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

Uwe Matterne; Merle Margarete Böhmer; Elke Weisshaar; Aldrin Jupiter; Ben Carter; Christian J Apfelbacher

doi:10.1002/14651858.CD012167.pub2

. 2019 Jan 22;2019(1):CD012167. doi: 10.1002/14651858.CD012167.pub2

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

Uwe Matterne ¹, Merle Margarete Böhmer ¹, Elke Weisshaar ², Aldrin Jupiter ², Ben Carter ³, Christian J Apfelbacher ^1,^✉

Editor: Cochrane Skin Group

PMCID: PMC6360926 PMID: 30666626

Abstract

Background

The symptoms of eczema can lead to sleeplessness and fatigue and may have a substantial impact on quality of life. Use of oral H1 antihistamines (H1 AH) as adjuvant therapy alongside topical agents is based on the idea that combining the anti‐inflammatory effects of topical treatments with the blocking action of histamine on its receptors in the skin by H1 AH (to reduce the principal symptom of itch) might magnify or intensify the effect of treatment. Also, it would be unethical to compare oral H1 AH alone versus no treatment, as topical treatment is the standard management for this condition.

Objectives

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

Search methods

We searched the following databases up to May 2018: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database (Global Resource of EczemA Trials; from inception). We searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We also searched the abstracts of four conference proceedings held between 2000 and 2018.

Selection criteria

We sought RCTs assessing oral H1 AH as 'add‐on' therapy to topical treatment for people with eczema compared with topical treatment plus placebo or no additional treatment as add‐on therapy.

Data collection and analysis

We used standard Cochrane methodological procedures. Primary outcome measures were 'Mean change in patient‐assessed symptoms of eczema' and 'Proportion of participants reporting adverse effects and serious adverse events'. Secondary outcomes were 'Mean change in physician‐assessed clinical signs', 'Mean change in quality of life', and 'Number of eczema flares'.

Main results

We included 25 studies (3285 randomised participants). Seventeen studies included 1344 adults, and eight studies included 1941 children. Most studies failed to report eczema severity at baseline, but they were conducted in secondary care settings, so it is likely that they recruited patients with more severe cases of eczema. Trial duration was between three days and 18 months. Researchers studied 13 different H1 AH treatments. We could not undertake pooling because of the high level of diversity across studies in terms of duration and dose of intervention, concomitant topical therapy, and outcome assessment. Risk of bias was generally unclear, but five studies had high risk of bias in one domain (attrition, selection, or reporting bias). Only one study measured quality of life, but these results were insufficient for statistical analysis.

Although this review assessed 17 comparisons, we summarise here the results of three key comparisons in this review.

Cetirizine versus placebo

One study compared cetirizine 0.5 mg/kg/d against placebo over 18 months in 795 children. Study authors did not report patient‐assessed symptoms of eczema separately for pruritus. Cetirizine is probably associated with fewer adverse events (mainly mild) (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.46 to 1.01) and the need for slightly less additional H1 AH use as an indication of eczema flare rate (P = 0.035; no further numerical data given). Physician‐assessed clinical signs (SCORing Atopic Dermatitis index (SCORAD)) were reduced in both groups, but the difference between groups was reported as non‐significant (no P value given). Evidence for this comparison was of moderate quality.

One study assessed cetirizine 10 mg/d against placebo over four weeks in 84 adults. Results show no evidence of differences between groups in patient‐assessed symptoms of eczema (pruritus measured as part of SCORAD; no numerical data given), numbers of adverse events (RR 1.11, 95% CI 0.50 to 2.45; mainly sedation, other skin‐related problems, respiratory symptoms, or headache), or physician‐assessed changes in clinical signs, amount of local rescue therapy required, or number of applications as an indicator of eczema flares (no numerical data reported). Evidence for this comparison was of low quality.

Fexofenadine versus placebo

Compared with placebo, fexofenadine 120 mg/d taken in adults over one week (one study) probably leads to a small reduction in patient‐assessed symptoms of pruritus on a scale of 0 to 8 (mean difference (MD) ‐0.25, 95% CI ‐0.43 to ‐0.07; n = 400) and a greater reduction in the ratio of physician‐assessed pruritus area to whole body surface area (P = 0.007; no further numerical data given); however, these reductions may not be clinically meaningful. Results suggest probably little or no difference in adverse events (mostly somnolence and headache) (RR 1.05, 95% CI 0.74 to 1.50; n = 411) nor in the amount of 0.1% hydrocortisone butyrate used (co‐intervention in both groups) as an indicator of eczema flare, but no numerical data were given. Evidence for this comparison was of moderate quality.

