedies, hydrotherapy, phototherapy, and ultraviolet therapy. This overview provides information regarding the various management and treatment options for pruritus.

Key Words:
pruritus, itch, urticaria

Pathophysiology of Pruritus

Pruritus is a complex process that involves the stimulation of free nerve endings found superficially in the skin. The sensation of pruritus is transmitted through the C-fibers in the skin to the dorsal horn of the spinal cord, and then, via the spinothalamic tract to the cerebral cortex for processing. Many chemicals have been found to be pruritogenic, therefore causing the itch sensation, including histamine, serotonin, cytokines, and opioids. There are six categories of pruritus: dermatologic, systemic, neurogenic, psychogenic, mixed, and other. Various treatment and management options exist depending on the category or cause.¹

Treatment

Treatment of pruritus can be categorized in several ways. A common method of grouping the various options is causative vs. symptomatic treatment. Causative treatment involves finding the underlying disorder and then correcting it, thereby eliminating the itch sensation. Symptomatic treatment involves substituting another sensation for the itch, using methods such as cooling, heating, or counter irritation (e.g., scratching). Symptomatic treatment can be used in addition to treating the underlying disease process in order to provide earlier relief. Most of the available treatment options are categorized under symptomatic therapy and management.

Prescription Medications

Prescription medications include topical and systemic antihistamines, corticosteroids, local anesthetics, and topical immunomodulators, among others. Some lower concentration preparations of these medications are available OTC.

Antihistamines

Itching occurs when histamine is released, causing redness, swelling, warmth, and consequently itchiness. Antihistamines, or H1 antagonists, act by blocking the histamines, and are the most widely used medications for this condition. They take approximately 15–30 minutes to be effective and can be short- or long-acting.²

Topical antihistamines are available in prescription as well as nonprescription forms. Camphor (Caladryl^®, Pfizer) is a common diphenhydramine preparation that has both antipruritic and anesthetic properties. This traditional therapy carries with it a small risk of contact dermatitis and allergic sensitization.³

Doxepin, a dibenzoxepin tricyclic compound, is a very active antihistamine that can be used for atopic dermatitis (AD) and also has a useful psychotherapeutic effect for pruritic patients. It acts by depressing cutaneous sensory receptors.⁴ The starting dose is 25–50mg, taken orally at bedtime. Doxepin cream 5% may be applied q.i.d. Some side-effects of this medication include drowsiness and localized burning or stinging, which are usually transient. Findings in a placebo-controlled, double-blind trial have confirmed the effectiveness of doxepin in the relief of pruritus caused by AD.⁵ In another study by Drake et al., topically applied doxepin was again found to be a safe and effective treatment for pruritus.5 Berberian et al. conducted a double-blind, controlled study that yielded similar results in which topical doxepin was added to topical hydrocortisone or topical triamcinolone resulting in a significantly faster and more substantial reduction in itching than corticosteroid alone, and a more prompt resolution of underlying AD.⁶

Hydroxyzine hydrochloride 25mg, po, t.i.d. or q.i.d., or diphenhydramine 25–50mg, po, may be given at bedtime when pruritus is usually at its worst.

Systemic antihistamines are effective in treating some, but not all causes of pruritus, for example, their role in treating AD is limited. They can provide some level of sedation, which may assist sleep, but may also carry with it the adverse effects of unwanted sedation and other anticholinergic properties such as dry mouth, gastrointestinal upset, stomach pain, nausea, and headache. This can be prevented by using nonsedating antihistamines such as fexofenadine (Allegra®, Aventis Pharmaceuticals).

