Topical treatments for eczema: a network meta‐analysis

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of different types of topical immunosuppressive treatments for eczema.

To generate rankings of the available topical immunosuppressive treatments for eczema, according to their efficacy and safety.

Background

Relevant terms used in the protocol are explained in the Glossary (Table 1).

1. Glossary of terms.

Term	Definition
Acneiform eruption	Dermatoses that resemble acne vulgaris, consisting of lesions, which may be papulopustular, nodular, or cystic
Atrophic	Wasting away or thinning of the protective later of an organ or body part
Boron	A chemical element primarily used in chemical compounds with low toxicity to mammals
Cyclooxygenase induction	Increase in the enzyme (cyclooxygenase), leading to a increased amount of chemical promoting inflammation and pain
Cyclic adenosine monophosphate (cAMP)	A chemical compound used in intracellular signal communications in various biological processes and pathways, including the pathway dealing with inflammation
Cytokine	A chemical secreted by certain cells of the immune system; it has an effect on other cells
Differentiation	The process by which a less specialised cell becomes a more specialised cell type
Eczema herpeticum	Viral infection of the skin, usually with the herpes simplex virus (HSV), causing extensive rashes in patients with pre‐existing skin disease, usually eczema
Endogenous	Internal factors that influence or drive a process
Erythematous	Redness of the skin
First‐line	Treatment regimen accepted by the medical establishment for initial treatment
Fissured	Cracking of the superficial layer of the skin
Glucocorticosteroid intracellular receptors	Group of steroid hormone receptors that are found inside the cells and on the cell surface. They initiate signals for steroid hormones, which lead to changes in gene expression over a time period of hours to days
Hirsutism	Excessive amounts of dark, course hair on body areas
Hyperglycaemia	A condition in which an excessive amount of glucose circulates in the blood plasma
Hyperpigmentation	Condition in which patches of skin become darker in colour than the normal surrounding skin, due to an excess deposition of melanin, the brown pigment that produces normal skin colour
Hypopigmentation	Condition in which patches of skin become lighter in colour than the normal surrounding skin, due to a decrease in the amount of melanin, the brown pigment that produces normal skin colour
Hypothalamic pituitary axis	A major neuroendocrine network comprising a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenals
Immunomodulate	Regulate the immune system, either via auto‐regulatory process (homeostasis) or therapeutically
Immunosuppressive	Reducing the activation or efficacy of the immune system
Lesions (Skin)	A region of the skin that has suffered damage through injury or disease of the skin
Lichenified	Thickening of the first layer of the skin with the skin lines being more obvious.
Mast cell	A specialised type of immune cells that can release substances and chemicals, such as histamine, during inflammatory and allergic reactions
Nitric oxide synthase	A family of enzymes catalysing the production of nitric oxide (NO), which serves as a cell‐signalling molecule involved in the immune defence system
Palmoplantar	Palms and soles
Papules	Small bump‐like swellings of the skin, forming part of the rash
Phosphlipiase A2	Enzymes that release chemicals from cell membrane via chemical reaction, which produce inflammation and pain at the site of the reaction
Purpura	Red or purple discoloured spots on the skin that do not lighten when pressure is applied. They are caused by bleeding underneath the skin
Second‐line	Treatment regimen that follows if there is failure of response to standard or first line therapy
Steroid atrophy	Thinning of overlying skin, due to long‐term or excessive use of steroids
Steroid rebound	Rebound phenomenon, due to corticosteroid withdrawal
Striae	Linear tearing of the second layer of the skin (dermis), accompanied by thinning of the superficial skin layer (epidermis)
T cell	Also known as the T lymphocyte; a type of lymphocyte or white blood cell that carries T cells; a T‐cell receptor on the cell surface
Tachyphylaxis	Rapidly decreasing response to successive applications of a drug, rendering it less effective
Telangiectasia	Threadlike red lines or patterns on the skin, caused by widened tiny blood vessels
Vasoconstriction	The narrowing of the blood vessels as a result of contraction of the muscular wall of the vessels, in particular, the large arteries and small arterioles
Xerotic	Dryness of the skin

Description of the condition

Eczema (also known as atopic eczema or atopic dermatitis) is a common and chronic, relapsing inflammatory skin disorder, characterised by intense pruritus and excoriation, with erythematous, xerotic, lichenified, fissured skin, and an increased risk of skin infections (Eichenfield 2014; Hanifin 1980; McCollum 2010; Weidinger 2016).

Eczema lesions vary in appearance, and papules, vesicles, scaling, fissuring, excoriations, crusting, oedema, and lichenification may be seen. Dry skin resulting from an impaired barrier function is also a key feature of eczema (Wollenberg 2016). Acute lesions typically comprise ill‐defined red scaly patches, often with oedema and vesicle formation, while lichenification and pigmentation are more typical of chronic lesions. Excoriations due to intense pruritus may be seen at any stage. Although eczema can develop on any area of skin, different distribution patterns are often observed at different stages of life. In children under two years of age, eczema typically arises on the face, the trunk, and limbs including the extensor surfaces. In older children and adults, involvement of the neck and flexural aspects of the limbs (on the inside of joints, such as behind the knees and in the elbow creases) is common, as is involvement of the hands (Akdis 2006; Bos 2010).

Commonly used criteria to diagnose eczema include the Hanifin and Rajka diagnostic criteria, the UK Working Party diagnostic criteria, the Japanese Dermatological Association criteria, and the American Academy of Dermatology criteria (Brenninkmeijer 2008; Vakharia 2018). The severity and extent of eczema is extremely variable, ranging from mild eczema, with localised, occasionally dry, mildly scaly patches; to moderate eczema, with slightly more redness and swelling, with little or no oozing or crusting; to a severe, generalised involvement of the whole body, resulting in acute skin failure with widespread, red, oozing, secondarily infected lesions. Both objective signs of eczema and subjective symptoms, such as itch and sleeplessness, contribute to the assessment of clinical severity (Schmitt 2014). The disease severity is routinely assessed during a patient's clinical consultation, to track the progress of the disease and judge the efficacy of therapy.

The main objective physician‐assessment tools used are the SCORAD (severity SCORing of Atopic Dermatitis) index (mild eczema corresponds to SCORAD levels below 25, and severe eczema to SCORAD levels above 50 (Kunz 1997)), the EASI (Eczema Area and Severity Index) score (Ricci 2009), and the Six‐Area Six‐Sign Atopic Dermatitis severity score (Charman 2002). The principal patient self‐assessment tools are the POEM (Patient‐Oriented Eczema Measure) scale (Spuls 2017), the SA‐EASI (Self‐Administered Eczema Area and Severity Index) rating scale (Housman 2002), and the ADQ (Atopic Dermatitis Quickscore (Carel 2008)). The Harmonising Outcome Measures for Eczema (HOME) initiative reached a consensus agreement that EASI should be the core instrument used for clinician‐reported signs and POEM should be used for patient‐reported symptoms (Schmitt 2014; Spuls 2017).

Eczema affects between 5% to 20% of children and 2% to 5% of adults worldwide, posing a significant burden for the affected patients, their families, and society (Johansson 2004; Odhiambo 2009). Eczema mainly affects infants and young children, but it can persist, relapse, or first develop in adulthood (Ellis 2012). About 80% of cases develop before the age of five years (Williams 2000). While it was previously estimated that about 25% of patients with early onset eczema progress to persistent eczema in adulthood (Williams 2005), the Odense Adolescence Cohort Study (TOACS) showed that up to 50% of patients had persistent eczema in adulthood (Mortz 2015). Similarly, another study found that 50% of subjects were still affected by age 20 (Margolis 2014). The clinical presentation of eczema is similar across different populations.

