Oral H1 antihistamines as ‘add-on’ therapy to topical treatment for eczema

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of oral H1 antihistamines as 'add-on' therapy to topical treatment in adults and children with eczema.

Background

Description of the condition

For unfamiliar terms see the Glossary of Terms in Table 1.

Table 1. Glossary of terms
TermDefinition
Adverse eventsThe occurrence of an unwanted effect due to a medication or medical procedure.
AntihistaminesAntihistamines (or histamine antagonists) are drugs that block the action of histamine (an endogenous messenger substance released e.g. in allergic inflammatory reactions). H1 antihistamines are predominantly used in the treatment of allergies.
ArrhythmiaIrregular heart beat.
AtopyThe term describes a genetic predisposition for hypersensitivity to common antigens (e.g. pollen, house dust or animal dander). Atopy can manifest in atopic diseases such as hay fever, allergic asthma or eczema. Atopy can be associated with increased IgE levels.
Axon reflex flareVasodilation and increased redness and sensitivity of the skin that is caused by stimulation of the peripheral nerves.
Clinical signsPhysician-assessed visible signs of eczema, such as erythema (redness) or dryness.
CorticosteroidsA group of naturally-occurring hormones or synthetic analogues of hormones. Corticosteroids are produced in the adrenal glands. According to their biological function, corticosteroids can be classified into: i) mineralocorticoids (hormones that influence the salt and water balance within the body), ii) glucocorticosteroids (=> see below) and iii) androgen/oestrogen (male/female sex hormones).
Cross-over studyA type of clinical trial in which subjects under study receive a sequence of different treatments in a randomly-selected order.
EdemaAbnormal accumulation of fluid in or under the skin.
EosinophilsWhite blood cells, one of the immune system components, that control mechanisms associated with allergy and asthma as well as parasitosis.
EmollientsEmollients (or moisturisers) are complex mixtures of chemical agents designed to soften the epidermis (external layers of the skin).
ErythemaRedness of the skin (or mucous membranes) that is caused by an increased blood flow into the superficial vessels and capillaries. It can occur e.g. with skin injuries, infections or inflammation.
ExcoriationsSkin lesions caused by repetitive, compulsive scratching of the skin. Of different colours e.g. yellow or red caused by tissue fluid and light bleeding, they are frequently found in patients suffering from itch.
FilaggrinA protein that binds to keratin fibres in the cells to form a functional barrier at the skin surface. There is a defective permeability of the barrier function (skin protecting function) in eczema. Defects of the filaggrin gene contribute to the defective permeability of the outer most layer of the skin.
FlexuralRelating to the action of bending or curving e.g. of the skin or a joint.
Gene polymorphismA gene is said to be polymorphic if more than one allele (one of two or more forms of a gene) occupies that gene’s locus (location of a gene on a chromosome) within a population.
GlucocorticosteroidsParticular class of corticosteroids. They have various functions within the human body, e.g. in the immune system and metabolism.
IgEA class of antibodies (immunoglobulins, Ig). The primary function of IgE within the immune system is to fight endoparasites. However, it is also responsible for some allergic reactions (e.g. local inflammation in eczema, airway constriction in asthma). People with an atopic predisposition often have increased IgE levels.
IL-31Belongs to the group of cytokines. These are mediators that communicate between different cell types. IL stands for interleukin.
ImmunomodulatorImmunomodulators are pharmacologically-active substances that affect the immune system. Examples of topical immunomodulators that used in the treatment of eczema are tacrolimus and pimecrolimus.
LichenificationThe term describes an extensive thickening of the skin accompanied by noticeable skin markings. Lichenification is a symptom of a number of chronic skin diseases, e.g. eczema.
MetabolitesSmall molecules which are intermediate or final products of the metabolism.
NeuropeptidesNeuropeptides are small molecules which can be found in the nervous tissue. They serve as messenger substances used by the nerve cells (neurons) to communicate with each other.
NoduleA palpable solid skin lesion usually 0.5 cm or larger in diameter. It can involve different depths of the skin and can vary in shape and surface.
PapuleA solid elevated palpable lesion usually less than 0.5 cm in diameter. It can have different shapes and surfaces e.g. flat-topped and rough.
PimecrolimusAn immunomodulating agent used in the treatment of eczema. Pimecrolimus is available as a topical cream.
PrurigoPrurigo and prurigo nodularis may be used synonymously. Prurigo describes a condition of nodular cutaneous lesions that itch intensely i.e. are pruritic. Prurigo nodules usually reflect a chronic state of itch and eczema.
Long QT intervalAbnormal pattern seen on the records of the heart's electrical activity measured by electrocardiography (ECG). Long QT-Syndrome is a disorder of the heart's electrical activity which can cause fast and chaotic heartbeats leading to a sudden fainting spell or, in some cases, death.
RCTRandomised controlled trial. A type of scientific study in which the subjects of the study population are allocated randomly into an experimental, placebo or control group. RCTs are often conducted to test the effectiveness of a new medication or medical procedure.
SymptomDeparture from normal function or feeling that is noticed by a patient, indicating the presence of disease or abnormality (Knol 2011), e.g. sleep loss, itching
TacrolimusAn immunosuppressive drug used mainly after organ transplantation to lower the risk of organ rejection. Tacrolimus is also used, among other indications, in a topical preparation for the treatment of eczema.
Th2 helper cellsTh2 helper cells are a functionally distinct subclass of T helper cells (lymphocytes, white blood cells) that play an important role in the immune system. They can stimulate IgE synthesis and are critical for favouring the differentiation of eosinophile granulocytes. They activate the release of local mediators that cause sneezing, coughing, or eczema.
TryptaseA protein-splitting enzyme (proteinase) that is produced by mast cells. These cells are located in the human dermis. Proteinases play a role in regulation of the immune response and cutaneous inflammation.
VesicleA cavity (smaller than 0.5 cm) filled with fluid. It may be non-palpable in thicker skin (e.g. palms, soles), breaks easily and releases its fluid onto the skin.