Several low-sedating antihistamines have become available in the last decade. These newer antihistamines, such as loratadine (Claritin®, Schering Canada), block histamine receptors and prevent the activation of cells by histamine, thus preventing an allergic response. Unlike the traditional antihistamines, loratadine, desloratidine (Clarinex^®, Schering-Plough; Aerius^®, Schering Canada), and cetirizine (Zyrtec^®, Pfizer) do not cross the blood-brain barrier and, therefore, do not cause drowsiness. However, these medications have had limited success in the treatment of pruritus.4

Corticosteroids

Corticosteroid medications are derivatives of the natural hormones produced by the adrenal glands and have many functions including the control of inflammatory responses. Topical formulations are applied to the skin and typically used for localized pruritus such as dermatitis. Low potency preparations are available without a prescription. This class of medications has proven to be successful in the treatment of pruritus for many years by reducing skin inflammation, thus reducing the itching. Corticosteroids seldom alleviate generalized pruritus without dermatitis, but may rarely be helpful if used with lubricants in elderly patients with dry skin. Corticosteroid creams or ointments applied t.i.d. as maintenance therapy are most effective, especially for AD. Emollients, such as white petrolatum, hydrogenated vegetable oil, or hydrophilic petrolatum may be used as a supplement between corticosteroid applications to help hydrate the skin. Corticosteroids should not be used for prolonged periods because of the risk for skin atrophy.4

Oral corticosteroids, such as prednisone, should be considered a last resort, but if given, are best used in 1–2 week courses. Alternate-day use of this drug at 20–40mg every other morning may help to reduce side-effects.4

Local Anesthetics

Topical anesthetics work by directly interfering with the transmission of impulses along the sensory nerve fibers or by depressing cutaneous sensory receptors. Those drugs that interfere with transmission include benzocaine, diperodon, and lidocaine.⁷ Hercogova suggested that caine-based anesthetics should be avoided due to risk of sensitization, but lotions or creams containing 0.25% – 0.5% menthol can be useful.⁴

Pramoxine, another topical anesthetic, has a documented antipruritic effect and is most useful for mild-to-moderate pruritus. It may be combined with coolants, such as menthol, to increase its effectiveness.⁸ One study demonstrated that both the magnitude and duration of histamine-induced itch were reduced by pramoxine.⁹

Capsaicin, the active ingredient in cayenne and red pepper, owes its antipruritic properties to the desensitization of nociceptive nerve endings responsible for transmitting the itch sensation. It is useful at concentrations of 0.025–0.075% in localized intractable pruritus,¹⁰ but may cause localized burning and stinging which can limit its use and reduce compliance in patients. This irritation will subside with repeated use of the medication if the patient chooses to overcome the initial irritations.

⁸

Calcineurin Inhibitors

Topical calcineurin inhibitors pimecrolimus (Elidel^® Cream 1%, Novartis) and tacrolimus (Protopic^® Ointment, Astellas) possess anti-itch properties and, similar to corticosteroids, they reduce skin inflammation. However, they have a different mechanism of action and, thus, are not associated with the same adverse effects. Calcineurin inhibitors prevent T-cell activation, inhibit inflammatory cytokine release, and down-regulate high affinity immunoglobulin E receptor expression on the Langerhans’ cells.¹¹ They are second-line therapies indicated for short-term and non-continuous chronic treatment of mild-to-moderate AD in non-immunocompromised people ages 2 and older who have failed to respond adequately to other topical prescription treatments or when those treatments are not advisable.

Pimecrolimus is an ascomycin macrolactam. It shows activity not only against T-cell activation, but also against mast cells and pruritus. In a study of real-life usage by Lubbe et al., incorporation of 1% pimecrolimus cream into patients’ standard treatment regimen was well tolerated and improved AD in approximately two-thirds of patients.¹²

Tacrolimus is a macrolide lactone isolated from Streptomyces tsukubaensis. The release of cytokines, such as interleukins 4 and 5, are inhibited by this drug.¹³ A study by Drake, et al. demonstrated that topical tacrolimus ointment was associated with significant quality of life benefits in adult and pediatric patients with AD.¹⁴

There is concern about continuous long-term use of calcineurin inhibitors, because of the risk of cancer development. This is based on the FDA’s public health advisory regarding information from animal studies, as well as case reports in a small number of patients. The FDA has received reports of lymphoma and skin cancer in children and adults treated with these drugs, however it has not been clearly established whether the reported cancers are associated with direct use of these products.¹⁵ Based on these findings, we suggest caution in prescribing these drugs for long-term use. Application should be limited to areas of the skin affected by AD.