The International Study of Asthma and Allergies in Childhood (ISAAC) phase 3, conducted in children aged six to seven years old and 13 to 14 years old, found a decreased prevalence of eczema in some formerly high‐prevalence countries in the developed world, especially in Northwest Europe, but an increased prevalence in many formerly low‐prevalence developing countries, particularly in the younger age group (Williams 2008). Latin America emerged as a region of comparatively high prevalence of eczema symptoms, and a new area of high prevalence was also seen in Southeast Asia (Odhiambo 2009). A UK‐based cross‐sectional survey of 1760 children with eczema, aged between one to five years, classified 84% as having mild disease, 14% with moderate disease, and 2% as having severe disease. Referral to a dermatologist was correlated with disease severity, and 43% of severe cases had been seen by a dermatologist over the preceding year (Emerson 1998).

Eczema is a complex condition, caused by a combination of genetic and environmental influences, and characterised by cutaneous inflammation, immune dysregulation with a T helper 2 cell‐biased response, and epidermal barrier dysfunction. It is strongly associated with genetic factors, in particular loss‐of‐function mutations in filaggrin, a key protein involved in the formation of the skin barrier, making a primary skin barrier defect the likely primary trigger of eczematous skin inflammation (Flohr 2014; McAleer 2013).

Eczema often occurs in families with atopic diseases, including asthma, allergic rhinitis, hay fever (and food allergy), and atopic eczema. These diseases share a common pathogenesis, and frequently are present together, in the same individual and family. The word atopy refers to the genetic tendency to produce immunoglobulin E (IgE) antibodies in response to small amounts of common environmental proteins, such as pollen, house dust mites, and food allergens (Stone 2002; Thomsen 2015). Around 30% of people with eczema develop asthma, and 35% develop allergic rhinitis (Luoma 1983). However, it is known that atopy does not occur concurrently in all patients with atopic eczema. In view of this, there have been recent proposals to use the term 'eczema' to define patients both with and without atopy. Therefore, in agreement with the 'Revised nomenclature for allergy for global use' (Johansson 2004), and similar to other Cochrane reviews evaluating eczema therapies (van Zuuren 2017; Yew), we will use the term 'eczema' throughout the review.

Several environmental factors, such as hard water, hygiene practices, and use of antibiotics early in life have been associated with eczematous skin inflammation (Flohr 2014). Patients' skin may be prone to inflammation in the presence of environmental insults, such as soaps and detergents, washing with hard water, and exposure to house dust mites (Cork 2009).

Many studies have assessed the ways in which eczema can affect quality of life. This condition can have a profound impact on the social, emotional, and physical health of an affected individual. Symptoms and visible lesions can cause behavioural problems, dependency, irritability, sleep loss, pain, itch, physical fatigue, shame, low self‐esteem, anxiety, problems with relationships, and emotional distress (Maksimović 2012). There is also an important economic impact, due to frequent visits to physicians, frequent treatments, and days lost at work, which may also lead to fewer opportunities (Brenninkmeijer 2009; Chamlin 2004). Patients often need to alter their daily routine to incorporate regular use of emollients and other topical treatments. Topical treatments can be messy, and can cause staining of bed sheets and attire. Many make changes to the style of their attire to hide their rashes in public. The severity of the condition bears a close relation to the degree of impact on an affected individual’s quality of life. There is also a significant component of out‐of‐pocket direct expenses for the treatments. A systematic review estimated the annual direct and indirect costs of eczema in the United States to be USD 364 million to USD 3.8 billion (Mancini 2008).

The clinical presentation of eczema is similar across different populations. Eczema is most commonly treated with topical medications. Based on expert opinion, the threshold for using systemic immunosuppressant treatment or more potent topical therapy in children with eczema would typically be higher than for adults (Flohr 2013).

Description of the intervention

Topical treatment is often the first‐line therapy for mild to moderate eczema. It is also an important adjunctive treatment to phototherapy and other systemic treatments for more severe eczema. The aim of topical treatment is to cure the active inflammation, restore the skin's barrier function, and treat any infections. Topical immunosuppressive agents ameliorate the active inflammation, while moisturisers and emollients restore the skin's barrier function (van Zuuren 2017). Topical antimicrobials address the skin infections (Birnie 2008). We will only be reviewing topical immunosuppressive therapies. While we will look at combined topical immunosuppressive agents (concomitant use of more than one topical treatment over various body sites in a single patient), we will not be reviewing combination treatment, i.e. systemic agents or phototherapy treatment combined with topical treatment, as this is beyond the scope of our review.

Emollients and moisturisers are part of eczema's standard of care, and are often the comparator intervention that other active topical treatments are compared against in clinical trials. Another Cochrane Review, 'Emollients and moisturisers for eczema', reviewed this in detail (van Zuuren 2017). The Cochrane Review 'Interventions to reduce Staphylococcus aureus in the management of atopic eczema' evaluated antimicrobial Interventions for Staphylococcus aureus infections (Birnie 2008).

Topical immunosuppressive therapy includes corticosteroids, calcineurin inhibitors, the newly approved phosphodiesterase‐4 (PDE‐4) inhibitor, and other newly emerging topical therapies currently under investigation. Effective topical therapy depends on four fundamental principles: sufficient strength, sufficient dosage, correct application, and correct site of application. It is also important to apply the topicals at the correct frequency and regimen of applications. The site of application is another important consideration for percutaneous absorption, particularly for sites where the skin might be thinner and more sensitive, such as the face, axilla, and groin. Hairy sites might be more prone to occlusion folliculitis, especially with ointment‐based topicals. Treating sun‐exposed sites, such as the face, with topical calcineurin inhibitors might also be a potential problem. Counselling patients to decrease sun exposure when using topical applications on sun‐exposed sites is recommended to mitigate the risk of cutaneous malignancy (Novartis 2010).

Topical corticosteroids (TCS)

Topical corticosteroids are first‐line topical immunosuppressive therapies for eczema. Endogenous glucocorticosteroids, such as cortisol, occur naturally in the human body to regulate inflammatory immune reactions. The chemical compound of hydrocortisone was developed by modifying the original corticosteroid structure (reduction of the ketone group to the hydroxyl group). Topical versions of hydrocortisone were first produced for use as topical corticosteroids (Ahluwalia 1998).

Topical corticosteroids are ranked, in terms of potency, into four groups, consisting of seven classes: from Class 7 (weakest) to Class 1 (most potent (WHO 1997)). Based on this classification, Class I is considered to be ultra high potency, Classes II and III are high potency, Classes IV and V are moderate potency, and Classes VI and VII are low‐potency topical corticosteroids. Examples include the following:

• clobetasol propionate: ultra high potency, Class I (ointment and cream);

• betamethasone dipropionate: high potency, Classes II and III (ointment and cream);

• mometasone furoate: high and moderate potency, Classes II and IV (ointment and cream);

• fluticasone propionate: high and moderate potency, Classes III and V (ointment and cream);

• hydrocortisone butyrate: moderate potency, Class V (ointment and cream);

• betamethasone valerate: high and moderate potency, Classes II and V (ointment and cream);

• fluocinolone acetonide: moderate potency, Classes IV and V (ointment and cream);

• triamcinolone acetonide: moderate potency, Class V (ointment and cream);

• clobetasol butyrate: moderate potency, Class V (ointment and cream);

• desonide: low potency, Class VI (cream); and

• hydrocortisone acetate: low potency, Class VII (ointment and cream).

