Many patients with mild to moderate atopic dermatitis (AD) are managed by identifying and avoiding allergens and irritants, ensuring skin moisturization, and graded use of topical corticosteroids and/or calcineurin inhibitors. There is little consensus on the next step. Most systemic therapies are “off label” in the United States and include phototherapy, cyclosporine, mycophenolic acid precursors, azathioprine, and methotrexate. The decision to use these therapies should be based on efficacy and safety readouts from well designed, long-term trials. This article reviews the long-term randomized, controlled trials examining safety and/or efficacy of interventions recommended for patients with mild to severe AD.
Key points
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Proactive, twice weekly therapy with either a topical corticosteroid or topical calcineurin inhibitor can decrease frequency of flares in patients with moderate to severe disease.
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The long-term efficacy and safety of current systemic treatments for atopic dermatitis is poorly studied and comparative trials are low powered; newer, safer alternatives are needed.
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Cyclosporine is the second-line agent with the most evidence of efficacy, and phototherapy is likely the safest.
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Methotrexate or mycophenolate mofetil/sodium may be as efficacious as cyclosporine for long-term use with potentially fewer side effects.
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Additional evidence is required before a definitive recommendation can be made.
Introduction
Atopic dermatitis (AD) is a common inflammatory systemic disease characterized by eczematous skin lesions and pruritus, and frequently accompanied by a host of other allergic disorders that manifest in the upper or lower airways, eyes, and/or the gastrointestinal tract. Therefore, the ideal, long-term management of AD may need to address both the cutaneous and systemic inflammation that is present in the circulation and even in distant organs. There is little consensus on what constitutes “long-term” treatment for chronic, inflammatory diseases. For example, in rheumatoid arthritis, long-term treatment has been defined as 1 year or longer. In contrast, 12 weeks has been referred to as “long-term” in AD literature, which may simply reflect the paucity of interventional randomized, controlled trials (RCTs) greater than 3 months in duration.
Outcome measures in the trials vary widely, making direct comparisons between trials and consequently between treatments or treatment regimens difficult. This literature uses terms such as remission, relapse, flare, and rebound, but how these terms are defined is not always clear or consistent. Fortunately, the Harmonizing Outcome Measures for Eczema group is working toward standardizing outcome measures so trial comparisons in the future may be more accurate and informative ( Box 1 ).
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There is no consensus on the definition.
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Thirty-five percent of trials in a recent review used an arbitrary cutoff (eg, Investigators Global Assessment >4).
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Twenty-three percent of trials used the need to step-up treatment, in the physicians or patients opinion.
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The remainder used a composite or had no relapse definition.
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Nonflared AD is referred to stabilized AD or in “remission.”
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Abbreviation: AD, atopic dermatitis.
Introduction
Atopic dermatitis (AD) is a common inflammatory systemic disease characterized by eczematous skin lesions and pruritus, and frequently accompanied by a host of other allergic disorders that manifest in the upper or lower airways, eyes, and/or the gastrointestinal tract. Therefore, the ideal, long-term management of AD may need to address both the cutaneous and systemic inflammation that is present in the circulation and even in distant organs. There is little consensus on what constitutes “long-term” treatment for chronic, inflammatory diseases. For example, in rheumatoid arthritis, long-term treatment has been defined as 1 year or longer. In contrast, 12 weeks has been referred to as “long-term” in AD literature, which may simply reflect the paucity of interventional randomized, controlled trials (RCTs) greater than 3 months in duration.
Outcome measures in the trials vary widely, making direct comparisons between trials and consequently between treatments or treatment regimens difficult. This literature uses terms such as remission, relapse, flare, and rebound, but how these terms are defined is not always clear or consistent. Fortunately, the Harmonizing Outcome Measures for Eczema group is working toward standardizing outcome measures so trial comparisons in the future may be more accurate and informative ( Box 1 ).
- •
There is no consensus on the definition.
- ○
Thirty-five percent of trials in a recent review used an arbitrary cutoff (eg, Investigators Global Assessment >4).
- ○
Twenty-three percent of trials used the need to step-up treatment, in the physicians or patients opinion.
- ○
The remainder used a composite or had no relapse definition.
- ○
Nonflared AD is referred to stabilized AD or in “remission.”
- ○
Abbreviation: AD, atopic dermatitis.