Definition

The variable use of the terms 'eczema', 'atopic eczema', and 'atopic dermatitis' has resulted in some confusion and inconsistency in their application. The nomenclature review committee of the World Allergy Organization (WAO) has proposed the use of the word 'eczema' as a unifying term (Johansson 2004) and therefore 'eczema' will be used universally throughout this review.

Eczema is a chronic inflammatory non-infectious skin disease. It is among the most common of skin diseases, which, although predominantly affecting children, may also persist into adulthood (Thomas 2008). The main sites of eczema migrate from infancy to childhood. The final typical location is in the folds of the elbows, the hollows of the knees and frequently also in the neck in adolescence and adulthood (Archer 2000; Thomas 2008).

Clinical features and symptoms

Eczema is characterised by an itchy red rash, but it may also present with a wide spectrum of clinical signs such as erythema, papules, vesicles, prurigo nodules, crusts, scales, dry skin and lichenification (Hanifin 1980). Burning, pain, and itch are the most frequent and distressing symptoms. It has been stated that “the diagnosis of eczema cannot be made if there is no history of itch” (Hanifin 1980). People with eczema often feel a strong urge to scratch as a consequence of itching (Darsow 2012). Scratching, together with skin inflammation, frequently produces a reddening of the skin. The symptoms of eczema can lead to sleeplessness, fatigue and may have a substantial impact on the quality of life of those affected.

Various sets of diagnostic criteria for eczema have been developed and validated, but there is no consensus about their use (Brenninkmeijer 2008). The most extensively validated and widely used set of diagnostic criteria has been proposed by a United Kingdom (UK) working party (Williams 1994). According to these criteria, an individual must have an itchy skin condition in the last 12 months, plus 3 or more of the following criteria: onset in the first 2 years of life, a history of flexural involvement, a history of generalised dry skin, a history of other atopic disease, visible flexural dermatitis.

Epidemiology and causes

In many countries, eczema is the most frequently encountered chronic condition during infancy, but there is wide variation in prevalence at global level. Recent data from the International Study of Asthma and Allergies in Childhood (ISAAC) have shown that the prevalence of eczema (itchy flexural rash in the past 12 months) ranges from 0.9% to 22.5% in 6 and 7 year old children, and from 0.2% to 24.6% in the age group 13 to 14 years (Odhiambo 2009). For adults, recent studies have estimated the one year prevalence at 14.3% (Vinding 2014) and 10.2% (Silverberg 2013a) in Denmark and the United States (US), respectively.

