¹Associate Professor, University of Toronto, Toronto, ON, Canada
²University of Western Ontario, Windsor, ON, Canada
³Clinical Instructor, University of British Columbia, Vancouver, BC, Canada
⁴Dermatologist, Calgary, AB, Canada
⁵Dermatologist, Montreal, QC, Canada
⁶Dermatologist, Quebec City, QC, Canada
⁷Dermatologist, West Vancouver, BC, Canada
⁸Clinical Associate Professor, University of Calgary, Calgary, AB, Canada
⁹UMC St Radboud, Nijmegen, The Netherlands

Conflicts of interest: The consensus meeting was supported by an educational grant from Aspri Canada. All authors of this article participated in the meeting.

Introduction

Acne is the most common disorder encountered in dermatologic practice¹, and can have a highly significant negative impact on quality of life. Our evolving understanding of the role of hormones in acne, along with a growing body of data from clinical trials, calls for a reappraisal of the role of hormonal therapy for acne.

Epidemiology and Impact

• 85% of 15 to 17-year-olds have acne¹
• 45% of women aged 21-30 years²
• 26% of women aged 31-40 years²
• 12% of women aged 41-50 years²
• Acne is associated with mood symptoms.
  • Suicidal ideation is two times more common with substantial acne versus little to no acne in girls, and three times in boys.³
  • Degree of distress and psychologic harm caused by acne does not always correlate with clinical severity.⁴

Role of Androgens in Acne

• Adrenarche
  • ~Age 8 or 9 years adrenal gland starts to produce large quantities of dehydroepiandrosterone (DHEA) sulfate⁵ ➝ increased sebum, abnormal keratinization of the follicular epithelium.¹
• Androgens
  • Produced by: adrenal glands, gonads, and sebaceous glands in the skin.⁶
  • Sebocytes, sweat glands and dermal papilla cells convert circulating DHEA and androstenedione to more potent steroids
  • DHEA ➝ testosterone ➝ dihydrotestosterone (DHT) by 5α reductase.⁶
  • Sebum production ➝ comedone formation & provides a growth medium for P. acnes.⁶
  • Women with excessive levels of androgens, as in polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia, are more likely to develop acne.^1,2
  • Most people with acne have androgen levels within normal limits. In these patients, increased sensitivity of sebaceous glands to androgens may account for the development of acne.⁶

Hormonal Therapy

• Aim is to reduce androgen action on cutaneous pilosebaceous units in women with elevated and normal androgen levels.⁷
• First-line option in women with hyperandrogenism.⁸
• Among women with normal androgen levels, hormonal therapy is usually reserved for those who are not trying to conceive and cannot be effectively managed with topical therapy
• May be particularly effective in adult women with inflammatory acne that involves the lower face and neck.⁷
• Can also be considered in women whose acne appears linked to their menstrual cycle (e.g., premenstrual flares).^7,8

Role of Spironolactone in Acne Treatment

• Despite lack of high grade evidence for efficacy, spironolactone is a frequently recommended option in the management of acne in women.
• Competitive androgen receptor blocker.⁷
• May also inhibit 5-alpha-reductase and increase steroid hormone binding globulin.⁷
• 50 to 200 mg taken with meals ➝ decrease sebum excretion by 30 to 50%.⁹
• Can be used as monotherapy in adult women with cyclic or late onset acne or in combination with other topical and oral agents.¹⁰
• Has been prescribed in doses of up to 200 mg/day, but clinical improvement may occur with doses as low as 25 mg/day, and most physicians do not recommend above 100mg/day.¹¹
• Therapy may be started with a lower dose with subsequent upward titration.¹⁰
• Although a 2009 Cochrane review found insufficient evidence to establish the efficacy of spironolactone¹², several low quality studies have reported a clinically significant benefit, with reductions in lesions from 50 to 100%.⁹
• Data for truncal acne as well as facial acne.¹⁰
• Spironolactone and Diane-35 have both shown similar efficacy in improving acne in women with PCOS.¹³

