¹Skin Centre for Dermatology, Peterborough, ON and Queen’s University, Kingston, ON, Canada
²Associate Professor, University of Toronto, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada
⁴Clinical Instructor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁵Assistant Professor in Clinical Teaching faculty of medicine, Sherbrooke University, Sherbrooke, QC, Canada
⁶Assistant Professor, Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁷Dermatology, CHU de Québec-Université Laval, Quebéc, QC, Canada
⁸Centre hospitalier universitaire Dr-Georges-L.-Dumont, Moncton, NB, Canada
⁹Assistant Professor, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
¹⁰Queen’s University, Kingston, ON, Canada
¹¹Clinical Associate Professor, Memorial University of Newfoundland, St. John’s, NL, Canada
¹²Clinical Assistant Professor, Discipline of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
¹³Associate Clinical Professor Dermatology, University of Calgary, AB, Canada
¹⁴Associate Professor, Dalhousie University, Halifax, NS, Canada
¹⁵Université de Montréal, Montréal and Dermatologie Sima Recherches, Verdun, QC, Canada
¹⁶Dermatology, CHU de Québec-Université Laval, Québec, QC, Canada
¹⁷Ottawa, ON, Canada
¹⁸Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada
¹⁹Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Introduction

Chronic hand dermatitis (CHD) can affect up to 10% of the population and have a significant impact on quality of life (QoL).^1-3 It presents as a chronic, recurrent, inflammatory condition with erythema, scaling, fissuring, pruritus and lichenification of the hands. The etiology is multi-factorial and includes both genetic and environmental factors.¹Treatment is notoriously difficult as symptoms frequently recur despite standard therapy. Undertreated CHD can lead to a substantial burden on patients as well as an economic burden on society due to reduced work productivity and many work-related compensation claims.^2-5

Recently, practical guidelines for the management of CHD were published in the Skin Therapy Letter, Family Practice Edition (October 2016).⁶ This series of cases using alitretinoin (Toctino®, GlaxoSmithKline and distributed by Actelion, Laval, QC) is a follow on to that publication to put the guidelines into context.

Abbreviations: AEs – adverse events, CHD – chronic hand dermatitis, ENT – ear, nose, and throat, HD – hand dermatitis, QoL – quality of life

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 exposures to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum, as needed.

Case

Case 1:

A 39-year old dairy farmer presented with a 15-year history of redness, scaling and painful fissuring of the hands. He has used multiple potent topical steroids over the years with only temporary benefit. Despite the continued use of topical steroids he reported that his symptoms always return. After a skin scraping for fungal culture was taken and reported negative, he was referred to a dermatologist for assessment.

A diagnosis of CHD was confirmed. Given the failure of potent topical steroids for >8 weeks and inability to attend regular phototherapy sessions, his dermatologist started him on alitretinoin 30 mg PO QD for a 6-month course. By week 12, his hands were almost clear and by week 24, his hands were clear. He stopped the medication after a 6-month course of alitretinoin and entered into remission. At follow up appointments at year 5 and year 11, his hands remained clear. (Figure 1 and 2)

• Alitretinoin (9-cis retinoic acid) is an endogenous retinoid (physiological vitamin A derivative) and is the only systemic agent approved for CHD. It has proven to be safe and effective for the treatment of CHD in controlled clinical trials7-10 and in real-world experience.^11-15
• In the pivotal BACH trial, 1032 patients with CHD were treated with alitretinoin (10 mg, 30 mg) or placebo for up to 24 weeks. The group that received alitretinoin 30 mg QD had up to a 75% median reduction in signs and symptoms and 48% were clear or almost clear at the week 24 time point.⁸
• In patients who were clear/almost clear, 67% did not relapse within 24 weeks off therapy. In those patients who did relapse, 80% of those re-treated with 30 mg QD recaptured their response.⁹
• Approximately half of those patients receiving 10 mg QD and 40% of those receiving 30 mg QD who did not initially respond to alitretinoin, did respond to retreatment with the 30 mg QD dose for an additional 24 weeks.¹⁰
• The majority of patients do not require long-term management with alitretinoin as some patients enter a remission period with 24 weeks of therapy. For those who relapse and require re-treatment, the majority recapture their response⁹ and in those patients who require ongoing therapy, there are no safety concerns with continuous dosing.^10,12,13

Figure 2. No further prescribed systemic or topical treatments since 2005. (2A) Year 5, (2B) Year 11.Photos courtesy of Dr. Yves Poulin

Case 2:

A 52-year old female teacher presented with a 15-year history of recurrent CHD. She had tried numerous moisturizers and mild to superpotent topical steroids over the years without relief. She tried 6 months of narrowband UVB phototherapy with only partial resolution. She was frustrated and looking for a better solution. Her past medical history is significant for obesity and hypothyroidism. Her dermatologist started her on alitretinoin 30 mg PO QD with excellent response. However, her baseline liver enzymes were 1.5 times the upper limit of normal and 2 months after initiating therapy, increased to 3 times the upper limit so the alitretinoin was discontinued.