Eczema is a complex disease and is most likely to be caused through gene and environmental interactions. In addition to allergic sensitisation and gene polymorphisms, a large number of environmental and lifestyle factors are potentially involved in the aetiology. These include pet exposure, breastfeeding and tobacco smoke (Apfelbacher 2011), climate factors (Silverberg 2013b) and microbial exposure (Flohr 2014).

It has been thought that an immunological defect in the Th2 helper cells may give rise to increased IgE production (Bieber 2008). Moreover, as a result of abnormal lipid metabolism or epidermal protein formation (e.g. caused by filaggrin mutation (Baurecht 2007)), the skin barrier in eczema functions poorly and gives rise to dry skin. Skin inflammation and epidermal barrier disruptions are phenomena that reinforce each other (Weidinger 2016).

The rate of microbial colonisation of the skin is caused by a number of defects in the innate cutaneous immunology, for example with staphylococcus aureus colonisation in eczema (Ring 2012a). Psychological factors such as stress can influence the clinical course of eczema and the itch-scratch cycle (Ring 2012b). Other co-factors can have an effect, such as: abnormal microbial colonisation leading to skin infections; and psychosomatic factors influencing the autonomic nerve system and production of mediators like, for example, neuropeptides and eosinophils (Bieber 2009; Buddenkotte 2010; Ring 2012a; Ring 2012b).

Description of the intervention

There is a range of topical and systemic management options for eczema, in addition to other therapies such as ultraviolet (UV) phototherapy. Oral H1 antihistamines (H1 receptor antagonists) are widely used as systemic 'add-on' therapy to topical treatments which include glucocorticosteroids, immunomodulators such as pimecrolimus or tacrolimus, tar preparations, anti-infective topicals and doxepin (Ring 2012a). Four distinct types of histamine receptors are recognised: H1 involved in allergic responses, H2 in gastric acid secretion, H3 in neurotransmission and H4 in immune responses. H1 antihistamines are especially prescribed with the intention of alleviating the itch accompanying eczema (Greaves 2005).

Agitation, confusion, somnolence, tachycardia, constipation, urinary retention and adverse cardiac reactions have been reported as adverse effects of antihistamines, particularly of first-generation antihistamines such as chlorpheniramine (Yanai 2012). Because of side effects such as sedation and drowsiness, the use of these drugs has been limited in the daytime (Greaves 2005).

The aim of developing antihistamines of the second generation (such as astemizole or terfenadine) which do not penetrate the blood-brain barrier was to produce more tolerable agents without sedative side effects, but with the same effectiveness as first-generation antihistamines (Kay 2000). Motor and cognitive function are substantially less impaired with the use of second-generation antihistamines (Herman 2003). However, astemizole and terfenadine have been found to cause ventricular tachycardia, although this occurs rarely (Woosley 1996).

The goal of the development of a third generation of antihistamines was to produce agents that are not cardiotoxic, by using therapeutically-active metabolites of established parent drugs (Handley 1998). Fexofenadine, for instance, is the active metabolite of terfenadine.

How the intervention might work

The pathophysiology of itch (pruritus) in eczema is complex (Ständer 2002). Acetycholine and histamine provoke itch by directly binding to itch receptors. Mediators such as cytokines, neuropetides and proteases indirectly contribute as they are thought to play a role in the release of histamine.

Antihistamines used in eczema are histamine 1 (H1)-blockers. H1 antihistamines suppress histamine's actions such as itch, increased vascular permeability of the skin, histamine release that is IgE mediated, and local vasodilation (Greaves 2005).

The use of systemic antihistamines as adjuvant therapy together with topical agents such as, for example, topical corticosteroids or topical immune modulators in eczema (Kawashima 2003) is based on the idea that combining the anti-inflammatory effects of topical treatments with blocking the action of histamine on its receptors in the skin by H1 antihistamines might magnify or intensify the effect of treatment (Greaves 2005; Kawashima 2003).

Why it is important to do this review

The first systematic review on the use of antihistamines in atopic dermatitis was performed in 1999 (Klein 1999). Sixteen studies were included, but 13 of these lacked randomisation, had no placebo group or had fewer than 20 participants per group. Of the three remaining studies, two trials refuted and one trial supported the use of antihistamines in relieving pruritus in atopic dermatitis.