Side Effects of Spironolactone

• Generally, well tolerated and the side effects are dose-related with lesser frequency at doses ≤100 mg/day.^12,14
• Side effects include: menstrual irregularities, breast tenderness, minor gastrointestinal symptoms, orthostatic hypotension, headaches, dizziness, and fatigue.
• Potassium-sparing diuretic thus hyperkalemia is a potentially serious adverse effect. But most likely to occur at high doses and in patients with renal insufficiency or severe heart failure.¹⁵
• Educate about avoiding foods that are high in dietary potassium (ex. low-sodium processed foods and coconut water). However, testing for potassium in young and healthy women taking spironolactone for acne is unnecessary.¹⁵
• Concern over induction of estrogen-dependent malignancies raised over the years.
  • No definitive evidence linking human breast or other estrogen-dependent tumors to the use of spironolactone exists.^10,16
  • Unclear whether there is increased risk for women with a personal or family history of breast or other estrogen-dependent malignancies.¹⁶
• Co-administration of spironolactone with an oral contraceptive is advised because of serious fetal effect (feminization of the male fetus), along with the menstrual irregularities that may occur during treatment.¹⁷

Role of Oral Contraceptives in Treatment of Acne

Oral Contraceptives (OGs)

• Reduce acne lesions by increasing estrogen levels and decreasing free testosterone and androgen levels.⁷
• Estrogens in OCs inhibits androgen production by the ovaries and possibly the sebaceous glands.¹¹
• Progestins in OCs may have androgenic properties (which are counteracted by the anti-androgenic properties of the estrogen component) or anti-androgenic properties.¹⁷
• OCs indicated for acne are effective across the spectrum of disease severity.¹⁸
• In Canada, 4 OCs (Alesse/Alysena, Diane 35/Cleo 35, Yaz/Yasmine and Tri-cyclen) are indicated for the treatment of acne. These agents all contain estrogen, and progestins with either minimal androgenicity or with anti-androgenic potential.¹⁸
• OCs^18,19 may play a role:
  • Mild acne – adjunct to topical therapy for female patients desiring contraception.
  • Moderate acne – form of systemic therapy.
  • Severe acne – primary form of therapy or form of contraception in women treated with systemic isotretinoin.
• Clinical trials have consistently supported the efficacy of OCs for acne.
• Cochrane review of 31 trials of combined oral contraceptives (COCs) for acne with a total of 12,579 participants.
  • 9 placebo-controlled trials with suitable data for analysis, COCs reduced acne severity and lesion counts in all trials vs. placebo.²⁰
  • Some differences²⁰ in the comparative effectiveness of COCs containing varying progestin types and dosages were observed, but they were not pronounced and data for each comparison were limited:
  • OCs that contained cyproterone acetate (examples – Diane 35/ Cleo 35) improved acne to a greater degree than levonorgestrel (example – Alesse/Alysena), although this apparent advantage was based on limited data.²⁰
  • Levonorgestrel (example Alesse/Alysena) showed a slight improvement over desogestrel (example Marvelon) in acne outcomes, but results were not consistent.²⁰
  • A drospirenone (example Yaz/Yasmine) COC appeared to be more effective than norgestimate (example Tri-cyclen) or nomegestrol acetate plus 17β-estradiol, but less effective than cyproterone acetate (examples Diane 35/Cleo 35).
• Oral contraceptive versus other treatments
  • Review of 32 randomized controlled trials of OCs and antibiotics
    • Antibiotics superior after 3 months of treatment,
    • OCs and antibiotics had equivalent efficacy at 6 months.²¹
    • At 6-month oral antibiotics and OCs reduced acne lesions by an average of 52.8% and 55% respectively.²¹
  • If considering long-term therapy (over 6 months) it may be more reasonable use OC rather than antibiotics due to emergence of antibiotic resistance.

Side Effects of Oral Contraceptives

• Main adverse events to consider when selecting hormonal treatments: cardiovascular disease, stroke, breast cancer, pulmonary emboli, deep vein thrombosis, arterial thrombosis and abnormal vaginal bleeding.²¹
• Decreased risk of ovarian cancer after five years of use, but there has been concern about the possible association between oral contraceptive use and the risk of breast cancer.²² The net effect of COC use may well be positive (i.e., slight increase in life expectancy).²³
• A safety review of drospirenone-containing oral contraceptives (example Yaz/Yasmin) in 2011 determined they may be associated with a 1.5-to-3 per 10 000 patients per year risk of blood clots versus 1 per 10 000 patients per year in Levonorgestrel containing pills (example Alesse).²⁴
• Similar review of cyproterone acetate/ethinyl estradiol-containing OCs (Diane 35/Cleo 35) was completed in 2014. The review, concluded that the risk of blood clots from these COCs in people without additional risk factors (e.g., obesity, smoking, decreased mobility) is very low and that these agents have a favourable benefit/risk profile when used as prescribed.²⁵

Case-based Treatment Approaches

Rationale

• A case-based approach may facilitate a treatment selection process that reflects real-world scenarios and patient-specific challenges.