Method
RCTs of 12 weeks or longer were identified by a Pubmed search for terms “atopic dermatitis,” “atopic eczema,” and “long-term” along with a review of the Global Resource of Eczema Trials database (greatdatabase.org.uk), consensus papers, and systematic reviews. Repeated short courses of treatment were included as long as the cumulative treatment period was at least 12 weeks. Trials not searchable by Pubmed were excluded. Only trials with a primary outcome of treatment efficacy or safety were included. Trials were excluded if information deemed necessary were missing (eg, study population ages or duration of treatment).
Bathing
Bathing can hydrate the skin while promoting the removal of irritants and allergens. Expert consensus recommends up to once daily bathing, for a short period of time with lukewarm water. Application of a moisturizer or a topical antiinflammatory agent immediately after bathing, often referred to as the “soak and smear” technique, is strongly encouraged ( Box 2 ).
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Optimal frequency or duration of bathing.
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Efficacy of the soak and smear technique.
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Optimal cleanser composition.
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Efficacy of bath additives (eg, oatmeal, Epsom salts, vinegar, or essential oils).
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Efficacy of water softeners.
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Comparison of soap versus synthetic detergents (Syndets).
a Long-term randomized, controlled trials in patients with atopic dermatitis.
Cleanser composition and pH affect skin barrier structure and function. Normal skin has a slightly acidic pH (pH 4–5.5). Soap, which typically has an alkaline pH, is thought to have detrimental effects on stratum corneum proteins and lipids. Although there are no long-term RCTs evaluating cleansers, an acidic or neutral, nonsoap cleanser (eg, synthetic detergent [Syndet]) should be recommended to AD patients.
Sodium Hypochlorite (Bleach) Baths and Antiseptics
Only 1 small, long-term RCT found that twice weekly bleach baths (along with 7 d/mo of intranasal mupirocin) had a significant reduction in eczema area and severity index (EASI) and body surface area (BSA) affected ( Table 1 ). These pediatric patients were randomized after an episode of clinically infected AD treated with 2 weeks of oral cephalexin. Compliance was similar between the groups. Surprisingly, bleach baths did not affect Staphylococcus aureus skin colonization as measured by standard culture techniques ( Box 3 ).
| Randomized Controlled Trial | Investigational Agent | Control | Study Population (Age Range, Severity) | Duration of Treatment | No. of Subjects | |
|---|---|---|---|---|---|---|
| Bleach | Huang et al, 2009 (SB) | Intranasal mupirocin 7 d/mo plus sodium hypochlorite (bleach) baths 2×/wk | Intranasal petrolatum 7 d/mo plus plain water baths 2×/wk | 6 mo–17 y moderate- severe | 12 wk | 31 |
| Moisturizer | Åkerström et al, 2015 (DB) | 5% urea cream, Canoderm (ACO HUD Nordic, Sweden) BID | Miniderm without glycerol (ACO Hud Nordic, Upplands Väsby, Sweden) BID | ≥18 y moderate on average | Until relapse or 26 wk | 172 |
| TCSs 2×/wk | Berth-Jones et al, 2003 (DB) | Fluticasone propionate 0.05% cream or 0.005% ointment 2×/wk | Emollient base 2×/wk | 12–65 y moderate-severe | 16 wk | 295 |
| Fukuie et al, 2016 (SB) | Betamethasone valerate 0.12% (extremities) hydrocortisone butyrate 0.1% (face <2 y, trunk) or tacrolimus 0.03% (face for patients ≥2 y); 2×/wk | TCS during flares only (same treatments) BID | 3 mo–7 y moderate-severe | 52 wk | 30 | |
| Glazenburg et al, 2009 (DB) | Fluticasone propionate 0.005% ointment 2×/wk | Vehicle 2×/wk | 4–10 y moderate-severe | 16 wk | 75 | |