Loratadine versus placebo

A study of 28 adults compared loratadine 10 mg/d taken over 4 weeks versus placebo. Researchers found no evidence of differences between groups in patient‐assessed pruritus, measured by a 100‐point visual analogue scale (MD ‐2.30, 95% CI ‐20.27 to 15.67); reduction in physician‐assessed clinical signs (SCORAD) (MD ‐4.10, 95% CI ‐13.22 to 5.02); or adverse events. Study authors reported only one side effect (folliculitis with placebo) (RR 0.25, 95% CI 0.01 to 5.76). Evidence for this comparison was of low quality. Number of eczema flares was not measured for this comparison.

Authors' conclusions

Based on the main comparisons, we did not find consistent evidence that H1 AH treatments are effective as 'add‐on' therapy for eczema when compared to placebo; evidence for this comparison was of low and moderate quality. However, fexofenadine probably leads to a small improvement in patient‐assessed pruritus, with probably no significant difference in the amount of treatment used to prevent eczema flares. Cetirizine was no better than placebo in terms of physician‐assessed clinical signs nor patient‐assessed symptoms, and we found no evidence that loratadine was more beneficial than placebo, although all interventions seem safe.

The quality of evidence was limited because of poor study design and imprecise results. Future researchers should clearly define the condition (course and severity) and clearly report their methods, especially participant selection and randomisation; baseline characteristics; and outcomes (based on the Harmonising Outcome Measures in Eczema initiative).

Plain language summary

Do H1 antihistamine tablets or liquids help improve eczema symptoms in people who are already using creams or ointments for their eczema?

Review question

Are H1 antihistamines (which inhibit the action of chemicals released as part of an allergic reaction; known as 'histamines'), taken as tablets or liquid, effective and safe in people of any age with diagnosed eczema, if given in addition to creams and ointments, compared to treatment with an inactive substance (placebo) or nothing added to creams and ointments?

Background

Eczema (also known as 'atopic eczema/dermatitis') is a skin disorder frequently affecting both children and adults. In developed countries, 10% to 20% of all people are affected by eczema during their lifetime. The main symptom is itch, which results in scratching and, together with skin inflammation, frequently produces reddening of the skin. The symptoms of eczema can lead to sleeplessness and fatigue, lowering quality of life. Antihistamines are frequently given for itch (specifically H1 antihistamines taken by mouth), and they may alleviate the symptoms of eczema when given in addition to conventional treatments directly applied to the skin (e.g. emollients, moisturisers, steroid creams), although they are not thought to cure it. Many antihistamines are available without prescription, for instance, cetirizine or loratadine. Although H1 antihistamines are frequently prescribed for treating eczema, we do not know whether they are effective and safe.

Study characteristics

We searched for relevant studies up to May 2018. We included 25 randomised controlled trials with 3285 participants of all ages with diagnosed eczema. Eight studies included children or adolescents, and 17 included adults. The gender of participants and the severity of symptoms often were not reported. All studies were conducted in secondary care settings, including hospital clinics, research clinics, dermatology centres, and surgery centres, meaning that participants were likely to have more severe eczema than if recruitment occurred from first point of contact settings (i.e. primary care). All but one study compared H1 antihistamine versus placebo. Researchers studied 13 different H1 antihistamines, most of which were less sedating H1 antihistamines (known as 'second‐generation antihistamines'). Studies lasted between three days and 18 months. Seven trials received funding from pharmaceutical companies; they are the largest trials included in this review.

Key results

We found no convincing evidence that H1 antihistamines help patients with eczema.

One study compared cetirizine 0.5 mg/kg/d versus placebo (in children over a period of 18 months). No data were provided on patient‐assessed itch symptoms of eczema. Cetirizine is probably associated with fewer (mainly mild) adverse events and the need for slightly less additional H1 antihistamine to prevent flares. Even though physician‐assessed clinical signs were reduced in both groups, results show no differences between groups (all moderate‐quality evidence).

When compared with placebo, we found no evidence that an increased dose of cetirizine 10 mg/d over four weeks makes a difference in terms of patient‐assessed itch, number of side effects, physician‐assessed signs, or number of eczema flares as measured by the amount of treatment used (all low‐quality evidence). Side effects reported in both groups included drowsiness, skin‐related problems, breathing issues, and headaches.

Compared with placebo, fexofenadine 120 mg/d given to adults for one week probably slightly improves patient‐assessed itch, as well as producing a greater reduction in the area of itch, as assessed by a physician, and it probably makes little or no difference in the number of participants experiencing side effects (mostly drowsiness and headaches) or in the extent of treatment required as an indicator of the number of eczema flares (all moderate‐quality evidence).