Approach

• A panel of 8 dermatologists was convened for a meeting on May 2, 2015 in Toronto, to discuss, refine and select patient profiles compatible with hormonal therapy for acne. Draft cases were developed by the group prior to the meeting.
• The panel developed 5 case in which hormonal therapy can be considered. The cases were selected to cover a spectrum of real-world acne presentations compatible with the use of hormonal therapy.

Case 1: 34-year-old female with facial acne that varies with menstrual cycle
	Her acne is present since adolescence, is mainly inflammatory and often located along the jawline, chin and periorally. She is otherwise healthy and has normal menses. She reports that her acne significantly interferes with her quality of life. Previous topical acne therapy caused dryness, peeling, and irritation. She failed a trial of oral antibiotics. To the best of her recollection, past use of OCs (for contraception) did not significantly improve her acne.
Discussion Negative experience with topical therapy consider systemic therapy. Her acne appears to have a hormonal component. Has used OCs in the past for contraception rather than acne, the lack of observed improvement in her acne argues against OC monotherapy as a first choice. Thus, spironolactone10-12 seems a reasonable option to consider, either alone or in combination with OCs.13
Case 2: 17-year-old female presents with sensitive skin, moderate-to-severe acne and potential sexual activity
	She first developed acne at the beginning of puberty, and it has since progressively worsened. She has tried many topical treatments, which yielded generally poor results and caused dryness and irritation on her face. A light smoker for the past 2 years, she reports that she is not yet sexually active but has a steady boyfriend. She has no signs of elevated androgen levels, but has bothersome skin oiliness. She and her parents are opposed to using antibiotics, and her mother is concerned that using OCs could promote sexual activity.
	Discussion Adolescent acne tending toward the severe end of the spectrum – had not responded to topical treatment and scarring is a concern thus systemic therapy seems appropriate in this case.19 Options include OCs18,20, spironolactone10,18, isotretinoin26 and antibiotics.19 OCs could be considered as a first-line option18,20, with the addition of isotretinoin if response is suboptimal.13
Case 3: 30-year-old sexually active female with severe truncal-predominant acne located mainly on the upper back
	She has no signs of hyperandrogenism. Certain fabrics irritate her back, and application of topical treatments on this area has proven challenging. For this reason, she finds topical products inconvenient. She has tried oral antibiotics in the past, and they only worked while she was taking the medication. She had a similar experience with isotretinoin, which she does not want to try again. She quit smoking 2 years ago after smoking for 11 years. She lives alone and is occasionally sexually active.
Discussion All systemic therapies (OCs, spironolactone, isotretinoin, antibiotics) can be considered.19,26,27 Because of the patient’s time-limited response to prior oral antibiotic therapy, this option should be kept in reserve in case the other options prove unsatisfactory.19 OCs are effective in truncal acne and provide added benefit of birth control.18 PCOS should be addressed by appropriate evaluations. BPO wash can be considered concomitantly.19
Case 4: 34-year-old female with multisite acne of variable severity and features consistent with PCOS
	She was diagnosed with type 2 diabetes a year ago and is currently taking metformin. She has Class I obesity (BMI 30.9). Upon questioning, she states that her periods have always been irregular and also has excessive facial hair that requires her to shave every few days. She also has a lot of hair on her abdomen and arms. She mentions that her mother is similarly hirsute. Her voice is lower than average, but within the normal female range. Upon testing, the patient’s follicle-stimulating-hormone (FSH) levels are normal, but her luteinizing hormone (LH) levels are elevated. Her fasting insulin levels were also high. Other lab results are normal, and pelvic ultrasound results are equivocal, with “possible” signs of polycystic ovaries. Overall, these results are consistent with PCOS.
Discussion Would benefit from OCs26, 27 or spironolactone.10 Target the hormonal abnormalities underlying acne and provide other benefits such as diminution of hirsutism and regularization of menses.16
Case 5: 32-year-old female with skin of colour and moderate-to-severe acne including some painful lesions, scarring and PIH
	She has some scarring and post-inflammatory hyperpigmentation (PIH). Previous acne therapy has resulted in dryness, peeling and irritation. She in a long-term relationship, has two children, and is not currently trying to conceive.
Discussion Would benefit from OCs26, 27 or spironolactone.10 Target the hormonal abnormalities underlying acne and provide other benefits such as diminution of hirsutism and regularization of menses.16

