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Management of Adult Moderate-to-Severe Atopic Dermatitis: A Practical Guide for Primary Care

M. Gooderham, MD, MSc, FRCPC
Queens University, Kingston, ON, Canada; SKiN Centre for Dermatology, Peterborough, ON, Canada; Probity Medical Research, Waterloo, ON, Canada

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, pruritic, inflammatory condition involving the skin which can have a significant impact on the quality of life (QoL).1,2 Although many patients may be controlled with topical therapy, a subset of those affected will require systemic therapy to control their disease.3 There are currently no approved systemic therapies in North America for the long-term management of moderate-to-severe atopic dermatitis and many treatments are currently being used off-label. This article will guide the family practitioner on how to manage adults with moderate-to-severe AD and when to refer for specialist management.

Abbreviations: AD – atopic dermatitis; ADHD – attention deficit hyperactivity disorder; BSA – body surface area; HPA – hypothalamic-pituitary-adrenal, HTN – hypertension; IL – interleukin; PGA – Physician's Global Assessment; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroids; Th2 – T helper cell type 2; TPMT – thiopurine methyltransferase

Background

  • Atopic dermatitis is a common chronic inflammatory disease in both children and adults.
  • In developed countries, it is a common skin disorder, affecting up to 20% of children and 1% to 3% of adults.4
  • Approximately 10% of adults are not controlled with topical therapy alone and require systemic therapy for disease control.3
  • Many immunosuppressants are used off-label to control this disease. Cyclosporine is approved for use in AD only in Europe and Japan.5,6
  • The pathogenesis of AD is thought to be due to a defect in the skin barrier primarily through abnormal filaggrin and alterations of the innate and acquired immune system, with interleukin (IL) 4 and 13 as key players.7
  • Increased knowledge of the immunopathogenesis of AD has allowed for the development of new, targeted therapies.8

The Burden of AD

  • Up to two thirds of patients with AD also suffer from other atopic comorbidities including asthma, rhinitis and food allergies.9-11
  • A recent epidemiologic study from Germany showed that in addition to atopic comorbidities, patients with AD have a two-fold increased risk of developing ADHD.11
  • In one Phase 2b study, 86% of patients reported daily pruritus and 55% reported that itch disturbed their sleep 5-7 nights per week.12
  • AD has a significant impact on patients and their families: itch, sleep disturbance, anxiety and depression can lead to a reduced QoL and stress on the family.13
  • Risk factors for depression in patients with AD include an increasing severity of AD, female gender and increasing age. In addition to depression, there is also an increased risk of suicidality in this population and therefore, patients should be screened appropriately.13
  • In a large US study, (2013 National Health and Wellness Survey:N=75,000), patients with AD reported overall lost work productivity of 30% compared to 16% in those workers without AD; an even greater loss of work productivity was noted when moderate-to-severe patients were compared to those with mild AD, 37% versus 23%, respectively.14

AD Management

  • Non-prescription therapies are often used to help control the disease: moisturizers and emollients should be the cornerstone of any AD regimen.15,16
  • Controlling itch is also key for management as frequent scratching may put the patient at risk for infection.
  • Dilute bleach baths can be helpful for patients who suffer from frequent bacterial infections due to their anti-staphylococcal activity, when used in conjunction with intranasal mupirocin. To prepare a bleach bath see Tip #1.15,17
  • Wet wrap therapy can also be an effective treatment to manage flares. This involves applying a wetted layer of gauze where TCS or TCI have been applied to the skin, and then cover with a second, outer dry layer of gauze. Wet wrap therapy provides more rapid improvement as it will increase medication penetration and provide a barrier to scratching.18

Tip #1: Dilute bleach baths at a concentration of 0.005% - 0.009% can help reduce colonization and recurrent infections in patients with AD.15,17

How to prepare a bleach bath

  • ¼ cup of bleach in a half tub of water to ½ cup bleach in a full bath tub of water
  • Repeat 2 times per week

Topical Treatment and Phototherapy

  • The gold standard of topical therapy is treatment with TCS and/or TCI.15,16
  • Both TCS and TCI can be used twice daily as needed for acute flares, or as maintenance therapy with a scheduled reduced frequency of application, such as 2-3 days per week.15
  • Topical antihistamines and topical antimicrobials are not recommended for use in AD due to lack of efficacy and risk of contact dermatitis.15
  • If available, phototherapy can be used in both the acute situation for management of flares, and as maintenance therapy for refractory or chronic disease; attention should be paid to any concomitant photosensitizing medications and underlying skin cancer risk.19

Tip #2: Topical or systemic antihistamines are NOT recommended for the routine care of patients with AD.