Ultrasound demonstrated fatty liver and further work up revealed diabetes. After initiation of metformin and 10 kg of weight loss, the patient’s transaminases returned to within the normal range but her CHD flared. A repeat course of phototherapy and superpotent topical steroids failed again. Slow re-introduction of alitretinoin at 10 mg, followed by 20 mg and then 30 mg led to recapture of response and her transaminases have remained within normal range throughout a continued 3-year course of therapy with alitretinoin.

• In clinical trials, alitretinoin was well tolerated by the majority of patients, although a dose dependent effect was noted with the AE of headache (up to 21.6% with 30 mg dose, 11.6% with 10 mg dose) and with mucocutaneous side effects.^8-10
• Laboratory abnormalities consistent with a retinoid class effect were noted in the trials, with dose dependent elevations in serum cholesterol and triglycerides most commonly noted; reduced thyroid stimulating hormone was reported, but there were no cases of clinical hypothyroidism.^8-10
• A hepatic effect of alitretinoin was not identified in the clinical trials^8-10 or in real-world studies,^11,14 however transient and reversible increases in transaminases have been noted in the product monograph.¹⁶ In the case presented, her transaminitis was likely related to her underlying fatty liver; she had no further issues with ongoing alitretinoin use, once she had proper management of her comorbid conditions (obesity, diabetes). If persistent elevations in transaminases are noted, reduction of the dose or discontinuation should be considered.¹⁶
• Post-marketing surveillance of the use of alitretinoin has identified AEs of special interest in the retinoid class that were not identified in clinical trials. Depression has been reported as well as very rare cases of inflammatory bowel disease and benign intracranial hypertension.¹⁴
• Work-up and monitoring for patients taking alitretinoin is similar to other commonly used retinoids (isotretinoin, acitretin) and should include: baseline hepatic transaminases and lipid profiles, repeated at one month, and then every 2-3 months during therapy. Beta-HCG should be done in women of child-bearing potential prior to initiation of therapy and repeated monthly during therapy and one month after discontinuation.¹⁶
• Retinoids are potent teratogens so practitioners should follow the Pregnancy Prevention Program,¹⁶ and women of child-bearing potential should be counselled on strict pregnancy prevention, use of two highly effective forms of birth control simultaneously and be monitored monthly with a serum pregnancy test.¹⁶
• Of 2 pregnancies reported in the clinical trials and 12 in post-marketing reports, 13 pregnancies were terminated early (elective or spontaneous abortion) and one healthy baby was born. No congenital abnormalities have been reported to date.¹⁴

Case 3:

A 68-year old retired woman had been suffering from hand dermatitis for the past 3 years since she had been at home caring for her elderly husband. She had been applying emollients throughout the day and trying to avoid frequent hand washing. Neither the potent topical corticosteroid nor the topical calcineurin inhibitor prescribed for her have helped. She was finding chores at home difficult with fissured finger tips and could not enjoy her hobbies of knitting or gardening because of the painful fissures. She was started on alitretinoin at 30 mg PO QD and noted good response, however she suffered from frequent headaches. Her dose was reduced to 10 mg PO QD with partial return of her CHD symptoms. Addition of a potent topical steroid and a course of narrowband UVB phototherapy to the alitretinoin 10 mg QD provided an effective combination regimen to control her CHD.

• Although clinical trials excluded concomitant therapy with topical medications or phototherapy, these concomitant treatments are often continued or added in real-world practice.^11,13
• Narrowband UVB phototherapy has been shown to be effective in CHD.¹⁷
• We know from vast experience in treating psoriasis, the combination of retinoids and UVB phototherapy is a very safe and effective way to optimize treatment outcomes and can reduce the cumulative dose of UVB exposure.^18,19
• According to expert opinion based on the experiences of the authors, combination of alitretinoin with topical corticosteroids or phototherapy is safe, can improve responses and may be a good option for patients who can only tolerate the 10 mg QD dose or who have not reached clear/almost clear status with the 30 mg QD dose.¹³
• Regardless of the combination of treatments selected, always remember to assess adherence and counsel each patient on appropriate prevention and avoidance strategies, regular moisturization and proper use of medications.⁶ (see Figure 3)

Case 4:

A 34-year-old mechanic presented with a 3.5-year history of CHD. His job is dependent on the use of his hands and he has a young family to support. He responded poorly to multiple courses of mid to superpotent topical steroids and a topical calcineurin inhibitor. Contact dermatitis was suspected and he was referred to a dermatologist for patch testing.