Adherence

• Adherence to topical agents is related to duration of treatment, complexity of the treatment regimen, as well as therapy cost, patient self-image and QoL.^8,35
• Demands associated with disease management can create a significant treatment burden for patients with chronic diseases. This burden combined with general life demands (e.g., job, family) comprises the overall patient workload.
• Treatment fatigue is common, with disengagement from recommended health behaviors when a person’s workload exceeds their capacity, a primary contributing factor to non-adherence.³⁶
• When considering cost of therapy, it is important to remember both direct (e.g., prescription drug costs, physician visits, treatment in day clinics) and indirect costs (e.g., loss of time from work, loss of income, non-prescription drug costs). These costs are likely exacerbated by non-adherence to medication. In psoriasis particularly, QoL is adversely affected with people coping by avoiding social situations and covering their lesions.⁸
• With topical dermatologic products, studies suggest that patients prefer, and are more adherent to, certain topical vehicles based on convenience and cosmetic acceptability.³⁷

Conclusion

• In appropriately selected patients, hormonal therapy provides an effective alternative to topical and oral antibiotics.²⁹
• While relatively few OCs are approved for the use in acne, clinical trials suggest that many other OCs are also effective.³⁰
• The benefits of hormonal therapy may extend beyond improvement of acne in some patient subgroups, such as those with PCOS or those with menstrual irregularities.
• More research into the subtypes of acne most responsive to hormonal treatment, as well as the comparative efficacy of available hormonal treatments, will help tailor treatment to different acne patient presentations.

Introduction

Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, or non-dermatophyte molds. Results from a large international study show that onychomycosis affects up to 23% of the population.¹ The rates of onychomycosis in people older than 40 is even higher, and has been reported to be greater than 50%.¹ Risk factors for onychomycosis include increasing age, atopy, sports, diabetes, obesity, peripheral arterial disease, immunosuppression, and pre-existing nail disease.¹

Diagnostic Features

• The clinical diagnosis of onychomycosis can be challenging given that inflammatory disorders of the nails can mimic onychomycosis.
  • The differential diagnosis of onychomycosis includes psoriasis of the nails, idiopathic onychodystrophy, traumatic onychodystrophy, lichen planus, and alopecia areata.
  • Onychomycosis accounts for approximately 50% of nail disorders.²
• In patients with mycologically proven onychomycosis the most common clinical findings are:
  • Discoloration of the nail (85%), hyperkeratosis (80%) and onycholysis (43%).
  • The rates of damaged nail (13%) and paronychia (7%) were lower.¹
• To confirm a diagnosis of onychomycosis, clippings can be obtained from the distal nail, curettings can be obtained from below the nail plate with a 1mm curette, or a scalpel can be used to pare down the overlying normal nail plate to get to the debris beneath the nail for KOH and/or culture.³
• Curetting beneath the nail plate increases the sensitivity of KOH and culture when done in conjunction with either clipping or paring alone.³

Treatment Rationale

• • Onychomycosis impacts patients’ psychosocial functioning.
  • In a survey on how adults with onychomycosis are perceived by others, survey respondents said they would:⁴
    • Perceive those with onychomycosis as less likely to be able to form good relationships.
    • Be more likely to exclude those with onychomycosis from social activities.
    • Feel uncomfortable sitting or standing beside an infected person.
  • Many patients with onychomycosis have associated pain, which can be underestimated by physicians.⁵
  • Onychomycosis in diabetic patients may be associated with serious consequences.
    • Diabetic patients with onychomycosis have higher rates of infections and of foot ulcers⁶ compared to diabetic patients without onychomycosis.
    • The presence of onychomycosis in a patient increases the risk of diabetic foot complications from moderate to high risk.⁷

