Atopic%20dermatitis Treatment

Goals of Therapy

• Reduce symptoms
• Achievement of clear or almost clear skin
• Prevent exacerbations and maintain long-term remission
• 75% improvement in severity scores
• Improved quality of life
• Minimize therapeutic risks and avoid drug-related toxicities

Topical Therapy

• Fingertip unit rule (FTU) which is the amount of ointment expressed from a tube with a 5-mm nozzle and measured from the distal skin crease to the tip of the index finger and measuring about 0.5 gram should be followed in applying topicals including anti-inflammatory agents
  • Covers approximately 2% of an adult body surface area
• Approaches to topical anti-inflammatory therapy:
  • Reactive management is when topical anti-inflammatory is applied to skin lesions and stopped or rapidly tapered once visible lesions are cleared or almost cleared
  • Proactive management is a combination of predefined, long-term anti-inflammatory treatment applied 2 times a week to previously affected skin areas in combination with liberal daily use of emollients on the entire body
    • Begins after treatment of acute flare, when lesions have been successfully treated with regular anti-inflammatory therapy
    • Duration depends on the severity and persistence of atopic dermatitis

Systemic Therapy

• Recommended for patients with high composite score (eg SCORAD >50), or for patients unresponsive to optimized topical therapy, or for patients unable to perform normal activities of daily living while following an adequate treatment regimen
  • Recommended if signs and symptoms of atopic dermatitis are not controlled sufficiently with appropriate topical therapy and UV-light therapy
  • Recommended to reduce the total amount of topical corticosteroids in patients needing large amounts of potent topical corticosteroids for large body areas over prolonged periods to control atopic dermatitis

Topical Corticosteroids

• Used as first-line treatment for mild to severe atopic dermatitis and when non-pharmacological interventions have been unsuccessful 
• Rapid symptomatic relief for acute flare-ups; also used for prevention of relapses
• Choice of product will depend on severity of flare-up, distribution and site of lesions, patient’s age and preference, and other factors eg humidity
• Anti-inflammatory and antipruritic activity through several mechanisms
  • Alteration in leukocyte number and activity
  • Suppression of mediator release (histamine, prostaglandins)
  • Enhanced response to agents that increase cyclic adenosine monophosphate (prostaglandin E₂ and histamine via the histamine-2 receptor)

• Follow the recommended restrictions regarding intensity and duration of use especially in children on delicate skin areas (eg face, neck, genitals and skin folds)
  • Intermittent use (1-2 times/week) in combination with moisturizers is historically the standard therapy for atopic dermatitis
  • Continuous use can lead to adverse effect

• Available in different potencies from mildly potent to very potent
  • Potency is also affected by the vehicle the product is formulated in (eg ointment, cream, lotion in decreasing order of efficacy)
  • Potency of topical corticosteroid does not relate to percentage stated (eg Hydrocortisone 2.5% versus Betamethasone dipropionate 0.05%)
  • Least potent but effective product should be used, especially if for long-term use
  • May use mid- and high-potency preparations (except when lesions are on face, groin or axillae) to control acute flares and then follow with lower potency preparations after clinical improvement is seen
    • Mid-potency topical corticosteroids can be used 2 times/week as maintenance therapy to decrease flares and relapse
  • Rebound flaring can occur if higher potency preparations are discontinued abruptly
  • A gradual decrease in potency should follow use of higher potency preparations
  • Therapy-resistant lesions may require potent topical corticosteroid used under occlusion

Solutions

• Useful for the scalp or other hirsute areas
• Alcohol content may be irritating when used on inflamed lesions

Lotions

• Useful for minimal application to a large area or on hirsute areas
• May also be used on exudative lesions and in hairy areas

Creams

• Usually preferred for moist/weeping lesions
• May be preferred during periods of excessive heat or humidity
• Easier to apply but may be less effective

Ointments

• Generally used for dry, scaly or lichenified lesions or if a more occlusive effect is needed (most occlusive vehicle)
• Usually less additives are used
• Evaporative losses are decreased

Systemic Corticosteroids

• Short-term treatment (up to 1 week) should only be considered in treatment-resistant atopic dermatitis, acute severe exacerbations and as a bridge therapy to other steroid-sparing systemic treatments
• Recommended dose: 0.5 mg/kg body weight 
• Improve lesions but rebound flare-up usually occurs upon discontinuation
• Use short-term and decrease chance of rebound effect by tapering oral form slowly while increasing topical corticosteroid treatment and continuously hydrating the skin
• Various oral corticosteroids are available. Please see the latest MIMS for specific formulations and prescribing information.