Patch testing with the North American Contact Dermatitis Group standard series revealed a positive reaction to methylisothiazolinone, which happened to be an ingredient in the citrus hand scrub he used at work and in the wet wipes he used when changing his child’s diaper. Modification of his home and work place environment to avoid this allergen has improved his CHD somewhat but it is not clear and is still causing problems at work. He was fearful of jeopardizing his employment and requested further treatment. A course of alitretinoin at 30 mg QD was initiated with good response and he continued to avoid methylisothiazolinone at work and home.

• CHD may be related to a contact dermatitis, which can be either irritant contact dermatitis or in some cases allergic contact dermatitis.²⁰ Many times patients also have an underlying atopic diathesis putting them at increased risk of developing hand dermatitis.²¹
• Contact dermatitis should be suspected when patients are not responding to treatment or worsening despite therapy; these patients should be referred for patch testing.^20,21
• Many different allergens can be responsible for the onset or exacerbation of CHD. In this particular patient’s case, methylisothizolinene, a common preservative in personal care products,^21-23 was a factor. This outlines the importance of patch testing, and considering contact dermatitis in the differential diagnosis.
• Whether the patient has CHD of unknown etiology or due to irritant contact dermatitis, allergic contact dermatitis or underlying atopic dermatitis, alitretinoin is still an option for management as second line therapy after failure of potent or superpotent topical steroids. Patch testing can help determine if an allergen should be avoided as part of the management plan, although lengthy wait times for this test in some jurisdictions should not delay therapy. In some cases, once identified, allergen avoidance may be all that is necessary for symptom resolution.
• In the real-world observational study, PASSION, it was shown that treating CHD with alitretinoin resulted in significant and rapid improvement in symptoms, increased QoL and reduced work impairment. The number of patients rated as ‘disabled’ was reduced from 12.4% at baseline to 2.2% at week 24, and those reporting no work impairment increased from 2.7% at baseline to 63.7% at week 24, showing that alitretinoin can significantly reduce work incapacity.¹⁵

Conclusions

CHD is a common condition causing a significant impact on quality of life and an economic burden due to reduced productivity and cause for disability. Many patients do not respond to standard treatments, making it a challenging condition to manage. This case series is a follow on to a recent publication of practical guidelines for the general practitioner on the management of CHD, to put the use of alitretinoin in context. The addition of alitretinoin to our therapeutic armamentarium has changed the way we are able to manage patients who suffer from this condition, providing a safe and effective treatment option to improve QoL and reduce work impairment. When managing patients with CHD, we must always remember to confirm the diagnosis, assess adherence, counsel our patients on prevention and avoidance strategies, encourage moisturization and proper use of medications and refer patients for patch testing if a contact allergy is suspected.

Patient Resources:
https://eczemahelp.ca/
http://www.eczemacanada.ca/

Acknowledgement

The authors wish to acknowledge Evert Tuyp, MD, FRCPC for his editorial assistance in the preparation of this manuscript.

References

1. Thyssen JP, et al. Contact Dermatitis. 2010 Feb;62(2):75-87.
2. Lynde C, et al. J Cutan Med Surg. 2010 Nov-Dec;14(6):267-84.
3. Kouris A, et al. Contact Dermatitis. 2015 Jun;72(6):367-70.
4. Augustin M, et al. Br J Dermatol. 2011 Oct;165(4):845-51.
5. Cvetkovski R, et al. Br J Dermatol. 2005;152(1):93-8.
6. Gooderham M, et al. Skin Therapy Letter, Family Practice Edition. 2016 Oct;11(1):1-5.
7. Ruzicka T, et al. Arch Dermatol. 2004 Dec;140(12):1453-9.
8. Ruzicka T, et al. Br J Dermatol. 2008 Apr;158(4):808-17.
9. Bissonnette R, et al. Br J Dermatol. 2009 Feb;162(2) :420-6.
10. Lynde C, et al. Clin Exp Dermatol. 2012 Oct;37(7):712-7.
11. Diepgen TL, et al. Acta Derm Venereol. 2012 May;92(3)251-5.
12. Gulliver WP, et al. J Cutan Med Surg. 2012 May;92(3):251-5.
13. Ham K, et al. J Cutan Med Surg. 2014 Oct;18(5):332-6.
14. Morris M, et al. J Dermatolog Treat. 2016;27(1):54-8
15. Thaçi D, et al. J Dermatolog Treat. 2016 Nov;27(6):577-83.
16. Toctino® (alitretinoin) soft capsules (product monograph on the Internet). Mississauga (ON): GlaxoSmithKline Inc, Distributed by Actelion Pharmaceuticals Canada, 2016 [revised 04 APR 2016].
17. Sezer E, Etikan I. Photodermatol Photoimmunol Photomed. 2007 Feb;23(1):10-4.
18. Green C, et al. Br J Dermatol. 1992 Jul;127(1):5-9.
19. Ruzicka T, et al. Arch Dermatol. 1990 Apr;126(4):482-6.
20. Diepgen TL, et al. JDDG. 2015 Jan;13(1):77-85.
21. Mowad C, et al. J Am Acad Dermatol. 2016 Jun;74(6):1029-40.
22. Ham K, et al. Dermatitis. 2015 Jul-Aug;26(4):166-9.
23. Cahill JL, et al. Med J Australia. 2014 Mar;200(4):208