As part of a comprehensive health technology assessment of treatments available for atopic eczema, randomised controlled trials investigating the effects of antihistamines in atopic eczema were summarised in an HTA report (Hoare 2000). The authors identified 21 RCTs of any oral antihistamines for the treatment of atopic eczema. Of these, studies investigating sedating antihistamines or studies investigating H2 antihistamines (alone or combined with H1 antihistamines) were unable to demonstrate a clear benefit of the intervention. Studies investigating less sedating antihistamines showed conflicting results. For instance, one RCT investigated the effect of various doses of cetirizine, demonstrating a possible effect for a very high dose (Hannuksela 1993). Generally, the authors of the HTA report state that study reporting was poor, rendering it difficult to draw firm conclusions. We believe that it is important to update the evidence base 16 years after the publication of the HTA report.

A systematic search of the literature was also undertaken to inform the guideline of care for the management of atopic dermatitis by the American Academy of Dermatology (AAD) (Sidbury 2014). It concluded that the short-term, intermittent use of sedating antihistamines may bring some benefit in the case of sleeping problems arising as a consequence of itch. No recommendation was made for non-sedating antihistamines as a routine treatment for eczema. One of the studies cited is the Early Treatment of the Atopic Child (ETAC) trial in which infants from 12 to 24 months of age were randomised to either cetirizine or placebo for a period of 18 months (Diepgen 2002). No significant difference in the control of eczema between the groups was found. The evidence was graded using a three-point scale that combines considerations of study design (including e.g. cohort studies and case series) with the “overall focus” (patient-oriented evidence versus disease-oriented evidence) of the study.

We will only look at RCTs and will perform a comprehensive 'Risk of bias' assessment for each of the included studies. Of note, none of the three systematic reviews mentioned has undertaken a meta-analysis, which we will attempt following an analysis of heterogeneity.

A recent systematic review did not identify any randomised controlled trial investigating single use of oral H1 antihistamines versus placebo for eczema, so currently no evidence exists to support or refute the effectiveness of H1 antihistamines used alone (Apfelbacher 2013). It seems that physicians and researchers alike are reluctant to withhold anti-inflammatory topical treatment from patients for ethical reasons on the grounds of established effectiveness. However, in clinical practice, antihistamines are often used as 'add-on' therapy to topical treatment in the management of eczema. It is therefore important to systematically review studies investigating whether adding H1 antihistamines to topical treatment improves eczema over and above the improvement due to topical treatment alone.

Objectives

To assess the effects of oral H1 antihistamines as 'add-on' therapy to topical treatment in adults and children with eczema.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

People of all ages with a clinical diagnosis of eczema, identified as 'atopic eczema' or 'eczema', which was made by either a dermatologist or a physician. If the diagnosis was confirmed by a general medical practitioner this must have involved the use of standardised diagnostic criteria such as the Hanifin and Rajka definitions (Hanifin 1980) or the UK modification (Williams 1994).

Other forms of eczema such as those caused by, for example, contact allergens, skin irritants or mixed forms of eczema will be excluded.

Types of interventions

Oral antihistamines (H1-antagonists) of all classes (sedating, non-sedating), as add-on therapy to topical treatment  for eczema, e.g. topical corticosteroids, topical immunomodulators or other topical eczema therapy or both.

The comparators will be placebo as an add-on therapy to topical treatment, or no additional treatment as add-on therapy to topical treatment. 

Types of outcome measures

These pre-specified outcomes will not be considered as criteria for study eligibility. See section 5.1.2 of the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1 (Higgins 2011). The outcomes include the core outcome set as suggested by the Harmonising Outcome Measures in Eczema (HOME) initiative (Schmitt 2012; Schmitt 2014): clinical signs, symptoms, quality of life and long-term control of flares.

We will consider outcomes measured up to 1 week (short term), 1 to 6 weeks (medium term) and greater than 6 weeks (long term) separately.