Topical corticosteroids with the appropriate potency are chosen based on the age of the patients, and extent, severity, and location of the eczema lesions. For example, low‐ to moderate‐potency topical corticosteroids are suitable for mild eczema, or eczema over sensitive sites with thin skin, such as the face and flexural areas. This is in contrast to high‐ to ultra high‐potency topical corticosteroids, which are used in severe, thick eczematous plaques over thicker skin sites, such as limbs and palmoplantar surfaces (WHO 1997). Topical corticosteroids, of appropriate potency, are usually applied twice a day until the eczema is controlled, after which use is tapered.

Local side effects of topical corticosteroids include mainly atrophic skin changes, such as steroid atrophy, telangiectasia, striae, purpura, easy bruising, and ulceration (Hengge 2006). Other local side effects include infections, acneiform eruption, steroid rebound, tachyphylaxis, hirsutism, hyper‐, and hypopigmentation. Uncommonly, there may be cases of allergic contact dermatitis in response to topical corticosteroid use. There might also be an unsubstantiated risk of developing cataracts when topical corticosteroids are applied near the eyes (Callen 2007).

Systemic side effects of topical corticosteroids can sometimes occur after chronic use of high‐potency corticosteroids on large areas or areas with high permeability or poor skin integrity: hypothalamic pituitary axis suppression or hyperglycaemia can sometimes occur (Gilbertson 1998). Steroid phobia among patients and physicians has motivated the development of newer topical agents such as calcineurin phosphodiesterase 4 inhibitors or other agents, which target more specific inflammatory pathways (Pallor 2016). There are no known drug interactions with topical corticosteroids.

Topical calcineurin inhibitors

Topical calcineurin inhibitors are topical immunosuppressive therapies containing chemicals with a structure and mechanism of action similar to that of cyclosporine, an oral calcineurin inhibitor. They are applied as either tacrolimus ointment or pimecrolimus cream. Tacrolimus is available in 0.03% and 0.1% ointment, while pimecrolimus is available in 1% cream. They are recommended as second‐line therapies for the short term, and for non‐continuous treatment of patients who do not respond adequately to topical corticosteroids, or in whom corticosteroids are contraindicated (Astellas 2011; Novartis 2010). However, it is unlikely that topical calcineurin inhibitors are more efficacious than topical corticosteroids of appropriate potency, and corticosteroid allergy can often be circumvented by different corticosteroids products. Tacrolimus ointment has been demonstrated to have comparable efficacy to topical corticosteroids in both adults and children (Reitamo 2002a; Reitamo 2002b). By avoiding the local adverse effects associated with topical corticosteroids, they also have a special role in the treatment of problem areas with thin skin, such as the face and intertriginous or anogenital sites (Ashcroft 2005). The recommended dose for topical calcineurin inhibitors is usually application twice daily to the affected area, according to a study that evaluated the treatment effect over a three‐week period, and found this to be the more effective regime (Reitamo 2004).

Tacrolimus ointment has been reported to be more effective, and have a faster onset of action than pimecrolimus cream, in both adults and children (Paller 2005). However, pimecrolimus cream is noted to be more tolerable in terms of burning sensations, and has better formulation attributes (Kempers 2004). It is also associated with a lower systemic drug absorption compared to tacrolimus ointment (Draelos 2005). It is demonstrated to be safe in the treatment of atopic dermatitis in infants (Eichenfield 2002; Ho 2003). Therefore, the choice of tacrolimus ointment or pimecrolimus cream would depend on factors, such as the disease severity, and patient factors and tolerability.

High‐quality long‐term safety data were published in 2008 from a four‐year tacrolimus study and a 26‐week pimecrolimus study (Langley 2008; Reitamo 2008). The most common side effect was transient burning sensation at the application site. Generalised viral infections, e.g. eczema herpeticum, have occasionally been reported. Although there have been previous reports of lymphoma risk and non‐melanoma skin cancer, further data did not reveal an increased risk (Arellano 2007; Margolis 2007). However, avoiding sun exposure on sites where topical calcineurin inhibitors have been applied has been recommended (Novartis 2010). Based on the expected amounts of absorption, drug interactions between topical calcineurin inhibitors and systemic drugs are unlikely to occur, but cannot be ruled out. Extensive use of topical calcineurin inhibitors in patients receiving concomitant oral medicines, such as erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers, or cimetidine should be considered with caution (Astellas 2011; Novartis 2010).

Topical phosphodiesterase‐4 (PDE‐4) inhibitors

Topical phosphodiesterase‐4 (PDE‐4) inhibitors are a form of topical immunosuppressive therapy for eczema. Currently, crisaborole ointment is the only U.S. Food and Drug Administration (FDA)‐approved topical PDE‐4 inhibitor for the treatment of eczema (Zebda 2018). It is approved for use in adults and children aged two years and older, with mild to moderate eczema. It is known to be absorbed into the epidermis and dermis, and quickly metabolised into an inactive form, preventing any likely systemic exposure (Jarnagin 2016). It is likely to be used over other topical treatments, especially topical corticosteroids, on thin skin sites, or in patients who are unable to tolerate other treatments. Twice a day application of 2% crisaborole ointment is recommended, and was noted to be superior to once‐daily application at the end of 29 days of treatment (Stein 2015). Its side effects' profile has been reported to be favourable; main adverse effects were stinging or burning sensation at the application site, a worsening of the eczema, or site infection (Pallor 2016). Nausea, vomiting, or other gastrointestinal side effects, which are common with oral PDE‐4 inhibitors, are rare (Eichenfield 2017). There are no known drug interactions with topical PDE‐4 inhibitors (Anacor 2016).

Emerging topical treatments

Coal tar and other new aryl hydrocarbon receptor activators

Coal tar is a by‐product of coal production, and its topical preparations have been used in the treatment of chronic skin diseases, such as psoriasis and eczema, for decades (Roelofzen 2010). It is a complex mixture of more than 100,000 chemical compounds. Some of these compounds have been shown to be carcinogenic in animal studies (Boffetta 1997). However, a large historical cohort study showed no significant increased risks of cancers when coal tar was used as a treatment for psoriasis or eczema (Roelofzen 2010). A number of newer, and more specific compounds and plant extracts, with a mode of action similar to coal tar but with much lower carcinogenicity, have been developed, as part of a new topical treatment class for eczema. An example of such a compound is tapinarof cream. A randomised controlled trial recently tested the effects of a twice‐daily application in adults with moderate to severe atopic dermatitis; they reported good efficacy and a few cases of folliculitis and contact dermatitis at the end of 12 weeks of treatment (Bissonnette 2012).

It is not known yet if there are any known drug interactions with these compounds. Like the topical calcineurin inhibitors and topical PDE‐4 inhibitors, these compounds are likely to be used over thin skin sites, or if patients are unable to tolerate other topical treatments. For coal tar preparation, patients' acceptance of its appearance and smell will likely play an important role in whether it is used over other treatments. We will analyse studies on coal tar preparations separately from studies of the newer aryl hydrocarbon receptor activators, despite the similar mechanism of action, as coal tar preparations might have other undiscovered mechanisms of action.