Calcineurin inhibitors are not indicated for use in children 4

Cholestyramine

Pruritus is a common and sometimes disabling manifestation of cholestasis. Cholestyramine is a nonabsorbable, basic polystyrene that serves as an anion exchange resin binding bile salts in the gut lumen. It is effective in a large proportion of cases of cholestasis-related pruritus. The resin depletes the serum bile salt pool, and has a greater affinity for dihydroxy bile salts than for trihydroxy bile salts. Cholestyramine also has complex effects on absorption of a variety of compounds other than bile salts, and it has been reported to improve pruritus in polycythemia rubra vera and uremia. Side-effects are mild, but common, and include constipation, fat malabsorption, and an unpleasant taste. These side-effects may make compliance an issue.¹⁶

Rifampicin

Rifampicin is an antibiotic that has also been shown to lower hepatocyte bile salt concentrations by competing for the uptake of these salts into the hepatocyte. In one study, pruritus disappeared in 11 of 14 subjects receiving rifampicin 600mg/day and three experienced partial improvement. 16

Naltrexone

Naltrexone, an opiate receptor antagonist, was studied in a randomized, double-blind, placebo-controlled trial to assess the antipruritic effects in patients with chronic cholestatic liver disease. The investigators found that oral naltrexone may be an effective and well-tolerated alternative for pruritus, refractory to regular antipruritic therapy. In this study, five of eight patients treated had considerably less itching.¹⁷ In another study, nine out of 20 patients receiving naltrexone had >50% improvement of pruritus. Side-effects in this study, including dizziness, nausea, vomiting, headache, drowsiness, dry mouth, and cramps, were transient and did not require specific treatment.¹⁸

Ultraviolet (UV) Light Therapy

UV phototherapy is used to treat various pruritic conditions including chronic renal failure; AD; HIV; aquagenic pruritus; solar, chronic, and idiopathic urticaria; urticaria pigmentosa; polycythemia vera; pruritic folliculitis of pregnancy; breast carcinoma skin infiltration; Hodgkin’s lymphoma; chronic liver disease; and acquired perforating dermatoses, among others. It is often undertaken after multiple attempts to treat stubborn itch, and can offer relief without many of the side-effects and risks of systemic medications. UV-based therapy utilizes UVB and UVA in both broadband and narrowband, as well as PUVA (psoralen UVA). Cost and side-effects can be a prohibitive factor for patients. Erythema is common in UVB, as is premature aging and photocarcinogenesis with both UVA and UVB. Side-effects associated with PUVA include redness, burning, headache, and nausea.^16,19

UVA, UVB, and PUVA light therapies have been especially useful in the treatment of pruritus in HIV patients, as well as in those patients with systemic mastocytosis and cutaneous T-cell lymphoma. It localizes the effect on the superficial nerve endings, sparing the remaining helper cells, and relieving the pruritus. Because of its more superficial penetration, UVB is believed to be safer than UVA. UVB also spares the remaining helper cells in HIV patients and may localize the effect on the superficial nerve endings, thus relieving pruritus. Systemic mastocytosis and cutaneous T-cell lymphoma also respond to UV therapy and because destruction of the proliferating CD4 clone is desirable, UVA is usually the preferred modality over UVB, although Millikan suggests that the relief of pruritus is more predictable with UVB than with UVA.3

Cutaneous Field Stimulation (CFS)

CFS, which electrically stimulates thin afferent fibers, including nocireceptive C-fibers, was reported to inhibit histamine-induced itching. The reduction in itching is accompanied by degeneration of the epidermal nerve fibers. In one open trial, localized itching responded to CFS treatment, and pruritus was reduced by 49% at the end of 5 weeks. Itch relapsed gradually after the discontinuation of CFS, which led the researchers to conclude that nerve fibers regenerated into the epidermis.20