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]

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

Introduction

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

Top

Overview of Atopic Dermatitis

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

Pathogenic and Other Contributing Factors

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

Top

Treatment Rationale

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

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

Top

Treatment Options

Topical Corticosteroids

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

Topical Calcineurin Inhibitors

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

Antimicrobials

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

Lifestyle/Non-pharmacologic Strategies

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

Top

A Paradigm Shift in the Management of Eczema

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

Top

Conclusion

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

References

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

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

Introduction

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

Overview of Atopic Dermatitis

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

Pathogenic and Other Contributing Factors

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

Treatment Rationale

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

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

Treatment Options

Topical Corticosteroids

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

Topical Calcineurin Inhibitors

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

Antimicrobials

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

Lifestyle/Non-pharmacologic Strategies

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

A Paradigm Shift in the Management of Eczema

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

Conclusion

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

References

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

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

Introduction

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

Top

Overview of Atopic Dermatitis

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

Pathogenic and Other Contributing Factors

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

Top

Treatment Rationale

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

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

Top

Treatment Options

Topical Corticosteroids

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

Topical Calcineurin Inhibitors

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

Antimicrobials

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

Lifestyle/Non-pharmacologic Strategies

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

Top

A Paradigm Shift in the Management of Eczema

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

Top

Conclusion

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

References

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

1. La Clinique de Dermatologie, Moncton, NB, Canada
2. Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Background

Human papillomavirus (HPV) is a very common sexually-transmitted disease that is associated with a number of benign, premalignant, and frankly malignant lesions of the anogenital tract. In Canada, its prevalence varies depending on a number of risk factors, but appears to be highest in people between 15-25 years of age. [Varela A, et al. Skin Therapy Lett – US FP Ed 1(2): 1-3 (2007 winter).] ThSkin The introduction of a relatively new immunomodulator, and the approval of a vaccine significantly improves treatment options in managing this condition.

Condyloma Acuminatum (anogenital warts) is a common form of HPV infection. The majority of these are due to infection with HPV 6 or 11, and are clinically benign. Genital warts are usually asymptomatic, but can cause pruritus, bleeding, or mild burning. The warts present as:

• small, verrucous papules
• discrete, sessile, smooth-topped papules or nodules
• large exophytic masses

Lesion color can range from flesh-colored to pink to reddish brown, and often they are multifocal. Lesion distribution generally corresponds with the areas of highest friction during sexual activity.

Risk Factors

• The number of sexual partners over a lifetime
• The sexual promiscuity of the sexual partners
• Correlations between oral contraceptives and smoking have been reported.[Trottier H, et al. Vaccine 24 Suppl 1:S1-15 (2006 Mar).] However, the literature has not consistently supported such findings.

Pathogenesis

The virus is inoculated directly into the epidermal layers of the skin through epithelial defects, especially with maceration. Genital infections are primarily contracted through sexual contact. These infections can then be transmitted to newborns via passage through the infected birth canal. [Kaye JN, et al. J Gen Virol 77(Pt 6):1139-43 (1996 Jun).]

Diagnosis

• Primarily made by visual inspection.
• For hard to detect lesions, particularly on the cervix, a 5% acetic acid solution can be applied to the suspected area. After a few minutes, the condylomata should appear as white patches on the mucosa. These changes are not diagnostic for HPV.
• A biopsy may be useful if:
  • diagnosis is uncertain.
  • lesions do not respond to standard therapy.
  • the disease worsens during therapy.
  • the patient is immunocompromised.
  • the warts are pigmented, indurated, fixed, bleeding, or ulcerated. [CDC. Genital Warts Treatment Guidelines 2006.