We found no evidence of a difference between placebo and loratadine 10 mg/d given to adults for four weeks in patient‐assessed itch, occurrence of side effects, or physician‐assessed signs of eczema (all low‐quality evidence). This study did not measure the number of eczema flares. Study authors reported only one side effect (folliculitis), which occurred with placebo.

Only one study measured quality of life, but results could not be analysed.

Quality of the evidence

For all outcomes across key comparisons, evidence was of low to moderate certainty. Reasons for lowering the quality of evidence include concerns over how studies were carried out and inclusion of too few participants, leading to less accurate results.

Summary of findings

Background

Description of the condition

For unfamiliar terms, see the Glossary of Terms provided in Table 6.

1. Glossary of terms.

Term	Definition
Adverse event	The occurrence of an unwanted effect due to a medication or a medical procedure
Antihistamines	Antihistamines (or histamine antagonists/histamine blockers) 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 heartbeat
Atopy	Describes a genetic predisposition for hypersensitivity to common antigens (e.g. pollen, house dust, animal dander). Atopy can manifest in atopic diseases such as hay fever, allergic asthma, or eczema. Atopy can be associated with increased immunoglobulin E (IgE) levels
Autonomic nervous system	A division of the peripheral nervous system that regulates smooth muscle and gland functioning. As such, it influences the function of internal organs. This is a control system that acts largely unconsciously and regulates bodily functions such as heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal
Axon reflex flare	Vasodilation and increased redness and sensitivity of the skin caused by stimulation of peripheral nerves
Cardiotoxic	Pertaining to the occurrence of heart electrophysiology dysfunction or muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore in circulating blood
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: (1) mineralocorticoids (hormones that influence the salt and water balance within the body), (2) glucocorticosteroids (=> see below), and (3) androgen/oestrogen (male/female sex hormones)
Cross‐over study	A type of clinical trial in which participants under study receive a sequence of different treatments in a randomly selected order
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)
Epidermal	Referring to the epidermis. The epidermis is the protective outer layer of the skin
Epithelial	Pertaining to the thin tissue forming the outer layer of a body's surface and lining the alimentary canal and other hollow structures
Erythema	Redness of the skin (or mucous membranes) that is caused by increased blood flow into superficial vessels and capillaries. This can occur, for example, with skin injury, infection, 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 defective permeability of the barrier function (skin‐protecting function) in eczema. Defects of the filaggrin gene contribute to the defective permeability of the outermost layer of the skin
Flexural	Related 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 1 allele (1 of 2 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, in 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	Pharmacologically active substance that affects the immune system. Examples of topical immunomodulators used in the treatment of eczema are tacrolimus and pimecrolimus
Lichenification	Describes extensive thickening of the skin accompanied by noticeable skin markings. Lichenification is a symptom of a number of chronic skin diseases (e.g. eczema)
Lipid	An organic compound (e.g. fats, oils, hormones) grouped together because components are not soluble in water
Mediators	Intermediary substances or agents that are released from cells to regulate or cause physiological consequences
Metabolites	Small molecules that are intermediate or final products of metabolism
Neuropeptides	Small molecules that can be found in the nervous tissue. They serve as messenger substances used by nerve cells (neurons) to communicate with one another
Nodule	A palpable solid skin lesion usually 0.5 cm or larger in diameter. Can involve different depths of the skin and can vary in shape and surface
Oedema	Abnormal accumulation of fluid in or under the skin
Papule	A solid elevated palpable lesion usually less than 0.5 cm in diameter. Can have different shapes and surfaces (e.g. flat‐topped and rough)
Pimecrolimus	An immunomodulating agent used in the treatment of eczema. Available as a topical cream
Polymorphism	A variation in the DNA that is too common to be due merely to new mutation. A polymorphism must have a frequency of at least 1% in the population
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
Pruritogen	Any substance that causes pruritus
Psychosomatic	Refers to the processes of psychological factors that influence physiological functioning
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 that 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 participants in the study population are allocated randomly to an experimental, placebo, or control group. RCTs are often conducted to test the effectiveness of a new medication or medical procedure
Somnolence	A state of strong desire for sleep, or sleeping for unusually long periods
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)
Tachycardia	A heart rate greater than 100 beats per minute (BPM) in adults. It means that the heart beats too fast
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	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 in favouring the differentiation of eosinophilic 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
Vasodilation	Refers to widening of blood vessels
Ventricular tachycardia	A type of tachycardia that arises from improper electrical activity in the ventricles of the heart
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