| Hanifin et al, 2002 (DB) | Fluticasone propionate 0.05% cream daily 4×/wk for 4 wk then 2×/wk for 16 wk | Vehicle daily 4×/wk for 4 wk then 2×/wk for 16 wk | 3 mo–65 y moderate-severe | 20 wk | 231 | |
| Jorizzo, 1995 (SB) | Desonide 0.05% ointment BID | Hydrocortisone 1.0% ointment BID | <1–12 y mild-moderate | 25 wk | 36 | |
| Kirkup et al, 2003 (DB) (2 trials) | Fluticasone propionate 0.05% cream for flares BID | Hydrocortisone 1% cream or hydrocortisone butyrate 0.1% cream for flares BID | 2–14 y moderate-severe | 12 wk | 265 | |
| Luger et al, 2004 (DB) | Triamcinolone acetonide 0.1% cream (trunk/limbs) and hydrocortisone acetonide cream 1% (face/neck, intertriginous area) for flares BID | Pimecrolimus 1% cream for flares BID | 18–79 y moderate-severe | 52 wk | 658 | |
| Mandelin et al, 2010 (DB) | Hydrocortisone acetate 1% ointment (face/neck and intertriginous) and hydrocortisone butyrate 0.1% ointment for flares +7 d BID | Tacrolimus 0.1% ointment for AD flares + 7 d BID | ≥18 y moderate-severe | 52 wk | 80 | |
| Peserico et al, 2008 (DB) | Methylprednisolone aceponate 0.1% cream 2×/wk plus emollient 5 d BID (and once daily on methylprednisolone days) | Emollient (Advabase; Intendis GmbH, Berlin, Germany) 7 d/wk BID | ≥12 y moderate-severe | 16 wk | 221 | |
| Reitamo et al, 2005 (DB) | Hydrocortisone butyrate 0.1% ointment (body) and hydrocortisone acetate 1% ointment (face/neck, intertriginous) for flares BID | Tacrolimus 0.1% ointment for flares BID | ≥18 y moderate-severe | 26 wk | 972 | |
| Sigurgeirsson et al, 2015 | Low-mid potency TCS, selected by the investigator | Pimecrolimus 1% cream for flares | 3–12 mo mild-moderate | 260 wk | 2418 | |
| Thomas, 2002 (DB) | Hydrocortisone 1% ointment “when required” for 7 d, BID | Betamethasone valerate 0.1% ointment (3 d) and emollient (4 d) “when required” BID | 1–15 y mild-moderate | 18 wk | 207 | |
| TCIs 2×/wk | Fukuie et al, 2016 (SB) | See TCS | ||||
| Gollick et al, 2008 (DB) | Pimecrolimus 1% cream for flares BID | Vehicle for flares BID | ≥18 y mild-moderate | 26 wk | 543 | |
| Hanifin et al, 2001 (DB) Soter et al, 2001 (DB) (2 trials) | Tacrolimus 0.1% or tacrolimus 0.03% ointment for flares BID | Vehicle for flares BID | 16–79 y moderate-severe | 12 wk | 631 | |
| Kapp, 2002 (DB) | Pimecrolimus 1% cream for flares BID | Vehicle for flares BID | 3–23 mo mild-severe | 52 wk | 250 | |
| Luger et al, 2004 (DB) | See TCS | |||||
| Mandelin et al, 2010 (DB) | See TCS | |||||
| Meurer, 2002 (DB) Meurer et al, 2004 (DB) | Pimecrolimus 1% cream for flares BID | Vehicle for flares BID | ≥18 y moderate-severe/moderate | 24 wk | 192/130 | |
| Paller, 2001 (DB) | Tacrolimus 0.1% or tacrolimus 0.03% ointment for flares BID | Vehicle for flares BID | 2–15 y moderate-severe | 12 wk | 351 | |
| Paller, 2008 (DB) Breneman, 2008 (DB) | Tacrolimus 0.03% 3×/wk/tacrolimus 0.03% (2–15 y) or 0.1% (≥16 y) ointment 3×/wk | Vehicle 3×/wk | 2–15 y moderate- severe/2–15 and ≥16 y | 40 wk | 105/197 | |
| Ruer-Mulard, 2009 (DB) | Pimecrolimus 1% cream BID | Pimecrolimus 1% cream daily | 2–17 y mild-severe | 16 wk | 268 | |
| Siegfried, 2006 (DB) | Pimecrolimus 1% cream for flares BID | Vehicle for flares BID | 3–143 mo mild-severe | 24 wk | 275 | |
| Sigurgeirsson, 2008 (DB) | Pimecrolimus 1% cream for flares BID | Vehicle for flares BID | 1–17 y mild-moderate | 26 wk | 521 | |
| Thaçi et al, 2008 (DB) Thaci et al, 2010 (DB) | Tacrolimus 0.03% ointment 2×/wk | Vehicle 2×/wk | 2–15 y mild-severe/moderate-severe | 52 wk | 250/153 | |
| Wahn, 2002 (DB) | Pimecrolimus 1% for flares BID | Vehicle for flares BID | 1–17 y mild-severe | 52 wk | 711 | |
| Wollenberg et al, 2008 (DB) | Tacrolimus 0.1% 2×/wk | Vehicle 2×/wk | ≥16 y mild-severe | 52 wk | 224 | |
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Efficacy and safety of sodium hypochlorite (bleach) baths as a monotherapy.