Over-the-Counter Treatments

In addition to the nonprescription medications mentioned above, there are other OTC treatments that can be helpful for treating and managing pruritus. Moisturizing after a bath is extremely important, and emollients such as white petrolatum, or petrolatum depositing moisturizing body washes, and in-shower moisturizers (e.g., Olay^® Ribbons^®, Procter & Gamble; emulsifying ointment USP) can be helpful when applied while the skin is still wet.²¹

There is new evidence to show that moisturizers containing niacinamide and glycerin (e.g., Olay^® Quench^®, Procter & Gamble) not only hydrate the skin, but improve the skin’s resistance to external factors and improve the barrier function. Glycerin is required for moisturizers to work quickly and add moisture to the skin, but the niacinamide helps to sustain that benefit over a longer period of time.²¹

Alternative Therapies

Several alternatives to traditional treatment of pruritus have been proposed. Often these therapies can be used in conjunction with prescribed or OTC medications to relieve symptoms quickly. Compounds that have been found to be effective for pruritus by depressing cutaneous sensory receptors include menthol, camphor, and phenol.⁷ Some other alternative therapies that have been suggested include herbal remedies, nutritional therapy, reflex therapy, and hydrotherapy.³

Herbal Remedies

Several herbs have been proposed as corticosteroid-sparing agents and may provide a viable alternative to topical steroids and their side-effects. Oatmeal baths appear to be most useful because of its colloidal protein and high mucilaginous content. Other herbs have been suggested because of their high mucilage content as well, including flax, fenugreek, English plantain, hearts ease, marshmallow, mulberry, mullein, and slippery elm.3 More extensive research needs to be conducted regarding their possible use and effectiveness for the treatment of pruritus.

Tannins, also derived from herbs, may be helpful as well. The exact mechanism of action is unclear, but may perhaps be related to the coagulation of proteins in the skin. The most common tannin-containing herb is witch hazel, but others include oak bar, English walnut leaf, goldenrod, Labrador tea, lady’s mantel, lavender, and St. John’s wort.

Other possible herbs that may be advantageous include chamomile, which has shown to be equivalent to low concentrations of hydrocortisone, aloe vera, and capsaicin.3 Some side-effects may include irritant or allergic contact dermatitis. Some herbals can be toxic if ingested as well. Some of the oldest group of medications used to soothe and cool pruritic skin is menthol and camphor, which are both considered low risk and safe to use topically. ^3,4

Nutritional Therapy

Nutritional therapy, despite not being sufficiently researched as a monotherapy for pruritus, may be helpful in combination with other anti-itch treatments. Vitamins D and E, and linolenic acid have shown some efficacy in the treatment of psoriasis and atopic eczema.³

Reflex Therapy, Acupuncture, and Hydrotherapy

While they are not traditionally used, reflex therapy, acupuncture, and hydrotherapy are three treatments that may be beneficial as adjunctive therapy, however further research is needed. There is little research available regarding the effectiveness of reflex therapy and hydrotherapy. These options may be considered in difficult-to-treat patients where traditional approaches have been unsuccessful. Acupuncture is based on the gate theory of neurotransmission, however it is infrequently used in the Western world, and therefore has insufficient evidence to fully support its use. ³

Management

The management of symptoms is paramount in the treatment of pruritus. Patients should be educated regarding the self-care aspects of this condition. Eliminating the use of irritating or tight clothing is recommended, as well as maintaining a cool environment. Patients should avoid the frequent use of soap, topical irritants in clothing, dry environments, and vasodilators such as caffeine, alcohol, and hot water. Patients should be advised to take brief, tepid or lukewarm baths using mild cleansers with a low pH. Soap film should be rinsed off completely and skin should be patted lightly, followed by the generous application of a moisturizing lotion or cream.^4,7,22

Conclusion

Pruritus is a common complaint, but one that can often be a challenge to treat. It can be a major quality of life issue for patients, so it is important that both the underlying disease and associated symptoms are treated as quickly and effectively as possible. Health teaching regarding the prevention and management of pruritus should be included in the overall treatment of the cause and symptoms.