Treatment/Management Options

Systemic Therapies

• • • Terbinafine
      • Terbinafine is currently the most efficacious systemic agent for treating onychomycosis.
        • Mycological cure – 74%
        • Complete cure – 38%
        • Assessed at week 48, after a 12 week treatment course.⁸
        • Mycological cure is defined as a negative KOH and negative fungal culture.
      • Complete cure is defined as mycological cure with 0% clinical nail involvement. There is a Health Canada Black box warning stating “Rare cases of liver failure, some leading to death or liver transplant, have occurred with the use of terbinafine tablets; Treatment with terbinafine tablets should be discontinued if biochemical or clinical evidence of liver injury develops.” The actual rates of idiosyncratic hepatobiliary dysfunction have been reported to range between 1 : 45 000 to 1 : 120 000.^9,10
      • The typical dosing for toenail onychomycosis is 250mg once daily for 12 weeks.
  • • Azoles
      • Ketoconazole
        • In 2013, the FDA issued a safety announcement that oral ketoconazole tablets should not be a first-line treatment for any fungal infection due to hepatotoxicity, adrenal insufficiency and drug interactions. The US label for ketoconazole now carries an FDA black box warning that systemic ketoconazole should only be used when other effective antifungals are not available or tolerated, due to hepatotoxicity and drug interactions leading to QT prolongation.¹¹
      • Itraconazole
        • Mycological cure – 54%
        • Complete cure – 14%
        • Black box warning: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.¹²
        • 200mg once daily for 3 months or pulse dosing: 3 pulses of 200mg bid for 7 days, with 3 week drug free intervals between pulses.

Topical Therapies

• • • Ciclopirox 8% nail solution¹³
      • The cure rates for ciclopirox in two double blinded Phase III trials were:
        • Mycological cure – 29-35%
        • Complete cure – 6%-9%
      • The treatment protocol for Ciclopirox 8% nail solution involves once daily application, with removal of the ciclopirox solution every 7 days with isopropyl alcohol, with removal of the unattached, infected nail as frequently as monthly for up to 48 weeks.
    • Efinaconazole 10% solution
      • Mycological cure – 55.2% and 53.4%
      • Complete cure – 17.8% and 15.2%
      • 48 weeks of treatment

Efinaconazole 10% Solution

Background

• • • Efinaconazole is a topical azole antifungal that inhibits ergosterol, a structural component of fungal cell membranes, leading to the loss of cell membrane integrity.^14,15
    • In vitro efinaconazole has been found to be active against dermatophytes, non-dermatophytes, and yeasts.16
    • It has low keratin affinity which allows enhanced penetration through the nail compared to ciclopirox, this presumably allows the topical to better treat fungus within and under the nail plate.¹⁷
    • Efinaconazole 10% solution has been shown to penetrate through nail polish, so that patients do not need to remove their nail polish to treat on a daily basis.¹⁸
    • The treatment course for efinaconazole 10% solution is once daily for 48 weeks, applied to the affected toenail, underside of the nail plate, and to the surrounding skin. Debridement or removal of previously applied efinaconazole 10% solution is not necessary as there is no buildup from daily application.¹⁹

Efficacy

• • • The efficacy of topical 10% efinaconazole was demonstrated in two Phase III studies with 1655 patients.
    • The cure rates at 52 weeks, 4 weeks after the completion of treatment, in the two Phase III studies were:
      • Mycological cure – 55.2% and 53.4%
      • Complete cure – 17.8% and 15.2%

Factors Affecting the Efficacy of Topical Efinaconazole 10% Solution

• • • Females had higher complete clearance rates than males (27.1% versus 15.8%, p=0.001).²⁰
    • Concomitant tinea pedis²¹
      • Treatment of concomitant tinea pedis – complete cure 29.4% and mycological cure 56.2%.
      • Without treatment of concomitant tinea pedis – complete cure 16.1% and mycological cure 45.2%.
    • Diabetes²²
      • Patients with controlled diabetes (n=69) were compared to non-diabetic patients (n=993).
      • Complete cure rates were 13% and 18.8% respectively, the difference was not statistically significant.
    • Duration of disease – There is a trend that patients with onychomycosis for less than 1 year had higher complete cure rates than those with a longer duration of disease.²³
      • < 1 year – 42.6% complete cure versus 16.7% for vehicle – not statistically significantly different from vehicle.
      • 1-5 years – 17.1% complete cure versus 4.4% for vehicle.
      • > 5 years – 16.2% complete cure versus 2.5% for vehicle.
    • Disease severity – Patients with less nail involvement had higher cure rates.²⁴
      • ≤ 25% nail involvement – complete cure rate 25.8%; mycological cure 58.2%.
      • >25% nail involvement – complete cure rate 15.9%; mycological cure 55.5%.