Primary outcomes
  1. Mean change in patient-assessed symptoms of eczema, as measured by a standardised or validated eczema symptoms score (e.g. Visual Analogue Scale for itching, Patient Oriented Eczema Measure (Charman 2004))

  2. Proportion of participants reporting adverse effects, and serious adverse events throughout the study period

Secondary outcomes
  1. Mean change in physician-assessed clinical signs, as measured by a standardised or validated eczema signs score (e.g. Eczema Area and Severity Index (Hanifin 2001) or SCORing Atopic Dermatitis index (ETFAD 1993))

  2. Mean change in quality of life, as measured by a standardised or validated quality of life measure (e.g. Dermatology Life Quality Index (Finlay 1994))

  3. Number of eczema flares, measured by, e.g. ‘escalation of treatment’ or ‘use of topical anti-inflammatory medications’ (Thomas 2015)

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

We will search the following databases for relevant trials:

  • the Cochrane Skin Group Specialised Register;

  • the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library;

  • MEDLINE via Ovid (from 1946);

  • EMBASE via Ovid (from 1974);

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

We have devised a draft search strategy for RCTs for MEDLINE (Ovid), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.

Trials registers

Two review authors (MB and EW) will search for ongoing trials in the following databases using the terms: eczema, atopic eczema, atopic dermatitis.

Searching other resources

References from published studies

Two review authors (EW and MB) will examine the bibliographies of the included and excluded studies for further references to potentially-eligible RCTs.

Adverse effects

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

Conference proceedings

Two review authors will scan the abstracts from the International Research Workshops on eczema and the conference proceedings of the European Academy of Dermatology and Venereology (EADV) from 2010 to 2015, the European Academy of Allergy and Clinical Immunology (EAACI) from 2010 to 2015, and of the American Academy of Dermatology (AAD) from 2012 to 2015, for further relevant RCTs.

Data collection and analysis

Some parts of the methods section of this review use text that was originally published in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Some parts of the methods section of this protocol use text that was originally published in other Cochrane protocols co-authored by BC and authors Esther J van Zuuren and Zbys Fedorowicz (predominantly van Zuuren 2013).

Selection of studies

Two authors (CA and MB) will independently assess the abstracts of trials resulting from the searches. We will obtain full-text copies of studies appearing to meet the inclusion criteria, or those with insufficient detail to make a clear decision from the title and abstract. Two authors (CA and MB) will independently review the full-text papers and disagreements over eligibility will be resolved by discussion, consensus, or with a third review author (BC).

Details of studies for which we obtained full-text copies but which we excluded will be listed with the reasons for their exclusion noted in the 'Characteristics of excluded studies' table in RevMan 5.3 (Review Manager (RevMan)).

Data extraction and management

Two authors (CA and MB) will enter details of the included trials into the 'Characteristics of included studies' tables in RevMan 5.3 (Review Manager (RevMan). Four authors (CA, MB, AJ, EW) will extract data using a previously developed and piloted data extraction form, and any disagreements on data extraction will be resolved by consensus. If necessary, trial investigators will be contacted and asked to provide missing data or clarify study details. Two authors (CA and MB) will check and enter the data into RevMan 5.3 (Review Manager (RevMan)).

Assessment of risk of bias in included studies

We will assess the risk of bias in included studies according to the guidelines in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The included studies will be assessed independently by two authors (CA and MB) using a simple contingency form and following the domain-based evaluation method (Higgins 2011). In a further step, the results of the evaluations will be compared. In the case of inconsistencies, these will be discussed and resolved within the whole author group.

The authors will assess the following domains as either low, unclear or high risk of bias:

  1. sequence generation;

  2. allocation concealment;

  3. blinding of participants and personnel;

  4. blinding of outcome assessment;

  5. incomplete outcome data addressed;

  6. selective outcome reporting;

  7. other bias.

The assessments for each trial will be reported in the 'Characteristics of included studies' tables and their associated 'Risk of bias' tables.

The authors will also categorise and report the overall risk of bias of each of the included studies according to the following:

  • low risk of bias (plausible bias unlikely to seriously alter the results) if all criteria met;

  • unclear risk of bias (plausible bias that raises some doubt about the results) if one or more criteria assessed as unclear; or 

  • high risk of bias (plausible bias that seriously weakens confidence in the results) if risk of bias is rated as high for any one of the six domains.

Measures of treatment effect

Dichotomous outcomes data will be presented as risk ratios (RR) with associated 95% confidence intervals (CI). Any outcomes that are statistically significant (P < 0.05) will be used to calculate a number needed to treat for an additional beneficial outcome (NNTB).

We will present continuous outcomes as mean differences (MD) with 95% CI. If instruments need to be rescaled, these will be converted to standardised mean differences (SMD).