Topical Janus kinase (JAK) inhibitors

In recent years, topical JAK inhibitors have been evaluated as novel topical treatments for inflammatory skin diseases, such as psoriasis or eczema. As a novel drug class, JAK inhibitors are chemicals that inhibit the JAK inflammatory pathways, bringing about a reduction in inflammation. Oral tofacitinib, an oral JAK inhibitor, was effective in the treatment of moderate to severe atopic dermatitis in a small study with six patients (Levy 2015). No adverse effects were reported in this small study, but serious adverse effects, such as solid organ malignancies, lymphoma, and serious infections have been reported in patients with rheumatoid arthritis who were treated with oral tofacitinib (Wollenhaupt 2014). It is believed that topical formulations of JAK inhibitors would be useful for localised treatment of inflammatory skin diseases, while minimising the potential systemic effects of its oral formulation. Two topical JAK inhibitors currently under investigation are topical tofacitinib and JTE‐052 (Bissonnette 2016; Nakagawa 2018). They were tested using twice‐daily application on adults with moderate to severe atopic dermatitis, with good efficacy at the end of four weeks of treatment. These compounds are likely to be used over thin skin sites, or if patients are unable to tolerate other topical treatments. Most of the current data on the use of topical tofacitinib comes from studies of patients with psoriasis. It has been shown to be safe and tolerable. Most side effects are limited to local application site reactions, such as stinging and burning (Papp 2016; Ports 2013). Some patients develop upper airway or urinary tract infections (Ports 2013). More studies on these new compounds are expected to be published in the next few years. It is not known yet if there are any drug interactions with these compounds.

Combined treatment

The development of newer topical immunosuppressive therapies, such as topical calcineurin inhibitors, topical phosphodiesterase‐4 inhibitors, and other therapies, was driven by the clinical need to avoid local side effects of topical corticosteroids, especially over thin skin areas (Ashcroft 2005; Pallor 2016). However, in clinical practice, these newer topical treatments are often used over thin skin sites, while the more potent topical corticosteroids are used over the thicker skin sites, such as the trunk, limbs, and palmoplantar surfaces. This combination treatment strategy allows the avoidance of the local side effects of topical corticosteroids over the thinner, more sensitive skin areas, while benefiting from the higher efficacy of the more potent topical corticosteroids, for thicker or recalcitrant skin sites.

In clinical trial settings, most studies focus on comparing monotherapy treatment arms of the treatments discussed above. However, trials evaluating the newer topical agents may allow concomitant use of topical corticosteroids in both treatment arms. The dose and frequency of application are likely to vary according to the individual's needs.

Standard care treatment (emollients)

Moisturising the skin with emollients and moisturisers is an important part of eczema care. It is part of standard treatment for mild eczema, and is an adjunctive treatment to other active treatment strategies in more severe eczema cases (Eichenfield 2014). Eczema patients receiving any form of active therapies are encouraged to moisturise their skin with emollients as part of standard care. They are often listed as part of the comparator or placebo intervention when compared to active topical treatments in clinical trials. Placebo/vehicle therapy in the comparator arm of topical eczema clinical trials is often delivered as an ointment or cream, which also serves as the emollient (Lane 1946). It helps to reduce the dryness in the skin, reduce water loss through the skin, and reduce the itchy sensation, to make patients more comfortable. Usually, emollients and moisturisers are applied two to three times a day, usually after bathing (Eichenfield 2014). Other adjunctive strategies that form part of standard eczema care are bathing with gentle soaps and washes, avoiding environmental triggers and allergens, wearing clothing with non‐irritating material, and itch control (Ring 2012).

How the intervention might work

Topical immunosuppressive therapies modulate several inflammatory pathways to bring about a decrease in the overall inflammation in the skin.

Topical corticosteroids

Topical corticosteroids affect many aspects of skin inflammation in eczema, including inflammatory cell, chemical, and tissue responses. The diffusion of corticosteroids, and subsequent binding to the glucocorticoid intracellular receptors, bring about an inhibition of phospholipase‐A2 activity, cyclooxygenase induction, nitric oxide synthase, cytokine and mast cell activity, and reduction of mast cell numbers (Ahluwalia 1998). Production of various inflammation cytokines, such as interleukin (IL)‐1, IL‐2, interferon (IFN)‐γ, and tumour necrosis factor (TNF) is reduced (Guyre 1982). Topical corticosteroids also lead to a vasoconstriction of the affected skin (Altura 1966). All of these lead to a decrease in overall inflammation of the skin, with amelioration of the eczema condition.

Topical calcineurin inhibitors

Calcineurin inhibitors bind to a cellular protein, which subsequently inhibits the enzyme, calcineurin, which in turn decreases T‐cell proliferation and pro‐inflammatory cytokine production of IL‐2, IL‐3, IL‐4, IL‐12, IFN‐γ, and TNF (Cury Martins 2015). The overall effect is a decrease in the inflammation of the skin.

Topical phosphodiesterase‐4 (PDE‐4) inhibitors

Skin inflammation in patients with eczema is associated with an increase in pro‐inflammatory cytokines in the skin, with an observed increase in PDE‐4 enzyme activity. PDE‐4 is an enzyme; its increased activity can lead to an increase in pro‐inflammatory cytokines. This leads to a decrease in the levels of intracellular cyclic adenosine monophosphate (cAMP), which in turn decreases the production of pro‐inflammatory cytokines (Zebda 2018). The small size of a PDE‐4 inhibitor makes it a suitable topical agent for easy skin absorption (Jarnagin 2016). Crisaborole has a novel boron chemistry that further contributes to this skin absorption (Jarnagin 2016). The PDE‐4 inhibitors block the increase in PDE‐4 activity in inflamed eczema skin, inhibiting the release of tumour necrosis factor‐alpha, IL‐12 and IL‐23, and other inflammatory cytokines (Schafer 2010).

Emerging topical treatment

Coal tar and other new aryl hydrocarbon receptor activators

Coal tar helps in eczema by reducing the rate of skin cell growth, softening the epidermis (uppermost layer of skin), and increasing the production of chemicals, such as filaggrin, that help the skin retain moisture (van den Bogaard 2013). The full mechanism of action of coal tar preparations is still poorly understood, as it is a complex mixture of many chemical compounds; it is believed that one mode of action is mediated via activation of the aryl hydrocarbon receptors in the skin. Aryl hydrocarbon receptors are proteins, which bind to various natural or synthetic chemical compounds, leading to the activation of chemical pathways in skin cells, and the production of proteins that help to strengthen the barrier function of the uppermost layer of the skin, retaining moisture, leading to a reduction of skin cell turnover, and increasing skin cell differentiation (van den Bogaard 2013). They also help in countering the effect of specific inflammatory responses in eczema. Newer aryl hydrocarbon receptor activators, such as tapinarof, specifically activate the aryl hydrocarbon receptors to bring about these changes (Furue 2017).

Topical Janus kinase (JAK) inhibitors

Topical JAK inhibitors improve eczema by decreasing the inflammation in the skin, and reducing the rate of skin cell growth. Their topical preparation contains molecules that inhibit the JAK inflammatory pathways in the skin. By inhibiting the inflammatory pathways, these molecules cause changes to the production of proteins related to inflammation of the skin, causing a general reduction of the inflammation in the skin (Bissonnette 2016; Nakagawa 2018). They are generally not absorbed into the body.

Combined treatment

When applied over individual and separate body sites, these three topical immunosuppressive therapies will decrease skin inflammation, by decreasing inflammatory cells and cytokines, via their own unique mechanisms of action that target the inflammatory pathways. The aim of combined treatment is to use topical therapies, tailored to body sites, while minimising unnecessary local side effects.

