Description of the condition
For unfamiliar terms see the Glossary of Terms in Table 1.
|Adverse events||The occurrence of an unwanted effect due to a medication or medical procedure.|
|Antihistamines||Antihistamines (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.|
|Arrhythmia||Irregular heart beat.|
|Atopy||The 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 flare||Vasodilation and increased redness and sensitivity of the skin that is caused by stimulation of the peripheral nerves.|
|Clinical signs||Physician-assessed visible signs of eczema, such as erythema (redness) or dryness.|
|Corticosteroids||A 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 study||A type of clinical trial in which subjects under study receive a sequence of different treatments in a randomly-selected order.|
|Edema||Abnormal accumulation of fluid in or under the skin.|
|Eosinophils||White blood cells, one of the immune system components, that control mechanisms associated with allergy and asthma as well as parasitosis.|
|Emollients||Emollients (or moisturisers) are complex mixtures of chemical agents designed to soften the epidermis (external layers of the skin).|
|Erythema||Redness 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.|
|Excoriations||Skin 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.|
|Filaggrin||A 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.|
|Flexural||Relating to the action of bending or curving e.g. of the skin or a joint.|
|Gene polymorphism||A 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.|
|Glucocorticosteroids||Particular class of corticosteroids. They have various functions within the human body, e.g. in the immune system and metabolism.|
|IgE||A 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-31||Belongs to the group of cytokines. These are mediators that communicate between different cell types. IL stands for interleukin.|
|Immunomodulator||Immunomodulators are pharmacologically-active substances that affect the immune system. Examples of topical immunomodulators that used in the treatment of eczema are tacrolimus and pimecrolimus.|
|Lichenification||The 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.|
|Metabolites||Small molecules which are intermediate or final products of the metabolism.|
|Neuropeptides||Neuropeptides 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.|
|Nodule||A 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.|
|Papule||A 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.|
|Pimecrolimus||An immunomodulating agent used in the treatment of eczema. Pimecrolimus is available as a topical cream.|
|Prurigo||Prurigo 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 interval||Abnormal 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.|
|RCT||Randomised 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.|
|Symptom||Departure 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|
|Tacrolimus||An 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 cells||Th2 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.|
|Tryptase||A 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.|
|Vesicle||A 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.|
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.