Clinical Pathway

• • In 2015 a group of Canadian dermatologists developed a clinical pathway for managing toenail onychomycosis (figure 1),²⁵ based on the available data.
  • The clinical pathway provides a guide toward a patient-centred treatment strategy, focusing on prevention, management, and minimizing re-infection of onychomycosis.
  • Treatment stragies are based on severity of disease:
    • >60% of toenail affected: oral terbinafine
    • 20-60% of toenail affected: topical efinaconazole +/- oral terbinafine
    • <20% of toenail affected: topical efinaconazole

Summary

• • • When making a diagnosis of onychomycosis, curetting beneath the nail plate with a 1mm curette combined with clipping the nail, can increase the sensitivity of clipping the nail alone.
    • Topical therapy appears most effective for patients with early disease and smaller amounts of nail involvement.
    • When treating topically, concurrently treating the concomitant tinea pedis appears to increase the complete cure rate.
    • Treatment with efinaconazole involves once daily application of the 10% solution to the nail plate, under the nail plate, and to the surrounding skin for 48 weeks with penetration through the nail plate, without removing nail polish; there is also no need to remove the solution from the nail plate on a weekly basis.
    • The complete cure rate with efinaconazole 10% solution is between 15.2% and 17.8%.
    • In terms of systemic therapy, terbinafine has a complete cure rate of 35%; ketoconazole has an FDA black box warning against using it first-line for any fungal infections.

References

• 1. Haneke E, Roseeuw D. Int J Dermatol. 1999 Sep;38(S2):7-12.
  2. Faergemann J, Baran R. Br J Dermatol. 2003 Sep;149(65):1-4.
  3. Hull PR. J Am Acad Dermatol. 1998 Dec;39(6):1015-7.
  4. Chan HH, et al. Biopsychosoc Med. 2014 Jul;8(1):15
  5. Drake LA, et al. J Am Acad Dermatol. 1999 Aug;41(2):189-96.
  6. Boyko EJ, et al. Diabetes Care. 2006 Jun;29(6):1202-7.
  7. Ibrahim A. Diabetes Res Clin Pract. 2017 May;127: 285-287.
  8. Novartis. Lamasil (terbinafine hydrochloride tablets). 2013.
  9. Hay RJ. J Am Acad Dermatol. 1993 Jul;29(1):50-4.
  10. Orion E, et al. Clin Dermatol. 2005 Mar-Apr;23(2):182-92.
  11. Janssen Pharmaceuticals. Nizoral (ketoconazole) tablets. 2014.
  12. Janssen Pharmaceuticals. Sporanox (Itraconazole) tablets. 2017.
  13. Sterimax Inc. Ciclopirox topical solution. 2013.
  14. Rodriguez RJ, et al. Biochim Biophys Acta. 1985 Dec 4;837(3):336-43.
  15. Parks LW, et al. Lipids. 1995 Mar;30(3):227-30.
  16. Jo Siu WJ, et al. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
  17. Sugiura K, et al. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
  18. Zeichner JA, et al. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
  19. Valeant Pharmaceuticals. Jublia (efinaconazole) topical solution, 10%. 2014.
  20. Gupta AK, et al. J Drugs Dermatol. 2014 Jul;13(7):815-20.
  21. Markinson B, Caldwell B. J Am Podiatr Med Assoc. 2015 Sep;105(5):407-11
  22. Vlahovic TC, Joseph WS. J Drugs Dermatol. 2014 Oct;13(10):1186-90.
  23. Rich P. J Drugs Dermatol. 2015 Jan;14(1):58-62.
  24. Rodriguez DA. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-29.
  25. Gupta AK, et al. J Cutan Med Surg. 2015 Sep-Oct;19(5):440-9.

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]