Standard care treatment (emollients)

Emollients serve as a preventive strategy for eczema, by replenishing the moisture and lipid content in the superficial layers of the skin, to restore the barrier function. Some moisturisers provide direct hydration of the skin, while other, more lipid‐based moisturisers form an occlusive layer to prevent loss of water from the skin layers (van Zuuren 2017). Some moisturisers contain humectants (e.g. urea, glycerol, lactic acid), which are molecules that attract water to the stratum corneum (the top layer of the skin (Lodén 2003)). Newer moisturisers add natural ingredients, such as ceramides, cholesterol, and fatty acids to replenish natural moisturising factors in the skin (Moncrieff 2013). Barrier dysfunction plays an important role in the pathogenesis of eczema (Palmer 2006). Restoring, or preventing a breakdown in the barrier function of the skin, prevents exacerbation of skin inflammation, and entry of allergens (Rerknimitr 2017).

Why it is important to do this review

Cochrane Skin undertook an extensive prioritisation exercise alongside the Global Burden of Disease and the World Health Organization to identify a core portfolio of the most clinically‐important titles. The expert panel for development, maintenance, and investment of resources identified this title as a clinically important priority. Novel topical immunosuppressive treatments for eczema (atopic dermatitis) have been recently introduced after a significant period during which there was a lack of new topical treatments. These new treatments attempt to address the issue of steroid phobia among patients in the treatment of eczema. They may also be potentially more effective. However, most of the clinical trials evaluating these treatments mainly make comparisons between the active ingredients and the application format. There is a lack of information on efficacy and safety from direct comparisons between these new topical immunosuppressive treatments and conventional topical corticosteroids therapy. With an increasing number of new topical immunosuppressive treatments likely to become available, we need to assess these treatments for efficacy and safety, and compare them directly with older, conventional topical therapies.

A network meta‐analysis approach will allow us to estimate efficacy and safety through indirect comparisons among various treatments that may or may not have direct head‐to‐head comparisons.

Our review is complemented by another Cochrane Review: Systemic treatments for eczema: a network meta‐analysis (Sawangjit 2018). Please note that because of this, there is considerable overlap in the background and methodology.

Objectives

To assess the effects of different types of topical immunosuppressive treatments for eczema.

To generate rankings of the available topical immunosuppressive treatments for eczema, according to their efficacy and safety.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomised controlled trials (RCTs) of one or more topical immunosuppressive treatments for eczema, including parallel‐group, cluster‐, and within‐participant RCTs. Cross‐over studies should have a sufficiently long washout (i.e. at least 14 days) period between interventions (Sandoval 2014). If there is no, or a minimal washout period, we will only assess the outcomes of the first intervention period.

Types of participants

We will consider participants of all ages with a clinical diagnosis of eczema. They could have fulfilled diagnostic criteria, such as the Hanifin and Rajka definition (Hanifin 1980; Appendix 1), or the UK modification (Williams 1994; Appendix 2), or been diagnosed clinically by a clinical healthcare professional, using the terms 'atopic eczema', or 'atopic dermatitis'.

We will pose no restrictions on age, sex, ethnicity of the participants, or severity of eczema.

We will exclude studies that include participants with other types of eczema, such as contact dermatitis, seborrhoeic eczema (seborrhoeic dermatitis), varicose eczema, and discoid eczema.

We will only include studies in which there is a subset of relevant participants (where not all participants in the study have eczema), when we can obtain specific and separate information on participants with eczema.

Types of interventions

We will consider studies to be eligible if they investigate active topical immunosuppressive treatments, delivered through any means, and in any dose, course duration, and follow‐up time, compared to other active topical immunosuppressive treatments, a vehicle, no treatment, or emollients as standard care. We will also include studies with more complex comparisons of combined treatment approaches, e.g. topical corticosteroids plus tacrolimus versus tacrolimus plus placebo, or topical corticosteroids plus placebo.

We will include the following active topical immunosuppressive treatments:

1. Topical corticosteroids, such as:

   • Clobetasol propionate

   • Betamethasone dipropionate

   • Mometasone furoate

   • Fluticasone propionate

   • Hydrocortisone butyrate

   • Betamethasone valerate

   • Fluocinolone acetonide

   • Triamcinolone acetonide

   • Clobetasol butyrate

   • Desonide

   • Hydrocortisone acetate

2. Topical calcineurin inhibitors, such as:

   • Pimecrolimus

   • Tacrolimus

3. Topical (phosphodiesterase) PDE‐4 inhibitors, such as:

   • Crisaborole

4. Coal tar and topical aryl hydrocarbon receptor activators, such as:

   • Coal tar

   • Tapinarof

5. Topical Janus kinase (JAK) inhibitors, such as

   • Topical tofacitinib

   • JTE‐052

6. Combinations of the above treatments

We will exclude studies that compare topical immunosuppressive treatments with oral systemic treatments or phototherapy, as the latter is being dealt with in another Cochrane network meta‐analysis.

We will not be reviewing combination treatment, i.e. systemic agents or phototherapy treatment combined with topical treatment.

We will compare different potencies of topical corticosteroids, but we will not compare different strategies of using topical corticosteroids (such as once daily versus twice daily, proactive versus reactive, cream versus ointment, before versus after emollient, etc.) to avoid overlap with another Cochrane Review 'What are the most effective and safest strategies for using topical corticosteroids in people with eczema?' (Chalmers 2018b).

Types of outcome measures

Outcomes of interest in this review will include the recommended core outcome domains for eczema trials following the global Harmonizing Outcome Measures for Eczema (HOME) initiative, including clinical signs (measured by using a physician‐assessed instrument), symptoms (measured by using a patient‐assessed instrument), health‐related quality of life, and long‐term control of eczema (Chalmers 2016; Chalmers 2018a; Schmitt 2014; Spuls 2017).

Timing of outcomes

We will define outcomes as short term (≤ 16 weeks of treatment), and long term, or maintenance (> 16 weeks of treatment (Blauvelt 2017)). For multiple times of outcome measurement, we will use the data at the end of study, and classify them as short‐term outcomes if the study period is ≤ 16 weeks. If the study period exceeds 16 weeks, we will use the data at the end of the study and classify them as long‐term outcomes. We will classify outcomes measured closest to 16 weeks as short‐term outcomes.

Primary outcomes

1. Clinical severity of eczema, measured by a validated or objective measure, such as the Eczema Area and Severity Index (EASI (Ricci 2009)), Scoring Atopic Dermatitis (SCORAD (Kunz 1997), the Six Area, Six Sign Atopic Dermatitis (SASSAD) severity score (Charman 2002), Investigators' Global Assessment (IGA), affected Body Surface Area (BSA), and other less reported measures. EASI will be the preferred instrument for this outcome measure, as there is consensus agreement by the HOME initiative that this should be a core instrument for clinician‐reported signs (Schmitt 2014).

2. Participant‐reported symptoms, measured by a validated measure, such as the Patient‐Oriented Eczema Measure (POEM (Spuls 2017)), Self Administered Eczema Area and Severity Index (SA‐EASI (Housman 2002)), Itch Severity Scale (ISS) (Majeski 2007), or other less validated measures, such as the Atopic Dermatitis Assessment Measure (ADAM (Charman 1999)), Patient‐Oriented SCORAD (PO‐SCORAD (Stalder 2011)), and the Leuven Itch Scale (LIS (Haest 2011)). POEM will be the preferred instrument for this outcome measure, as there is consensus agreement by the HOME initiative that this should be a core instrument for patient‐reported symptoms (Spuls 2017).

3. Adverse effects: we will consider the most common serious adverse effects of each systemic treatment, such as infection with all agents, conjunctivitis with the new biologic agents, renal function impairment and hypertension with cyclosporine, and stomach upset with mycophenolate mofetil.