Calcineurin Inhibitors - Topical Immunomodulators

• Steroid-sparing agents for acute and maintenance therapy, topical calcineurin inhibitors inhibit inflammatory cytokine transcription in activated T cells and other inflammatory cells through inhibition of calcineurin
• Second-line therapy for moderate to severe atopic dermatitis; first-line treatment over topical corticosteroids when atopic dermatitis is unresponsive to steroid therapy, with presence of atrophy or telangiectasia secondary to steroid use, when affected areas are either the face, anogenital area, and/or skin folds, and for long-term treatments 
• May be used on all body locations for extended periods of time, especially the face, hands and feet
• Also used in patients with inadequate response to other topical therapeutic agents
• Given that the absolute risk of developing lymphoma is low, cancer risk from topical calcineurin inhibitor use is likely not clinically significant

Pimecrolimus

• Safety and efficacy have been shown in children >2 years of age and adults with mild-moderate atopic dermatitis
  • Pruritus relief has been seen as early as day 3 of use; does not cause atrophy
  • Prevents flare-ups and results in significant steroid-sparing effect when used for up to 12 months
• When used in early stages of disease, it has shown to be therapeutically advantageous over typical moisturizers plus topical corticosteroids in long-term use

Tacrolimus

• Recommended for moderate to severe atopic dermatitis 
• Rapidly decreases the signs and symptoms of atopic dermatitis in adults and children >2 years of age
  • Improvement is seen within 3-7 days of therapy and sustained for at least 12 months
  • Well-tolerated with transient skin burning/irritation; less incidence of atrophy compared to steroids
• Tacrolimus 0.03% or 0.1% ointment is recommended for adults with atopic dermatitis
  • Studies have confirmed the efficacy of Tacrolimus 0.03% compared to low-potency topical corticosteroids in children and the efficacy of Tacrolimus 0.1% compared to mid-potency topical corticosteroids in adults

Phosphodiesterase Type-4 (PDE-4) Inhibitors

Apremilast

• May be considered in patients with moderate to severe atopic dermatitis unresponsive to standard treatments but further studies are needed to establish its efficacy and safety

Crisaborole

• May be considered for mild to moderate atopic dermatitis in patients ≥3 months old
  • Studies showed improvement in symptoms (ie erythema, induration, oozing) with Crisaborole use

Immunosuppressants

Abrocitinib

• Oral Janus kinase (JAK) 1 inhibitor used for the treatment of refractory moderate to severe atopic dermatitis which is inadequately controlled with other systemic drugs (including biologics) or when use of those therapies is not advisable   
• May be used with or without topical corticosteroids 
• Not recommended to be used in combination with other JAK inhibitors, biologic immunomodulators or with other immunosuppressants 
• A large, randomized, safety clinical trial showed an increased risk of malignancy (lymphoma and lung cancer), all-cause mortality (including sudden cardiovascular death), major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction, and stroke), and thrombosis (including pulmonary embolism and venous and arterial thrombosis) with another JAK inhibitor compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis 

Azathioprine

• Used for severe/refractory disease unresponsive or with contraindications to Ciclosporin therapy
• Thiopurine methyltransferase (TMPT) levels should be monitored while patient is on Azathioprine to test for myelosuppression
• Most children respond to low doses
• There is increasing evidence supporting its efficacy in severe refractory atopic dermatitis
• May cause nausea, fatigue, myalgia, liver dysfunction and bone marrow depression in patients deficient in thiopurine methyltransferase