References

1. Heymann WR. Itch. J Am Acad Dermatol 54(4):705-6 (2006 Apr).
2. DermNet NZ. Pruritus (itch). URL: http://www.dermnetnz.org/systemic/itch.html. Last accessed 2006 Dec 28.
3. Millikan LE. Alternative therapy in pruritus. Dermatol Ther 16(2):175-80 (2003).
4. Hercogova J. Topical anti-itch therapy. Dermatol Ther 18(4):341-3 (2005 Jul-Aug).
5. Drake L, Cohen L, Gillies R, et al. Pharmakinetics of doxepin in subjects with pruritic atopic dermatitis. J Am Acad Dermatol 41(2):209-14 (1999 Aug).
6. Berberian BJ, Breneman DL, Drake LA, et al. The addition of topical doxepin to corticosteroid therapy: an improved treatment regimen for atopic dermatitis. Int J Dermatol 38(2):145-8 (1999 Feb).
7. Beers MH, Berkow R, editors. The Merck Manual of Diagnosis and Therapy, 17th Ed. New Jersey: John Wiley & Sons (1999).
8. Yosipovitch G, Hundley JL. Practical guidelines for relief of itch. Dermatology Nurs 16(4):325-8 (2004 Aug).
9. Yosipovitch G, Maibach HI. Effect of topical pramoxine on experimentally induced pruritus in humans. J Am Acad Dermatol 37(2 Pt 1):278-80 (1997 Aug).
10. Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet 361(9358):690-4 (2003 Feb).
11. Hanifin JM, Pallor AS, Eichenfield L, et al. Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol 53(2 Suppl 2):S186-94 (2005 Aug).
12. Lubbe J, Friedlander SF, Cribier B, et al. Safety, efficacy, and dosage of 1% pimecrolimus cream for the treatment of atopic dermatitis in daily practice. Am J Clin Dermatol 7(2):121-31 (2006).
13. Kawashima M, QOL Research Forum for Patients with Atopic Dermatitis. Quality of life in patients with atopic dermatitis: impact of tacrolimus ointment. Int J Dermatol 45(6):731-6 (2006 Jun).
14. Drake L, Prendergast M, Maher R, et al. The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 44(1 Suppl):S65-72 (2001 Jan).
15. FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment.
16. Khandelwal M, Malet PF. Pruritis associated with cholestasis: a review of pathogenesis and management. Dig Dis Sci 39(1):1-8 (1994 Jan).
17. Wolfhagen, FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 113(4):1264-9 (1997 Oct).
18. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis: a crossover, double-blind, placebo-controlled study. J Hepatol 37(6):717-22 (2002 Dec).
19. Rivard J, Lim HW. Ultraviolet phototherapy for pruritus. Dermatol Ther 18(4):344-54 (2005 Jul-Aug).
20. Wallengren J, Sundler F. Cutaneous field stimulation in the treatment of severe itch. Arch Dermatol 137(10):1323-5 (2001 Oct).
21. Vender R. The management of itchy skin. Skin Therapy Lett – Pharm Ed 1(2):1-3 (2006 Sep-Oct).
22. Moses S. Pruritus. Am Fam Physician 68(6):1135-42 (2003 Sep).

Introduction

Itchy skin is a very common complaint seen in family practice as well as in dermatology practice. Causes of itchiness are extremely diverse and wide spread. A subset of nociceptive C neurons is responsible for the transmission of itch or pruritus, and these mediators (mainly histamine) can act centrally or peripherally. Skin disease that can mediate itchiness can originate in the skin or even in the central or peripheral nervous systems.

Dermatologic Diseases With Pruritus

Categories of Pruritus Therapy

Treatment of Specific Skin Disorders

Atopic Dermatitis

Moisturizing is extremely important for replenishing the skin’s water content and preventing water loss. Maintaining the barrier to keep out exacerbating factors from the skin, such as the external environment, is beneficial. Moisturizers should contain the following: emollients, humectants, occlusives, soothing agents and anti-irritants.