The instruments listed for outcomes one and two are in decreasing order of importance.

Secondary outcomes

1. Participant's self‐assessment of global response of improvement (e.g. Patients' Global Assessment (PsGA)) (Farina 2011);

2. Health‐related quality of life, measured by a validated measure, such as the Dermatology Life Quality Index (DLQI (Finlay 1994)), Quality of Life Index for Atopic Dermatitis (QoLIAD (Whalley 2004)), and Skindex (Chren 2012), in this order of decreasing hierarchy;

3. Long‐term control of eczema, following the HOME initiative, such as repeated measurement of clinical signs (flares), symptoms, and quality of life, plus a global patient assessment of eczema (Chalmers 2014).

Search methods for identification of studies

We aim to identify all relevant RCTs, regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

The Cochrane Skin Information Specialist will search the following databases:

• the Cochrane Skin Group Specialised Register (current date);

• the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (current issue);

• MEDLINE Ovid (from 1946 onwards);

• Embase Ovid (from 1974 onwards); and

• the GREAT database (Global Resource of EczemA Trials. Centre of Evidence Based Dermatology; www.greatdatabase.org.uk; current date).

The Cochrane Skin Information Specialist has developed a draft search strategy for RCTs for MEDLINE Ovid, which we included in Appendix 3. We will use this as the basis for search strategies for the other databases listed, edited as indicated.

Trial registers

Two review authors (KWL and JT) will search the following trials registers, using the keywords 'eczema' and 'topical' or 'topically', 'emollient' or 'emollients', 'ointment' or 'ointments', 'cream' or 'creams', 'moisturizer' or 'moisturizers', 'moisturiser' or 'moisturisers', 'oil' or 'oils':

• the metaRegister of Controlled Trials (www.isrctn.com);

• the US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov);

• the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);

• the World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch); and

• the EU Clinical Trials Register (https:// www.clinicaltrialsregister.eu/).

Searching other resources

References from published studies

Two review authors (KWL and JT) will examine the bibliographies of the included and excluded studies, and any relevant systematic reviews identified, for further references to potentially eligible studies.

Adverse effects

We will not perform a separate search for adverse effects of the target interventions. However, we will examine data on adverse effects from the included studies.

Correspondence

We (KWL and JT) will contact original authors for clarification and further data, if trial reports are unclear.

Data collection and analysis

Some of the following section contains text that was originally published in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a) as well as text that was originally published in the Cochrane Review 'Systemic pharmacological treatments for chronic plaque psoriasis: a network meta‐analysis’ (Sbidian 2017).

Selection of studies

We will use Covidence to manage screening. Two review authors (YYW and MSLH) will independently examine each title and abstract to exclude obviously irrelevant reports. The two authors will then independently examine full‐text articles to determine eligibility. We will contact study authors for clarification when necessary, and discuss disagreements to reach consensus. We will list excluded studies in a 'Characteristics of excluded studies' table, and document the primary reason for exclusion. We intend to follow the PRISMA statement and will create a flowchart for the selection of studies (Hutton 2015).

Data extraction and management

Two review authors (out of YYW, MSLH, KWL and JT) will independently extract the data from published and unpublished reports, using a standardised form. In the event of disagreements, we will discuss them among the group of reviewers doing the data extraction to reach a consensus. We will pilot test this data extraction form on a set of included trials. We will extract the data to populate the 'Characteristics of included studies' tables. We will extract baseline demographic and clinical characteristics of participants (age, sex, presence of atopic comorbidities, eczema severity, SCORAD, EASI score, Body Surface Area (BSA), QoL scale (DLQI)). One review author (JT) will check and enter the data into the Cochrane Review Manager 5 (RevMan 5) computer software (RevMan 2014). Another review author (KWL) will check the data in Revman 5 for accuracy. For some data reported in figures or graphs, we will use the WebPlotDigitizer tool to extract the data (WebPlotDigitizer 2017). We will contact the authors of the trials to ask them to provide missing data when required, and include a table in the review detailing all contact with study authors.

Assessment of risk of bias in included studies

We will use The Cochrane 'Risk of bias' tool to assess the risk of bias in each study. Two review authors (KWL and JT) will independently assess the risk of bias, and a third author (CSYE) will resolve any disagreement. For each of the following, and according to the general principles in section 8.4 of the Cochrane Handbook for Systematic Reviews of Interventions, we will grade the following 'Risk of bias' sources as low, high, or unclear (Higgins 2011a):

1. Random sequence generation (selection bias);

2. Allocation concealment (selection bias);

3. Blinding of participants and personnel (performance bias);

4. Blinding of outcome assessors (detection bias);

5. Incomplete outcome data (attrition bias);

6. Selective outcome reporting (reporting bias);

7. Other potential sources of bias (e.g. design‐specific risks of bias; baseline imbalance; differential diagnostic activity; contamination; fraud).

We will determine the overall risk of bias for each outcome (across domains) within studies as follows (Higgins 2011a):

1. Low risk of bias, when all domains are assessed as being at low risk, or plausible bias is unlikely to seriously alter the results;

2. Unclear risk of bias, when at least one domain is classified as being at unclear risk, or plausible bias raises some doubt about the results;

3. High risk of bias, when at least one domain is judged as being at high risk, or plausible bias seriously weakens confidence in the results.

We will determine the overall risk of bias for each outcome (across domains) across studies as follows (Higgins 2011a):

1. Most information is from studies at low risk of bias, or plausible bias is unlikely to seriously alter the results;

2. Most information is from studies at low or unclear risk of bias, or plausible bias raises some doubt about the results;

3. The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results, or plausible bias seriously weakens confidence in the results.

Measures of treatment effect

For each dichotomous outcome (i.e. occurrence of adverse effects), we will use risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect. For continuous variables (i.e. clinical severity, participant‐reported symptoms, quality of life scale, and global response of improvement), we will use mean difference (MD) or standardised mean difference (SMD) with 95%CI for treatment effect measures, when they are measured using different scales.

To rank the efficacy for all treatments, we will use the Surface Under the Cumulative Ranking (SUCRA) values (Salanti 2011). We will estimate the rank probabilities of all the groups, using a Bayesian framework (White 2011; Higgins 2009). Next, we will apply a step function to summarise the cumulative ranking, by estimating the SUCRA values of each group, ranging from zero to one. Thus, larger SUCRA values will indicated a better prognosis.

Unit of analysis issues

The primary unit of analysis will be the participant. We will take the within‐trial correlation into account in the network meta‐analysis.

Cluster‐randomised trials

In a cluster‐randomised trial, groups of participants randomised to different interventions will be the unit of analysis. We will use the summary measurement from each cluster, and number of clusters as the sample size, and proceed with the analysis as if the trial was individually randomised (Higgins 2011a).

Cross‐over trials

In a cross‐over trial, we will use the participants in each period of the allocation as the unit of analysis if the wash‐out period is appropriate (i.e. at least 14 days). Otherwise, we will only use the first period of allocation for analysis. If no information is available from the first period of allocation, we will impute standard deviations by assuming a particular correlation coefficient (Higgins 2011a). The value for a correlation coefficient will be estimated from another study in the meta‐analysis by adopting the formula provided in Chapter 16.4.6.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If no studies in the meta‐analysis provides the sufficient data for estimation, we will then conservatively assume the correlation coefficient as zero (Higgins 2011b).