Baricitinib

• Oral selective JAK1 and JAK2 inhibitor which blocks signals of immune response and inflammation
• May be given as an option for treatment of moderate to severe atopic dermatitis in adults who are unresponsive or contraindicated to at least 1 systemic immunosuppressant (eg Ciclosporin, Methotrexate, Azathioprine, Mycophenolate mofetil)
• May be an alternative to Dupilumab with best supportive care and may be offered with topical corticosteroids
• Studies showed Baricitinib, with or without corticosteroids, can reduce severity and symptoms of atopic dermatitis compared with placebo
• Assess patient after 8 weeks of treatment if there is adequate response
  • Adequate response is defined as reduction of at least 50% in EASI-50 score and at least 4 points in DLQI from the start of the treatment

Ciclosporin (Cyclosporin A)

• First-line option for short-term use in chronic, severe refractory disease in adults who require systemic immunosuppressive treatment
  • Condition tends to return after discontinuation of therapy but not always at the original severity level
• May be used in children and adolescents with refractory or severe disease
• Long-term use is not justified because of risks of hypertension and renal and liver dysfunction
• Combination therapy with UV light (eg UVA, UVB, PUVA) is not recommended due to increased risk of skin cancer

Methotrexate

• May be considered for severe/refractory disease unresponsive or with contraindications to Ciclosporin therapy
• Studies showed that efficacy of Methotrexate for atopic dermatitis is comparable to that of Azathioprine and Ciclosporin

Mycophenolate mofetil

• May be considered for severe/refractory disease unresponsive or with contraindications to Ciclosporin therapy 

Ruxolitinib

• Topical Ruxolitinib is a selective JAK1 and JAK2 inhibitor which is approved by the United States Food and Drug Administration (US FDA) for short-term therapy of mild to moderate atopic dermatitis in immunocompetent patients ≥12 years old whose disease is not controlled with other topical therapies

Upadacitinib 

• An oral selective and reversible inhibitor of JAK enzymes (preferentially JAK1 or JAK1/3), which are intracellular enzymes involved in the stimulation of hematopoiesis and immune cell function through a signalling pathway 
• Used in patients ≥12 years old with refractory moderate to severe atopic dermatitis which is inadequately controlled with other systemic drugs (including biologics) or when use of those therapies is not advisable 
• Not recommended to be used in combination with other JAK inhibitors, biologic immunomodulators or with other immunosuppressants 
• A large, randomized, safety clinical trial showed an increased risk of malignancy (lymphoma and lung cancer), all-cause mortality (including sudden cardiovascular death), major adverse cardiovascular events (MACE; defined as cardiovascular death, myocardial infarction, and stroke), and thrombosis (including pulmonary embolism and venous and arterial thrombosis) with another JAK inhibitor compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis

Various immunosuppressants are available. Please see the latest MIMS for specific formulations and prescribing information.

Biologic Therapy

Dupilumab

• A human immunoglobulin (Ig) G4 monoclonal antibody approved for use in patients ≥12 years of age with moderate to severe atopic dermatitis uncontrolled by first-line treatments and who are candidates for systemic therapy
• Binds to the interleukin-4Ra (IL-4Ra) subunit thereby inhibiting IL-4 and IL-13 cytokine-induced responses which includes proinflammatory cytokine, chemokines and IgE release
• Combination with emollients and as-needed topical anti-inflammatory agents is recommended

Tralokinumab

• Recommended for adult patients with moderate to severe atopic dermatitis uncontrolled by topical therapies and are candidates for systemic therapy
• A human, high-affinity IgG4 monoclonal antibody which acts by neutralizing IL-13
• Combination treatment with topical corticosteroids, topical calcineurin inhibitors, and UV light is possible

Other Biologicals

• Further studies are needed to prove the efficacy of Nemolizumab, Rituximab, Mepolizumab, Omalizumab, and Ustekinumab for atopic dermatitis
  • Trial treatment with Mepolizumab may be considered in select patients unresponsive to standard therapies
  • The following biologic agents are being studied for atopic dermatitis: Lebrikizumab, Nemolizumab, Tralokinumab, Tezepelumab