Oral antihistamines, especially those with sedating properties, e.g., hydroxyzine (Atarax^®) or diphenhydramine (Benadryl^®) may provide benefit for patients with pruritus. An antidepressant with potent antihistaminic properties, doxepin (Sinequan^®), can also be useful. The role of histamine in eczema is questionable. Alpha hydroxy acids can reduce scaling and roughness.

Urticaria

Histamine release has a central role in urticaria. There are many causes of urticaria that can be investigated by an allergist. Oral antihistamines, either sedating or nonsedating, are beneficial. Nonsedating antihistamines, such as loratadine (Claritin^®), desloratadine (Aerius^®), or fexofenadine (Allegra^®), can be used in combination with sedating antihistamines at bedtime.

Winter Itch

• The cold, dry air of Canadian winters increases transepidermal water loss and causes xerosis (severely dry skin).
• As we heat our homes, especially with electric heat, it reduces the humidity in the air.
• The skin tries to maintain an equilibrium, also causing an increase in transepidermal water loss.
• All ages can be affected.
• Can exacerbate underlying skin diseases associated with pruritus, which in turn can exacerbate pruritus further.
• Minimize soap. Nonsoap cleansers can be helpful (e.g., emulsifying ointment, Spectrogel^®, Cetaphil^®).
• Petrolatum depositing moisturizing body washes and in-shower moisturizers (e.g., Olay^® Ribbons) can be helpful.
• Moisturizing after a bath is extremely important.

There is new evidence to show that moisturizers containing niacinamide and glycerin (e.g., Olay^® Quench) not only hydrate the skin, but improve the skin’s resistance to external factors and improve the barrier function. Glycerin is required for moisturizers to work quickly and add moisture to the skin, but the niacinamide helps to sustain that benefit over a longer period of time.

Management

Conclusion

The causes and differential diagnoses are as diverse for pruritus as the treatment and management are nonspecific. This makes the workup of nonspecific itch difficult. With careful history and physical exam, as well as some laboratory investigations, most serious disorders can be ruled out and the patient’s itch can be relieved.

Faculty of Medicine, McMaster University, Hamilton, Ontario, Canada

This article will deal with the diagnosis and treatment of common eruptions on the feet. These conditions include:

Useful tests include:

• KOH (Potassium hydroxide) exam of scale for fungus from skin and nail
• Use a No. 15 blade and gently scrape scale from the edge of
  the plaques into the black transport paper, usually supplied by a diagnostic lab.
• Bacteriology culture swab
• Patch testing

Tinea Pedis (Skin and Nail)

• One of the most common dermatologic conditions
• Seen more often in men
• Almost always involves the lateral web spaces
• Soles involved and may spread onto the dorsal aspects, usually asymmetrically
• Nail involvement may follow from a skin infection or vice versa
• Cracking of the skin may create an entry site for bacterial infection producing secondary cellulitis
• Often asymptomatic but can be itchy
• Feet may be malodorous
• Painful if fissured

Tests

• KOH examination from the skin, subungual debris, or nail clippings confirms the diagnosis.
• Culture determines specific name of fungus. Check the dry scale or roof of blister. May be negative if significant inflammation.

Clinical Subtypes

• Web-space scaling and maceration. May have significant bacterial colonization.
• Dry type. Scaling can involve skin creases or the whole sole that has a powdery scale (moccasin type).
• Acute blistering. Small blisters often on instep
• Soggy white skin changes with cracking
• Nails can become involved and act as a reservoir for reinfection.

Treatment

• General measures, such as changes in footware to reduce heat and sweating
• Wear cotton or absorbent socks.
• Relapses are very common with any type of tinea infection of the feet, so intermittent maintenance using topical antifungals should be considered after clearance has been achieved.
• Antifungal powders are only of value as prophylaxis.

Topical Therapy for Tinea Pedis

Oral Therapy for Tinea Pedis

Tinea pedis

• Confirm with KOH and culture first.
• Terbinafine 250mg daily for 2 weeks
• Itraconazole (Sporanox®) studies suggest 400mg daily for 1 week or 100-200mg daily for 2-4weeks.
• Studies comparing these two drugs and using itraconazole at 100mg showed terbinafine to be much more effective.
• However, it is now known that a higher dose of itraconazole is required.
• Monitor appropriate blood work.