Within‐participant trials where different parts of the body are randomised to different interventions

The unit of analysis will be the separate body part. Similar to cross‐over trials, we will impute standard deviations by assuming a particular correlation coefficient (Higgins 2011a). In detail, the value for a correlation coefficient will be estimated from another study in the meta‐analysis by adopting the formula provided in Chapter 16.4.6.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If no studies in the meta‐analysis provides the sufficient data for estimation, we will then conservatively assuming the correlation coefficient as zero (Higgins 2011b).

For network meta‐analysis, we will use all groups of studies with more than two groups. For pair‐wise analysis, we will first judge if multiple interventions are eligible for the analysis. If not, we will only choose the eligible group for analysis; if yes, we will split the control groups into a smaller sample size (to avoid double counting) and include two or more (reasonably independent) comparisons.

Dealing with missing data

We will evaluate the number of randomised and analysed participants. When required, we will make requests by email for missing data, (i.e. numbers of events and numbers of participants for dichotomous outcomes, mean difference with standard deviation and number of participants for continuous outcomes) from trial authors or sponsors. For the main analysis, we will assume that any participant with missing outcome data did not experience clearance, whatever the group. We will also synthesise data as analysed in each trial (complete cases). Additional sensitivity analysis will be conducted to check the robustness of the main results by excluding studies with missing data.

Assessment of heterogeneity

We will assess clinical and methodological heterogeneity by carefully examining the characteristics and design of included trials. We will calculate the statistical heterogeneity using Chi² and I² statistics.

We will undertake meta‐analyses only if we judge participants, interventions, comparisons, and outcomes to be sufficiently similar (section 9.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a)). Potential sources of heterogeneity or inconsistency include participant baseline characteristics (weight, the duration of eczema), previous treatment, treatment doses, and duration of treatment. When feasible, we will investigate these sources of heterogeneity or inconsistency in subgroup analyses. We will investigate the distributions of these characteristics across studies and treatment comparisons. The latter allows us to assess transitivity, i.e. that there are no important differences between the trials making different comparisons other than the treatments being compared.

These are the three assumptions that should be met before proceeding to a network meta‐analysis. We will check these by producing PICO tables to check for design and methodological homogeneity (to validate pooling of head‐to‐head studies), similarity (to validate the indirect treatment comparisons), and consistency (to validate the pooling of direct and indirect evidence).

Assessment of transitivity across treatment comparisons

We will assess the assumption of transitivity by comparing the distribution of the potential effect modifiers across the different pair‐wise comparisons.

Assessment of local inconsistency

We will adopt a side‐splitting method in each comparison, to evaluate the potential loop inconsistency between estimates from direct and indirect evidence. This method evaluates the consistency assumption in every comparison in the network (Dias 2010). Then, the magnitude of the inconsistency factors and their 95% CIs can be used to infer about the presence of inconsistency in each loop.

Assessment of global inconsistency

To check the global inconsistency, we will use the design‐by‐treatment model. This method accounts for different sources of inconsistency that can occur when studies with different designs (two‐arm trials versus three‐arm trials) give different results, as well as disagreement between direct and indirect evidence (i.e. loop inconsistency). Using this approach, we will infer about the presence of inconsistency from any source in the entire network based on a global Wald test (Higgins 2012; White 2012).

Assessment of reporting biases

We will assess reporting bias using funnel plots. We will use funnel plot asymmetry tests for pair‐wise meta‐analysis, provided validity conditions are met (low heterogeneity, 10 or more studies with at least one with significant results, and a ratio of the maximal to minimal variance across studies greater than four (Ioannidis 2007)), and comparison‐adjusted funnel plots for network meta‐analysis. We will assess small‐study effects and related reporting bias for primary outcomes. In cases of evidence of small‐trial effects, we will perform sensitivity analyses according to a regression‐based adjustment model for every comparison with direct evidence available (Moreno 2009).

Data synthesis

Pair‐wise analysis

For dichotomous data (e.g. occurrence of adverse effects), we will apply a Mantel‐Haenszel analysis method, using a random‐effects model to estimate the pooled effect estimate. We will report risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect. For continuous data (i.e. clinical severity, participant‐reported symptoms, quality of life scale, and global response of improvement), we will use an inverse variance analysis method with a random‐effects model. We will report mean difference (MD), or standardised mean difference (SMD) if the same outcome is measured with different measurement tools, with 95% CI for the treatment effect measure.

Network meta‐analysis

We will implement a network meta‐analysis that estimates all possible comparisons between treatments, two by two. As recommended, we will examine individual trial reports and use individual trial data in our analyses. We will provide graphical depiction of the evidence network (i.e. we will assess the network geometry (Salanti 2011)), and then we will perform network meta‐analyses (Lu 2004). We will perform network meta‐analysis using a random‐effects model in Stata with the mvmeta command within the network suite of commands for network meta‐analysis (StataCorp 2017; White 2015). We will use other Stata commands for visualising and reporting results in network meta‐analysis, together with ranking of the various interventions (Chaimani 2015). We will include a table showing the direct, indirect, and network meta‐analysis estimates.

We will interpret a statistically non‐significant P value (e.g. larger than 0.05) as a finding of uncertainty, unless confidence intervals are sufficiently narrow to rule out an important magnitude of effect.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses:

1. age (e.g. children (age ≤ 12 years, age >12 years) versus adults);

2. sites of treatment;

3. treatment frequency;

4. duration of treatment;

5. study participants with previous inadequate response to topical corticosteroids (this will provide information to better evaluate newer agents that have been developed and marketed for the patient pool who do not respond adequately to topical corticosteroids, or in whom corticosteroids are contraindicated).

Formal statistical tests will be used to compare the differences between the subgroups, by adding the subgroup factor into the random‐effects model and testing its statistical significance in the model. If the P value for the factor is less than 0.05, we will consider the difference between the subgroup to be significant.

Sensitivity analysis

We will perform sensitivity analyses by excluding studies with high risk of bias. In cases of evidence of small‐trial effects, we may perform sensitivity analysis based on a network meta‐regression model, which assumes that biases are exchangeable across comparisons (Trinquart 2012).

Summary of findings and assessment of the certainty of the evidence

We will use the 'Summary of findings' table to summarise the key results of the review using the Confidence in Network Meta‐analysis (CINeMA) framework (Salanti 2014). We will include the following outcomes:

1. Clinical severity;

2. Participant‐reported symptoms;

3. Adverse events.

The key comparisons of this review are between the use of the newer non‐steroidal topicals and the standard conventional therapy of topical steroids. Therefore, we will be focusing on the following comparisons in our 'Summary of findings' tables:

A) Topical calcineurin inhibitors (TCIs) versus appropriate potency topical corticosteroids (TCS)

1. Topical pimecrolimus versus mild to moderate topical corticosteroids (TCS)

2. Topical tacrolimus 0.1% versus once‐daily TCS, such as mometasone or fluticasone

3. Topical tacrolimus 0.03% versus moderate TCS, such as clobetasone butyrate

B) Head to head comparisons between topical pimecrolimus versus topical tacrolimus

1. Topical pimecrolimus versus topical tacrolimus 0.03%

2. Topical pimecrolimus versus topical tacrolimus 0.1%

C) Topical crisaborole versus mild to moderate potency TCS

D) Emerging new topicals versus mild to moderate potency TCS

We will use the five GRADE criteria (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to evaluate the quality of a body of evidence as it relates to the studies that contributed data to the meta‐analysis for each prespecified outcome. Two review authors (YWY and ZQ) will independently make the judgements about quality of the evidence (high, moderate, low, or very low), and resolve disagreements by discussion (Salanti 2014).