Retinoid

• Alitretinoin is a derivative of Isotretinoin with anti-inflammatory effects used for severe chronic hand atopic dermatitis unresponsive to first-line treatments
• Concomitant treatment with topical corticosteroids, topical calcineurin inhibitors and emollients is possible

Allergen-specific Immunotherapy

• May be considered for select patients with severe disease with house dust mite, birch or grass pollen sensitization, and concomitant history of clinical exacerbation after exposure or positive atopy patch test

Antihistamines

• Oral sedating antihistamines are typically used for soporific effect to facilitate sleep, to prevent increase of itch intensity at night, and as an adjunctive therapy to topical anti-inflammatory therapy
• Studies of oral non-sedating antihistamines have shown variable results in controlling pruritus; however, they may be useful in a small group of patients with associated urticaria
• Topical antihistamines are usually not helpful in relieving pruritus and may cause allergic contact dermatitis
• Various antihistamines are available. Please see the latest MIMS for specific formulations and prescribing information.

Skin Infections

• Clinical infections at treatment sites should be cleared before starting anti-inflammatory agents
• May need to treat reservoirs of the disease to prevent recurrence (eg nose, groin)

Bacterial Infections

• Staphylococcus aureus is commonly cultured from eczematous skin and is often the cause of localized infections
• Short-term topical therapy
  • May be used to treat localized areas
  • Fusidic acid, Mupirocin, Neomycin and Retapamulin are treatment options
  • Neomycin may cause allergic contact dermatitis
  • Retapamulin is recommended for children >9 months
• Oral therapy
  • Usually necessary to treat widespread infected lesions
  • Anti-staphylococcal penicillins (eg Flucloxacillin), macrolides (eg Clarithromycin, Erythromycin), first- and second-generation cephalosporins, and Clindamycin are treatment options
    • Flucloxacillin is recommended as the first-line therapy for patients with secondary bacterial infection; alternative treatments to Flucloxacillin include Clarithromycin and Erythromycin

Fungal Infections

• May be considered as a possible complication of atopic dermatitis
• Antifungal therapy (eg topical Ketoconazole or Ciclopirox olamine, systemic Itraconazole or Fluconazole) may be considered in patients with head and/or neck involvement or with IgE-sensitization to Malassezia spp
• Superficial dermatophytosis and Pityrosporum ovale may be treated with systemic or topical antifungals

Viral Infections

• Patients may develop secondary herpes infections inclusive of eczema herpeticum and Kaposi’s varicelliform eruption and may require systemic Acyclovir or Valaciclovir treatment in a hospital setting
• Topical agents such as KOH, Cantharidin, Tretinoin, or Cidofovir and physical treatments such as cryotherapy and curettage, may be used for eczema molluscatum

Various antibiotics, antifungals and antivirals are available. Please see the latest MIMS for specific formulations and prescribing information.

Other Pharmacotherapeutic Options

• Further studies are needed to prove the efficacy of probiotics, topical sodium cromoglycate, vitamin D, Tofacitinib, mast cell stabilizers and leukotriene antagonists (eg Montelukast) in atopic dermatitis
  • Vitamin D supplementation and use of prebiotics/probiotics may reduce symptoms but are not routinely recommended

Avoidance of Trigger Factors

• Avoid foods identified as allergens in controlled food challenges
• Avoidance of aeroallergens (eg house dust mites, may result in improved symptoms)
  • Use dust mite-proof encasings on pillows, mattresses and box springs
  • Wash bedding weekly in hot water (>58°C)
  • Remove bedroom carpeting and curtains
  • Decrease indoor humidity to levels below 60%
  • Evidence suggests that allergen-specific immunotherapy may be an option in treating select patients with sensitivity to aeroallergens
• In most cases, trigger factors cannot be specifically identified
  • Apply holistic approach to avoidance since trigger factors are usually multiple