Candidates for systemic therapy have

  • Moderate-to-severe atopic dermatitis
  • Body surface area involvement ≥ 10%
  • Areas with significant burden: involvement of face, hands or genitals
  • Significant impact on QoL
  • Ongoing pruritus
  • Failed an adequate trial of TCS or TCI
  • Failed phototherapy or cannot access it

Patient Selection for Systemic Therapy

  • Patients with moderate-to-severe AD (PGA score ≥ 3) should be considered for systemic therapy when they have the following:
    • At least 10% body surface area (BSA) involvement
    • Ongoing significant impairment in QoL
    • Ongoing pruritus
    • Disease is not controlled with TCS or TCI or topical therapy is not appropriate
    • Treatment failure with phototherapy or phototherapy is not accessible
  • Topical therapy is not appropriate if there is a history of adverse effects from TCS such as atrophy, telangiectasia and striae.15
  • TCS are not appropriate if there is a need for application to large areas with a risk of absorption and hypothalamic-pituitary-adrenal (HPA) axis suppression.15
  • TCI therapy can cause transient burning and stinging with application that may not be tolerated by some patients and, therefore, not considered an appropriate therapy.
  • Special situations where systemic therapy may be considered appropriate include involvement of areas such as the face, hands or genitals, or when AD has a significant impact on a patient's daily functioning due to lack of sleep, fatigue, intractable pruritus or significant psychological distress.19,20
Physician Global Assessment (PGA)
0 - clear
1 - almost clear
2 - mild
3 - moderate
4 - severe
5 - very severe

Systemic Therapy

  • Antihistamines are not recommended; antihistamines used for the sedating effects have little to no impact on itch and may lead to disturbed sleep, so these are not typically recommended for regular use.15,19
  • Many immunosuppressants are used off label; the most commonly prescribed are cyclosporine, methotrexate, azathioprine and mycophenolate mofetil.3
  • Evidence supporting use of these agents is lacking due to methodological limitations in most trials, small numbers and short duration of therapy.3,21
  • The best evidence available supports the use of cyclosporine as first-line therapy for short-term use (Table 1).3
  • Systemic therapy is often limited by intolerance to common side effects (nausea, vomiting, headache) or by potential end-organ toxicity and sequelae of immunosuppression.21
  • Routine monitoring of these agents for adverse events is required.19
  • Oral corticosteroids should be considered as a rescue intervention for severe exacerbations and are not a suitable treatment option for the ongoing management of patients with AD.19

Tip #3: Avoid the use of systemic corticosteroids in the management of AD unless required as a rescue or salvage therapy of acute severe exacerbations of disease.

Treatment Dosing Duration of Treatment Side Effects Overall Recommendation
Cyclosporine 3-6 mg/kg/day; divided into BID dosing Maximum use: 1-2 years

Minimum use: N/A
Nausea, headache, paresthesia, renal impairment, HTN, sequelae of chronic immunosuppression First-line short-term treatment option for moderate-to-severe AD due to highest quality of evidence to date for oral therapy.
Azathioprine 1-3 mg/kg/day; ideal dose is determined by TPMT activity Maximum: There is no official recommendation

Minimum: 12 weeks to see benefit
Common: nausea, vomiting, gastrointestinal symptoms (bloating, anorexia, cramping), headache, hypersensitivity reactions and elevated liver enzymes Second-line treatment option for moderate-to-severe AD due to moderate-quality evidence for short- and long-term use (24 weeks).
Methotrexate Single weekly dose: 7.5-25 mg/week

Folic acid: 1 mg/day (except on methotrexate day)
Maximum: Based on toxicity

Minimum: Clinical improvement as early as 4 weeks
Nausea, elevated liver enzymes, pancytopenia, pulmonary toxicity Third-line treatment for adults with severe AD due to moderate quality evidence for short- and long-term use (24 weeks).
Oral Corticosteroids 0.75-1 mg/kg per day Maximum: 3 weeks

Minimum: 3 days
Diabetes, hypertension, gastric ulcers, osteoporosis, glaucoma, opportunistic infections and Cushing syndrome Not recommended for routine use. May be used in short-term (up to 1 week) for acute flares in exceptional and severe cases of AD as salvage therapy only.
Table 1. Non-approved systemic therapies for AD 3,21