What's new

Date	Event	Description
16 June 2020	Amended	Progress on this title has stalled and Cochrane Skin is waiting further resources to support its delivery.

History

Protocol first published: Issue 11, 2018

Notes

Progress on this title has stalled and Cochrane Skin is waiting further resources to support its delivery.

Appendices

Appendix 1. Hanifin and Rajka Diagnostic Criteria

Three or more basic features: Pruritus Typical morphology and distribution: Flexural lichenification or linearity in adults Facial and extensor involvement in infants and children Chronic or chronically‐relapsing dermatitis Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Plus 3 or more minor features:
Xerosis Ichthyosis/palmar hyperlinearity, keratosis pilaris Nipple eczema Cheilitis Recurrent conjunctivitis Dennie‐Morgan infraorbital fold Keratoconus Anterior subcapsular cataracts Orbital darkening Facial pallor, facial erythema Pityriasis alba Anterior neck folds White dermatographism, delayed blanch	Immediate (type 1) skin test reactivity Elevated serum IgE Early age of onset Tendency toward cutaneous infections (especially S. aureus & HSV), impaired cell‐mediated immunity Tendency toward non‐specific hand or foot dermatitis Itch when sweating Intolerance to wool or lipid solvents Perifollicular accentuation Food intolerance Course influenced by environmental or emotional factors (or both)

Appendix 2. UK Working Party Diagnostic Criteria

Mandatory: An itchy skin condition (parental report of scratching or rubbing in a child)

Plus 3 or more of the following:

History of involvement of the skin creases, such as folds of elbow, behind the knees, fronts of ankles, or around the neck (including cheeks in children under 10) A personal history of asthma or hay fever (or history of AD in a first‐degree relative in children under 4) History of general dry skin in the last year Visible flexural eczema (or eczema involving the cheeks, forehead, and outer limbs in children under 4) Onset under the age of 2 (not used if child is under 4)

Appendix 3. Draft search strategy MEDLINE Ovid

1. exp Eczema/ or eczema.ti,ab.
2. exp Dermatitis, Atopic/
3. neurodermatitis.ti,ab. or exp Neurodermatitis/
4. exp Dermatitis/ or dermatitis.ti,ab.
5. besnier$ prurigo.mp.
6. prurigo diathesique.mp.
7. or/1‐6
8. (topical$ adj3 corticosteroid$).ti,ab.
9. (topical$ adj3 steroid$).ti,ab.
10. exp Desonide/
11. alclometasone dipropionate.mp.
12. amcinonide.mp.
13. Beclomethasone/ or beclometasone dipropionate.mp.
14. exp Betamethasone/ or betamethasone benzoate.mp.
15. Betamethasone butyrate propionate.mp.
16. betamethasone dipropionate.mp.
17. (betamethasone adj2 valerate).mp.
18. budesonide.mp. or exp Budesonide/
19. clobetasol.mp. or exp Clobetasol/
20. clobetasone.mp.
21. clocortolone pivalate.mp.
22. (exp Cortisone/ or cortisone.ti,ab.) and (exp Administration, Topical/ or exp Ointments/ or Dermatologic Agents/)
23. Crisaborole.mp.
24. Deprodone propionate.mp.
25. desonide.mp.
26. exp Desonide/
27. desoximetasone.mp. or exp Desoximetasone/
28. exp Dexamethasone/ or dexamethasone.mp.
29. diflorasone.mp.
30. exp Diflucortolone/ or diflucortolone.mp.
31. eucrisa.mp.
32. fluclorolone.mp.
33. fludroxycortide.mp.
34. flumetasone.mp.
35. exp Flumethasone/
36. fluocinolone acetonide.mp. or exp Fluocinolone Acetonide/
37. fluocinonide.mp. or exp Fluocinonide/
38. fluocortin.mp.
39. exp Fluocortolone/
40. fluocortolone.mp.
41. fluprednidene.mp.
42. flurandrenolide.mp.
43. flurandrenolone acetonide.mp. or exp Flurandrenolone/
44. fludroxycortide.mp.
45. fluticasone.mp.
46. halcinonide.mp. or exp Halcinonide/
47. halobetasol.mp.
48. halometasone.mp.
49. exp Hydrocortisone/
50. (hydrocortisone or cortisol).ti,ab. and (exp Administration, Topical/ or exp Ointments/ or Dermatologic Agents/)
51. hydrocortisone butyrate.mp.
52. hydrocortisone aceponate.mp.
53. hydrocortisone acetate.mp.
54. hydrocortisone valerate.mp.
55. masipredone hydrochloride.mp.
56. exp Methylprednisolone/ or methylprednisolone aceponate.mp.
57. methylprednisolone acetate.mp.
58. mometasone.mp.
59. phosphodiesterase inhibitors.mp.
60. pimecrolimus.mp.
61. prednicarbate.mp.
62. (exp Prednisolone/ or prednisolone.ti,ab.) and (exp Administration, Topical/ or exp Ointments/ or Dermatologic Agents/)
63. Prednisolone valerate acetate.mp.
64. triamcinolone.mp. or exp Triamcinolone/
65. ulobetasol.mp.
66. exp Tacrolimus/
67. (tacrolimus adj3 (ointment$ or topical$)).mp.
68. protopic.mp.
69. fk506.mp.
70. exp Adrenal Cortex Hormones/ and (exp Administration, Topical/ or exp Ointments/ or Dermatologic Agents/)
71. exp Glucocorticoids/ and (exp Administration, Topical/ or exp Ointments/ or Dermatologic Agents/)
72. (topical$ adj3 glucocorticoid$).mp.
73. (topical$ adj3 corticoid$).mp.
74. exp Phosphodiesterase Inhibitors/
75. exp coal tar/
76. tapinarof.mp.
77. WBI‐1001.mp.
78. tofacitinib.mp.
79. JTE‐052.mp.
80. or/8‐79
81. randomized controlled trial.pt.
82. controlled clinical trial.pt.
83. randomized.ab.
84. placebo.ab.
85. clinical trials as topic.sh.
86. randomly.ab.
87. trial.ti.
88. 81 or 82 or 83 or 84 or 85 or 86 or 87
89. exp animals/ not humans.sh.
90. 88 not 89
91. 7 and 80 and 90

[Lines 81‐90: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision) (Lefebvre 2011)]

Contributions of authors

YWY was the contact person with the editorial base.
YWY co‐ordinated the contributions from the co‐authors and wrote the final draft of the protocol.
ESYC, LS, YKYW, and QZ worked on the methods sections.
YWY, MH, WLK drafted the clinical sections of the background and responded to the clinical comments of the referees.
ESYC, LS, YKYW, and QZ responded to the methodology and statistics comments of the referees.
YWY, MH, WLK, JT, ESYC, LS, YKYW, and QZ contributed to writing the protocol.
YKYW was the consumer co‐author and checked the protocol for readability and clarity. She also ensured that the outcomes were relevant to consumers.
YWY is the guarantor of the final review.

Disclaimer

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Skin Group, and was also supported by the Complex Reviews Support Unit, also funded by the National Institute for Health Research (project number 14/178/29). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Sources of support

Internal sources

• No sources of support supplied

External sources

• The National Institute for Health Research (NIHR), UK

  The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Declarations of interest

Yik Weng Yew: none known
Madeline Ho: none known
Wai Leong Kok: none known
Edwin Chan: none known
Luming Shi: none known
Qishi Zheng: none known
Yoko Wong Kin Yoke: none known
Jeremy Teoh: none known

Edited (no change to conclusions)