Common Trigger Factors

• Wool clothing, pollen, extreme temperature, sweat, products with perfumes or preservatives, foods, cigarette smoke and animal dander

Psychological Factors

• Emotional factors (eg anxiety, stress and anger) cause disease exacerbation, induce immune activation and increase pruritus and scratching
• Psychological evaluation and counseling should be considered in patients who have difficulty with emotional triggers or who have psychological problems

Skin Care

• Emphasis on the importance of holistic skincare routine which includes cleansing, moisturizing, treatment and sun protection
  • Improvement in symptoms and reduces side effects of topical therapy such as corticosteroids in atopic dermatitis, thus improves adherence to treatment
• Appropriate skin care reduces the incidence of flares and increases time between flares
• Hydration of skin with emollients and restoration of skin barrier function are essential to the treatment of atopic dermatitis
• Regular skin cleansing with the use of soaps, synthetic detergent (syndet) bars, and topical antiseptics and antibiotics helps reduce abnormal microbial colonization to restore the skin microbiome

Bathing

• Helps cleanse the skin by removing scales, crusts, bacteria, allergens, and irritants 
• Soap substitutes with minimal defatting activity, moisturizer-containing, fragrance-free, hypoallergenic, and a neutral to low pH are preferred
• Ideal hot water temperature for bathing or showering is approximately 38-40°C; skin temperature of ≥42°C induces itching response 
  • Once- or twice-daily, short, lukewarm water baths, followed by immediate application of moisturizers are recommended for atopic dermatitis patients
• If possible, limit soap use to hands, feet, genitalia, axillae
• Limit bathing to once daily for 5-10 minutes using warm water
• Pat dry after bath and apply moisturizer or bath oils within 2-3 minutes of bath
• Studies have shown a decrease in bacterial infection (eg staphylococcal, methicillin-resistant Staphylococcus aureus), disease severity, and flare-ups in patients taking regular bleach baths (1:1200 dilution of 6% hypochlorite bleach; 10-minute soak, 3x/week)
  • Bleach baths with intranasal Mupirocin are highly recommended for patients with moderate-severe disease with recurrent secondary bacterial infection
  • Topical antiseptic agents (eg Sodium hypochlorite 0.005% bath) may be considered in patients with chronic, treatment-resistant disease
• Salt baths may also be used to help shed dead keratin materials from the skin
• Oatmeal products added to bath may be soothing but do not increase water absorption by the skin
• Thermal spring water balneotherapy may be considered in patients with mild to moderate disease
• Topical medications are best applied after bathing because of greater penetration of hydrated skin
• Various products are available. Please see the latest MIMS for specific formulations and prescribing information.