BID - twice a day; HTN - hypertension; TPMT - thiopurine methyltransferase

Systemic Agents on the Horizon

  • Due to an increased understanding of the pathogenesis of AD, several targeted therapies are being developed.21 Monoclonal antibodies are among them, as they can provide reduced toxicity and improved efficacy compared to oral systemic agents that may have unintended effects and end organ toxicity.8
  • A number of small molecule targets and monoclonal antibodies which target Th2 cytokines such as IL-4, IL-5, IL-13 and IL-31, or their receptors, are in development.8
  • Dupilumab, a human monoclonal antibody against the receptor for IL-4 and IL-13 is the first agent to have demonstrated safety and efficacy in phase 3 trials.21,22
  • Dupilumab is furthest along in development and poised to be the first commercially available biologic for AD.
  • Tralokinumab and lebrikizumab, which target IL-13, mepolizumab which targets IL-5, and nemolizumab which targets the IL-31 receptor, are also in earlier stages of development.7

Next Steps

  • When your patient presents with ongoing difficulties managing AD, it is important to review their current treatment regimen and rule out other diagnoses, such as contact dermatitis.23
  • Encourage regular and generous use of emollients.
  • Discuss adherence to the application of topical medications; TCS and TCI should be applied twice daily when there is an acute flare, and when controlled, applied on a schedule of 2-3 times weekly for maintenance, to prolong the flare-free period.15,16
  • During flares, consider wet wrap therapy to improve the efficacy of the applied topical agents, TCS and TCI, and reduce scratching.18
  • If available and convenient, consider phototherapy for widespread acute or chronic disease.19
  • For patients experiencing frequent skin infections, consider dilute bleach baths with intranasal mupirocin to reduce Staphylococcal colonization and infection.17
  • Assess the patient for sleep loss, pruritus, and the impact on QoL and consider screening for depression, anxiety and suicidality.13
  • If the disease cannot be controlled by these measures, the patient should be managed with systemic medication such as cyclosporine, azathioprine or methotrexate.3,21
  • For physicians not familiar with prescribing immunosuppressive medications, a referral to a dermatologist should be made for the systemic management of AD.

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. Silverberg JI, Hanifin JM. J Allergy Clin Immunol. 2013 Nov;132(5):1132-8.
  2. Lundberg L, Johannesson M, Silverdahl M, et al. Acta Derm Venerol. 2000 Nov;80(6):430-4.
  3. Roekevisch E, Spuls PI, Kuester D, et al. J Allergy Clin Immunol. 2014 Feb;133(2):429-38.
  4. Williams H, Robertson C, Stewart A, et al. J Allergy Clin Immunol. 1999 Jan;103(1):125-38.
  5. Bieber T, Straeter B. Allergy. 2015 Jan;70(1):6-11.
  6. Saeki H, Nakahara T, Tanaka A, et al. J Dermatol. 2016 Oct;43(10):1117-45.
  7. Gandhi NA, Bennett BL, Graham NMH, et al. Nat Rev Drug Discov. 2016 Jan;15(1):35-50.
  8. Harskamp C, Armstrong A. Semin Cutan Med Surg. 2013 Sep;32(3):132-9.
  9. Zeppa L, Bellini V, Lisi P. Dermatitis. 2011;22(1):40-6.
  10. Langenbruch A, Radtke M, Franzke N, et al. J Eur Acad Dermatol Venereol. 2014 Jun;28(6):719-26.
  11. Radtke MA, Schäfer I, Glaeske G, et al. J Eur Acad Dermatol Venereol. 2017 Jan;31(1):151-7.
  12. Simpson EL, Bieber T, Eckert L, et al. J Am Acad Dermatol. 2016 Mar;74(3):491-8.
  13. Nicholas MN, Gooderham MJ. Atopic Dermatitis, depression, and Suicidality. J of Cutaneous Med Surg. 2017 Jan 9:1203475416685078.
  14. Whiteley J, Emir B, Seitzman R, et al. Curr Med Res Opin. 2016 Jun;32(10):1645-51.
  15. Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(6):116-32.
  16. Lynde C, Barber K, Claveau J, et al. J Cutan Med Surg. 2005;8(suppl 5):1-9.
  17. Ryan C, Shaw RE, Cockerell CJ, et al. Pediatr Dermatol. 2013;30(3):308-15.
  18. Devillers ACA, Oranje AP. Br J Dermatol. 2006;154(4):579-85.
  19. Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(6):327-49.
  20. Evers AW, Lu Y, Duller P, et al. Br J Dermatol. 2005 Jun;152(6):1275-81.
  21. Gooderham M, Lynde CW, Papp K, et al. J Cutan Med Surg. 2016;21(1):31-9.
  22. Simpson EL, Bieber T, Guttman-Yassky E, et al. N Engl J Med. 2016; 375(24):2335-48.
  23. Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70:338-51.

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