Unit of analysis issues

Cross-over trials

Unit of analysis issues can arise in studies where participants have been randomised to multiple treatments in multiple periods or where there has been an inadequate wash-out period between interventions. We will analyse these data based on the advice provided in section 16.4.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess the carry-over and period effects descriptively, and if there is a limited suggestion of these effects and there are adequate data, we will carry out a paired analysis.

Studies with multiple treatment groups

Studies that are reported with multiple treatment groups have the potential that participant data will contribute to multiple comparisons. We will assess which comparisons are clinically meaningful and amongst these, may only include those comparisons that address the primary outcome. If multiple pair-wise comparisons are identified, we will follow section 16.5.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and generate a 'shared' group.

Dealing with missing data

For studies less than 10 years old we will contact the investigators or sponsors of these studies where data are missing. We will inspect the missing data for evidence against the assumption that it is missing completely at random (Higgins 2011). If this assumption can be made we will re-analyse the data when and where possible using an ITT principle (section 16.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)).

When analysing dichotomous outcomes, if the investigators undertook a per protocol analysis, we will calculate an ITT analysis where possible by imputation. We will use the missing data after examining the imbalance in the drop-out rates between arms of the study to determine likely bias (section 16.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)).

When analysing continuous outcomes, a per protocol analysis will be conducted instead of using the ITT population.

Assessment of heterogeneity

We will consider the clinical diversity of the studies by observation of the context of the study designs, and statistical heterogeneity by examining the I² summary statistic. Studies will be pooled if the I² statistic is less than 60%, but not pooled if I² is greater than 80%. Where I² is between 60% and 80% and can be explained by a clinical and coherent argument, studies may be pooled into a meta-analysis.

Assessment of reporting biases

Reporting bias will be assessed by following the recommendations of funnel plot asymmetry (Egger 1997), as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Plots will be undertaken for outcomes if at least 10 studies are pooled. If asymmetry is discovered, possible sources will be explored with sensitivity analyses.

Data synthesis

Three review authors (CA, MB and BC) will analyse the data in RevMan (Review Manager (RevMan)) and will report them in accordance with the advice in chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If an adequate number of studies (n > 2) can be found that are clinically homogenous and do not exhibit worse than moderate heterogeneity, they will be entered into a meta-analysis (Treadwell 2006).

For dichotomous data, we will apply a Mantel-Haenszel analysis method using a random-effects model to estimate the pooled effect estimate. For continuous data, an inverse variance analysis method will be used with a random-effects model. A meta-analysis will be partitioned into subgroups, and the global effect across groups will only be presented if it can be interpreted in a meaningful way.

Where results are estimated for individual studies with low numbers of outcomes (< 10 in total) or where the total sample size is less than 30 participants and a risk ratio is used, we will report the proportion of outcomes in each group together with a P value from a Fisher’s Exact test.

Subgroup analysis and investigation of heterogeneity

We will carry out the following subgroup analyses if we identify at least moderate to substantial heterogeneity (as defined above):

  • atopic versus non-atopic participants (i.e. sensitised showing elevated levels of IgE antibodies to inhalant allergens);

  • concomitant hay fever versus no concomitant hay fever;

  • children versus adults;

  • sedating versus non-sedating antihistamines.

Sensitivity analysis

We will carry out sensitivity analyses to assess the robustness of the results of this review; by carrying out the following:

  • If enough studies with a low risk of bias (n > 2) are found, these will be entered into an additional meta-analysis;

  • We will look at those studies that were prospectively registered in clinical trials registers separately.

'Summary of findings' table

We plan to include a 'Summary of findings' table in our review to summarise the following outcomes listed according to priority for the most important comparison:

  1. mean change in eczema symptoms score;

  2. proportion of participants reporting adverse events, and serious adverse events;

  3. mean change in eczema clinical signs score;

  4. mean change in quality of life;

  5. number of eczema flares.

If we feel there are several major comparisons or that our findings need to be summarised for different populations, we will include further 'Summary of findings' tables (Higgins 2011).

We will assess the quality of the body of evidence using the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias), according to section 12.2.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Acknowledgements

The review authors thank the Cochrane Skin Group editorial base and the peer referees for their support and advice during the preparation of the protocol for this review.