Nail

• Confirm with KOH and culture first and monitor appropriate blood work, i.e., CBC and LFTsat baseline and at 1 month.
• Ciclopirox 8% nail lacquer is effective in the milder forms of nail infection. Mycological cures in the range of 52% can be achieved.
• Adding ciclopirox 8% nail lacquer to terbinafine significantly increases cure rates.
• Terbinafine is thought to be the treatment of choice at a dose of 250mg daily for 3 months. Using this drug for 1 week every month for 3 or 4 cycles is almost as effective, reducing both costs and worries about side-effects.

Dyshidrotic Eczema (Pompholyx)

• A recurrent eruption affecting hands and feet seen mostly in young adults
• Associated with atopy, hyperhidrosis, stress and an allergic contact dermatitis
• Acute
• Intensely itchy
• Tiny blisters, which may become multilocular on soles and toes
• Less commonly found in the web spaces
• If pustules are present, swab for bacterial infection such as Staphylococcus.
• Once the blisters settle there may be a dry, chronic, scaly, fissured rash.

Treatment

• Acute
  • Compress blisters with saline, tap water, or 10% aluminum acetate for 20 minutes q.i.d. Large blisters can be drained.
  • Moderate-to-high potency topical steroid creams should be used after compressing.
  • Studies show that immunomodulators, such as pimecrolimus (Elidel®) and tacrolimus (Protopic®), could be added with benefit.
  • Use oral antibiotics if there is a suspicion of bacterial infection, such as Staphylococcus or Streptococcus.
  • Oral antihistamines can help with itch (sedation).
  • In severe cases, oral prednisone (Deltasone®) for approximately 2 weeks should be utilized.
• Chronic
  • Change to moderate-to-high potency topical steroid ointment rather than cream.
  • Using a topical corticosteroid intermittently, such as on weekends only, and using topical immunomodulators on weekdays has been reported.

Juvenile Plantar Dermatosis

• • Seen in childhood up to the age of 15
  • A tender, glazed erythema on the weight-bearing forefoot and toes

Nonscaly and sometimes fissured

• No vesicles are observed
• Worsened by sweating; may be caused by alternating sweating and drying as experienced by those who wear ‘sneakers’.
• Rule out fungus by KOH exam.
• 10% are patch test positive.

Treatment

• Minimize occlusive foot wear; change to cotton or absorptive socks.
• Mild topical steroid ointments b.i.d.
• Emollients such as petroleum jelly can be helpful.
• Occlusive ointments such as zinc paste can help some.
• Tar ointments have been reported as useful (e.g., 10% LCD in hydrophilic petrolatum).

Pustular Psoriasis of the Palms and Soles

• Creamy yellow, sterile pustules on an erythematous base
• The lesions are at different stages, and the pustules mature into a brown color and then become scaly
• 30% of patients have psoriasis elsewhere
• In children, especially infants, vesicopustules on the soles could suggest scabies.

Treatment

• Mild disease can be controlled with medium-to-potent topical steroids.
• Long-term risk of atrophy. Some may respond to calcipotriol combined with a corticosteroid (Dovobet®).
• Topical UVB/PUVA is useful in some patients.
• Acitretin (Soriatane®) or methotrexate (Trexall®) for resistant disease

Contact Dermatitis

• Although irritant dermatitis can be seen, allergic contact is a more significant problem.
• Itchy eczematous dermatitis on the dorsal aspect of the feet raises the possibility of a contact dermatitis, especially to footwear.
• The rash may be well defined at the area of contact, e.g., shoe tongue. The condition worsens with conditions that increase sweating, and in the summer months.

Treatment

• Identify and avoid the allergen.
• Patch testing is a must if there is clinical suspicion.
• Topical corticosteroids are the treatment of choice, but will not clear the condition if the allergen contact is still present.