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Relative efficacy of bleach baths in patients noncolonized versus patients with colonized/infected AD.
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When and how to use mupirocin or other topical or systemic antibacterials.
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Efficacy of antibacterial clothing (eg, silver-coated textiles).
a Long-term randomized, controlled trials in patients with atopic dermatitis.
Moisturizers
Topical moisturizers contain variable amounts of emollient, occlusive, and humectant ingredients aimed at reversing the generalized xerosis and enhancing the barrier function measured by transepidermal water loss.
One long-term trial found twice daily moisturization decreased the median time to relapse from 30 to more than 180 days compared with no moisturization. In a long-term RCT in adults, moisturization with a 5% urea-based moisturizer decreased the risk of AD relapse by 37% versus a cream without urea (see Table 1 ).
Several prescription emollient devices have received approval as medical devices: EpiCeram, Atopiclair, Mimyx, HylatopicPlus, Tetrix, Tropazone, Neosalus, Zenieva, Neosalus, and Eletone. The FDA 510(k) approval process is a less rigorous process than the standard premarket approval process most drugs go through. Prescription emollient devices have ingredients thought to have skin hydration, antiinflammatory, or antipruritic properties. Unfortunately, there have been no long-term RCTs comparing these prescription creams with over-the-counter alternatives, some of which have also been formulated to replete AD deficiencies (eg, ceramides and filaggrin breakdown products).
Expert consensus recommends frequent moisturizer use, ideally with a moisturizer that is free of additives, fragrances, perfumes, and other potential sensitizing agents. Specific recommendations should be tailored to the extent and severity of AD, and based on physician and patient preference. Petrolatum-based ointments are widely seen as effective and often do not contain potentially irritating preservatives. Creams are a good alternative for AD patients who cannot tolerate ointments. Lotions should be avoided because they can cause a drying effect ( Box 4 ).
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More head-to-head trials with moisturizers.
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Ideal moisturizer formulation.
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Prescription emollient devices and over-the-counter moisturizers with filaggrin breakdown products and/or ceramides.
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Frequency of moisturization.
a Long-term randomized, controlled trials in patients with atopic dermatitis.
Topical antiinflammatories
The long-term topical antiinflammatory literature has examined both “reactive” treatment, that is, at the first signs and symptoms of an AD flare until resolved, and “proactive” treatment, that is, 2 to 3 weeks of treatment for nonflared AD ( Box 5 ; see Table 1 ).
Most trials investigating the proactive use of topical antiinflammatories recruit patients who are flaring and treat until they reach a specific eczema score (ie, 50% improvement) and at this point they are considered “stabilized” or in remission. The patients are then randomized to either proactive or vehicle control to the site of previous atopic dermatitis lesions.
Topical corticosteroids
Topical corticosteroids (TCS) assert broad, nonspecific antiinflammatory effects on a multitude of cell types, many of which are dysregulated in AD. TCS are classified from mild (group I in Europe, class VII in the United States) to superpotent (group IV in Europe, class I in the United States) based on results from vasoconstriction assays. There have been at least 110 TCS RCTs performed in patients with AD, with the results consistently demonstrating efficacy for the treatment of both active lesions and as prevention of flares (eg, proactive treatment). Most of the trials were short in duration and of poor quality by today’s data reporting standards.
Long-Term Reactive Topical Corticosteroids Treatment Trials
RCTs have demonstrated safety and continued efficacy of repeated courses of low- to mid-potency TCS on active AD skin until clearance for up to 5 years in children and up to 1 year in adults. Mid-potency TCS have been shown to be superior in efficacy over lower potency TCS for long-term reactive treatment in children (see Table 1 ). The longest TCS RCT to date, enrolling patients in infancy, showed continued improvement in BSA affected and disease control (Investigators Global Assessment of 0 or 1) over the 5-year trial period using low- to mid-potency TCS. This study argues against the notion that TCS lose effectiveness over time (tachyphylaxis).
Long-Term Proactive Topical Corticosteroids Prevention Trials
The proactive approach of applying low-mid potency TCS twice weekly (consecutive days or Thursday and Sunday) for the prevention of flares in stabilized AD has been shown to be effective in both adults and children ( Table 2 ).
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