Moisturizers

• Mainstay of atopic dermatitis treatment
  • Improves skin barrier function, reduces incidence of flares, increases time between flares and has steroid-sparing effect
• Recommended for all levels of atopic dermatitis severity ‒ for primary prevention, maintenance, during acute flares and for prevention of relapse
• Should contain anti-inflammatory and antioxidant properties
• Water-in-oil emollients are preferred; occlusive agents and humectants are also used
  • Useful for the treatment of active disease and both prevention and maintenance therapy
  • Helps reestablish and preserve the stratum corneum
• Effects:
  • Emollients (eg Glycerol stearate, lanolin, soy sterols) provide lubrication, improve the epidermal barrier, and help soften skin surface
    • Newly developed emollients contain ingredients that positively influence the skin microbiome of atopic dermatitis patients
  • Occlusive agents (eg Dimethicone, Mineral oil, petrolatum) provide a physical barrier against water evaporation
  • Humectants (eg Urea, Glycerol, Lactic acid, pyrrolidone carboxylic acid [PCA]) help retain moisture in the stratum corneum
    • Urea, lactate, PCA and amino acids (eg Arginine) are components of NMF which maintains adequate hydration of the skin thus optimizing the barrier function of the stratum corneum
• A comparative review of different clinical studies on moisturizers revealed that proper use reduces pruritus, reduces topical corticosteroid use, and prevents flares and recurrences
  • Clinically significant reduction in disease severity with moisturizer use compared to no moisturizers was seen
  • Moisturizer combined with Fluticasone propionate applied 2x/week was more effective in preventing flares compared to moisturizers alone
  • Better efficacy was noted in patients who used topical active treatment combined with moisturizers compared to using topical active treatment alone 
• Patient preference and treatment area will determine formula used in moisturizers (eg Ceramides, Hydroxypalmitoyl sphinganine, Palmitoylethanolamide [PEA], Liquid paraffin, Mineral oils, Glycerin, Hyaluronic acid, Shea [Butyrospermum parkii] butter, Telmesteine, Glycyrrhetinic acid, Lactic acid)
  • Urea-containing moisturizers reduce rate of flares but may cause transient burning and stinging after application
  • Oat- and Glycerol-containing moisturizers also reduce rate of flares but with lesser side effects and lessens the use of topical corticosteroids
  • Glycyrrhetinic acid and Allantoin have anti-inflammatory properties that help reduce pruritus
  • The anti-inflammatory and antibacterial properties of Licochalcone contained in some moisturizers are comparable to the efficacy of combination therapy of moisturizers and 1% Hydrocortisone acetate cream
  • Niacinamide and sunflower seed oil improve skin barrier function by reducing transepidermal water loss
• Emollients should be applied for at least 3 times daily (in the morning and afternoon immediately after bath and at night before bedtime) or in flare-up condition every 3-4 hours
• Avoid products with preservatives or fragrances; if product stings, seek expert advice
• Reports of studies suggest that the use of emollients in infants might prevent atopic dermatitis development in high-risk patients
• Various products are available. Please see the latest MIMS for specific formulations and prescribing information.

• Regular use of broad-spectrum sunscreens with SPF30+ and with inorganic UV filters (eg titanium dioxide, zinc oxide) is recommended
  • Should not be applied over inflamed skin

Wet Wrap Therapy

• May be used for chronic and refractory lesions or for moderate-severe weeping lesions
  • Cools inflamed skin, maintains hydration, and decreases scratching
  • Can help reduce water loss and disease severity in patients with moderate-severe atopic dermatitis including flares
• Combination with topical corticosteroids can be effective in treating refractory cases

Phototherapy

• Considered in patients with recalcitrant disease or when first-line therapy with topical agents has been unsuccessful
• Broad-band UVB and UVA, narrow-band UVB and UVA-1 or combined UVA and UVB can be useful
  • Treats chronic lichenified forms of moderate-severe disease; high doses of UVA-1 may be given for acute flares
  • Effectively reduces colonization of S aureus and Malassezia sp and mediate cytokine production
  • Narrowband UVB and medium-dose UVA-1 is recommended for patients with moderate to severe atopic dermatitis
    • May be used in children and adolescents after skin type assessment but only for a short period
    • Other phototherapy modalities (eg broad-band UVB and UVA, balneophototherapy) may be considered as second-line modalities
• Photochemotherapy with Psoralens and UVA (PUVA) should be restricted to patients with widespread severe atopic dermatitis
  • PUVA therapy may be considered only when previous treatment cycles with other phototherapies are ineffective or when approved drug therapies are contraindicated, ineffective or with adverse effects
• May be combined with corticosteroids and emollients in phases of acute flares and to prevent future flare-ups
• Relapse after therapy cessation frequently occurs
• Adverse reactions:
  • Short-term: Erythema, skin pain, pigmentation, itching
  • Long-term: Premature skin aging and potential cutaneous malignant diseases
• Not recommended in patients with history of skin cancer or with an increased risk of skin cancer
• Not recommended in patients who are treated with systemic immunosuppressants (eg Azathioprine, Ciclosporin) due to increased risk of cancer

• Treatment option for patients with severe, treatment-refractory disease with high serum IgE levels
• An extracorporeal technique that utilizes immunoadsorption columns to deplete the IgE serum level that may lead to the reduction of disease activity
• Studies showed significant decrease in SCORAD and disease activity improvement