The Cochrane Skin Group editorial base wishes to thank Hywel Williams, who was the Dermatology Editor for this protocol; Matthew Grainge and Sonia Ratib, who were the Statistical Editors; Ching-Chi Chi, who was Methods Editor; the clinical referee, Gil Yosipovitch; and the consumer referee, Amanda Roberts.

The authors wish to thank Esther J van Zuuren and Zbys Fedorowicz who were authors on earlier drafts of the protocol.

Disclaimer

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Skin Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service (NHS) or the Department of Health.

Appendices

Appendix 1. Draft MEDLINE (Ovid) search strategy

1. atopic dermatitis.mp.
2. exp Dermatitis, Atopic/
3. neurodermatitis.mp.
4. exp Neurodermatitis/
5. exp Eczema/
6. atopic ekzema.mp.
7. eczema.mp.
8. or/1-7
9. histamine H1 antagonist$.mp.
10. exp Histamine H1 Antagonists/
11. histamine antagonists/
12. exp Ethanolamine/ or ethanolamine.mp.
13. diphenhydramine.mp. or exp Diphenhydramine/
14. clemastine.mp. or exp Clemastine/
15. dimenhydrinate.mp. or exp Dimenhydrinate/
16. doxylamine.mp. or exp Doxylamine/
17. piperazine$.mp. or exp Piperazines/
18. (hydroxizine or hydroxyzine).mp.
19. meclizine.mp. or exp Meclizine/
20. cyclizine.mp. or exp Cyclizine/
21. chlorcyclizine.mp.
22. phenothiazine$.mp. or exp Phenothiazines/
23. chlorpromazine.mp. or exp Chlorpromazine/
24. promethazine.mp. or exp Promethazine/
25. trimeprazine.mp. or exp Trimeprazine/
26. ethylenediamine$.mp. or exp Ethylenediamines/
27. mepyramine.mp. or exp Pyrilamine/
28. tripelenamine.mp.
29. alkylamine.mp.
30. brompheniramine.mp. or exp Brompheniramine/
31. chlorpheniramine.mp. or exp Chlorpheniramine/
32. carbinoxamine.mp.
33. (teldane or terfenadine).mp.
34. exp Terfenadine/
35. astemizole.mp.
36. exp Astemizole/
37. hismanal.mp.
38. loratadine.mp.
39. exp Loratadine/
40. mequitazine.mp.
41. mebhydroline.mp.
42. semprex.mp.
43. fexofenadine.mp.
44. telfast.mp.
45. mizolastine.mp.
46. mizollen.mp.
47. azatadine.mp.
48. cyproheptadine.mp.
49. exp Cyproheptadine/
50. atosil.mp.
51. norastemizole.mp.
52. dimetapp.mp.
53. tavist.mp.
54. dramamine.mp.
55. benadryl.mp.
56. atarax.mp.
57. vistaril.mp.
58. actifed.mp.
59. thorazine.mp.
60. dimetane.mp.
61. (zyrtec or cetirizine).mp.
62. exp Cetirizine/
63. periactin.mp.
64. claritine.mp.
65. seldane.mp.
66. allegra.mp.
67. desloratadine.mp.
68. aerius.mp.
69. urtimed.mp.
70. rupatadine.mp.
71. or/9-70
72. randomized controlled trial.pt.
73. controlled clinical trial.pt.
74. randomized.ab.
75. placebo.ab.
76. clinical trials as topic.sh.
77. randomly.ab.
78. trial.ti.
79. 72 or 73 or 74 or 75 or 76 or 77 or 78
80. exp animals/ not humans.sh.
81. 79 not 80
82. 8 and 71 and 81

What's new

DateEventDescription
6 June 2016AmendedAcknowledgement added

Contributions of authors

Run search - Cochrane Skin Group
Identify relevant titles and abstracts from searches - AJ, EW, MMB
Obtain copies of trials - CA, EW, MMB
Select trials - CA, AJ, EW, MMB
Extract data from trials - CA, AJ, EW, MMB
Enter data into RevMan - MMB, CA
Carry out analysis - MMB, BC
Interpret data - CA, MMB, EW, BC
Draft final review - CA, AJ, BC, EW and MMB
Update review - CA, AJ, BC, EW and MMB

Declarations of interest

There are no financial conflicts of interest; the authors declare that they do not have any associations with any parties who may have vested interests in the results of this review.

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.

Ancillary