Differential Diagnosis

• Molluscum contagiosum
• Benign penile pearly papules
• Hymenal remnants
• Bowenoid papulosis
• Seborrheic keratosis
• Syphilitic condyloma lata
• Skin tags
• Squamous cell carcinoma
• Verrucous carcinoma (Giant condyloma of Buschke-Lowenstein)
• Vulvar dysplasia
• Linear epidermal nevus
• Lichen nitidus
• Angiokeratomas
• Milium
• Fordyce spots

In the majority of patients, treatment can induce wart-free periods; if left untreated, warts may resolve on their own, remain unchanged, or increase in size or number. Treatment can reduce, but does not eliminate, HPV infection. The choice of treatment should be guided by the preference of the patient, the available resources, and the health provider’s experience. No single treatment is ideal for all patients or all warts. The majority of patients require a course of therapy rather than a single treatment, and improvement will generally be seen within 3 months. [CDC. Genital Warts Treatment Guidelines 2006.] Before beginning any treatment, it is essential to screen patients for other sexually-transmitted diseases.

Most treatment modalities treat the symptom of the disease (warts) versus the disease itself. However, imiquimod, goes further by inciting an immunologic response, thereby providing a field effect in clinical and subclinical HPV.

There are three treatment modalities:

• Antiproliferative agents
• Destruction/excision therapies
• Immunomodulatory therapy
• Combination therapies

Antiproliferative Therapies

• Podophyllin resin 10%-25%
  • provider-administered
• Podophylox 0.5% solution or gel
  • can be applied by the patient
  • does not contain the mutagenic substances found in podophyllin resin.

Destruction/Excision Therapies

• Local cryotherapy is the most common destructive mode.
  • It is safe during pregnancy.
• Application of topical trichloracetic acid
• Electrocautery
• Ablative laser treatment
• Excision by scissor, curette, or scalpel
• All of these options have a risk of scarring.

Immunomodulatory Therapy

• Imiquimod
• Approved by Health Canada in 1999.
• Topical cream – administered by patient.
• Self-administration improves patient compliance.
• Enhances the cytotoxic immune response, which is usually seen as an inflammatory response.
• Applied directly to the affected skin 3 times per week for up to 16 weeks. Initially the frequency of applications can be reduced if the patient is over concerned by the degree of inflammation.
• Acts to reduce the viral load, thereby reducing recurrence rates to very low levels.
• A significant advantage is the ability to affect subclinical lesions.
• Is more effective in women than in men possibly because warts are more commonly found on mucosal skin.

Combination Therapy

• Often monotherapy can be inadequate for treating anogenital warts. Combination therapy can provide a better result.
• Treatment with imiquimod followed by excision of residual lesions may provide long-term clearance of anogenital warts in those patients for whom monotherapy was insufficient.[Carrasco D, et al. J Am Acad Dermatol 47(4 Suppl):S212-6 (2002 Oct).]

Figure 1: Algorithm for treatment of suspect lesions. [Adapted from Varela A, et al. Skin Therapy Lett – US FP Ed 1(2):1-3
(2007 Winter).] TCA= trichloroacetic acid

Prophylaxis

A quadrivalent HPV recombinant vaccine is now available in Canada, and is indicated in girls and women aged 9-26 years for the prevention of diseases caused by HPV types 6, 11, 16, and 18, which include genital warts, cervical cancer and other neoplasias of the cervix, vagina and vulva. It should be administered IM as three separate 0.5ml doses. Studies with this vaccine are now ongoing in males. Another bivalent HPV vaccine (for HPV types 16 and 18) is currently under review with Health Canada. There is no evidence for effectiveness in treating those who already have genital warts.

Conclusion

Most HPV infections are asymptomatic and can spontaneously clear on their own. However if treatment is required, there are a number of antiproliferative, destructive, immunomodulatory modalities available. Combination therapies have been shown to be advantageous. In general, the response time can be expected within 3 months of therapy. Patients should be evaluated throughout the course of therapy for treatment response and side-effects, and treatment should be changed if substantial improvement is not seen within that time frame. Cryotherapy combined with imiquimod appears to be very commonly used. A quadrivalent HPV recombinant vaccine is now available for girls and women 9-26 years of age, and a bivalent vaccine is under review with Health Canada. While not of benefit to those already infected, future generations may be spared considerable burden from external genital warts due to the development, approval, and release of HPV polyvalent vaccines. Not only does the vaccination largely prevent incident external genital warts, but it also protects against genital tract HPV-associated neoplasia.