	# of studies	Study ID	Type of study /grouping	Duration of intervention	Dose	Concomitant treatment	n randomised
Acrivastine	1	Doherty 1989	Parallel	10 days	24 mg/d	Twice‐daily application of 0.05% clobetasone butyrate ointment and aqueous cream as a soap substitute	27 adults
Azelastine	1	Henz 1998	Parallel	2 weeks	4 mg/d	Unspecified rescue hydrocortisone cream	56 adults
Cetirizine	7	Hannuksela 1993	Parallel	4 weeks	10, 20, 40 mg/d	"The use of emollients (Aqualan L or Novalan, Orion Pharmaceuticals) [was] allowed when it was felt necessary. Patients were given an emollient supply of 100g/week. In the event of failure hydrocortisone cream 1% ...could be used"	178 adults
		Cambazard 2001	Parallel	8 weeks	0.25 mg/kg bw/d; 0.50 mg/kg bw/d; 0.75 mg/kg bw/d; bw = bodyweight	"Patients were allowed to use 1% hydrocortisone (Cremicor) cream as rescue treatment for facial atopic dermatitis and clobetasone butyrate (Eumovatem) as rescue treatment for atopic dermatitis on other parts of the body"	223 children
		Jung 1989	Parallel	1 week	5 and 10 mg/d	"Throughout the duration of the study the patients were asked to apply an antibiotic ointment (Fucicdin) to all their lesions; a topical corticosteroid (Eumovat) was to be used only when absolutely necessary"	98 children
		LaRosa 1994	Parallel	8 weeks	5 to 10 mg/d	This study used disodium cromoglycate and procaterol, and 9 participants (82%) in the placebo group received other drugs, mainly disodium cromoglycate aerosol and nasal and cutaneous administration of topical steroids	23 children
		Henz 1998	Parallel	2 weeks	10 mg	Unspecified rescue hydrocortisone cream	29 adults
		Tharp 1998	Parallel	12 weeks	20 mg/d	This study allowed triamcinolone acetonide	106 adults
		Diepgen 2002	Parallel	18 months	0.5 mg/kg/d	"All concomitant medications were allowed but had  to be recorded by the parents/guardians on the  diary card and by the investigator in the case  report form"	795 children
Chlorpheniramine or chlorpheniramine maleate	3	Frosch 1984	Cross‐over	4 weeks	12 mg/d	"The patients were allowed to use at will a bland greasy ointment which did not contain an antiinflammatory active substance (e.g. vaseline or eucerin). They also received weighed containers of 0.1% betamethasone ointment...."	18 adults
		Munday 2002	Parallel	1 month	2 to 4 mg/d (age dependent) or twice that amount	This study allowed concomitant therapy with 1% hydrocortisone	151 children
		Nuovo 1992*	Cross‐over	2 weeks	16 and 24 mg/d	Concomitant therapy with topical corticosteroid	1 adult
Fexofenadine	1	Kawashima 2003	Parallel	1 week	120 mg/d	"In addition to 0.1% hydrocortisone butyrate twice daily, other topical agents necessary as emollients for the treatment of atopic dermatitis, including preparations containing heparinoids and zinc oxide ointment, were also permitted for concomitant use. All topical drugs for use on the face and head were allowed, along with agents that were considered to have no effect on the drug under investigation. Patients recorded in their diaries the use of 0.1% hydrocortisone butyrate and investigators recorded in clinical records the use of topical drugs or concomitant treatment"	411 adults
Hydroxyzine	1	Monroe 1992	Parallel	1 week	75 mg/d	This study permitted, but did not specify, concomitant treatment	27 adults
Ketotifen	3	Leon 1989	Parallel	9 weeks	2 mg/d	"Only the topical application of cold cream and baths with oat colloid were allowed in both groups"	20 children
		Iikura 1992	Parallel	52 weeks	0.8 to 1.2 mg/d	"Beta2 agonists (by inhaled or oral route) and theophylline were permitted. Use of external preparations (nonsteroidal ointments and mild steroid preparations) was allowed"	121 children
		Falk 1993	Parallel	3 months	2 mg/d	All participants received concomitant 1% hydrocortisone cream and 2 mg dexchlorpheniramine maleate (Polaramine) twice a day systemically	60 adults
Levocetirizine	2	Kircik 2013	Parallel	4 weeks	5 mg/d	Not reported	40 adults
Levocetirizine	2	Simons 2007	Parallel	18 months	0.25 mg/kg/d	Not reported	510 children
Loratadine	4	Monroe 1992	Parallel	1 week	10 mg/d	This study permitted, but did not specify, concomitant treatment	27 adults
		Langeland 1994	Cross‐over	2 weeks	10 mg/d	"emollients and if needed, mild topical steroid ointment (hydrocortisone 17alpha‐butyras)"	16 adults
		Ruzicka 1998	Parallel	2 weeks	5 to 20 mg/d	This study permitted, but did not specify, concomitant treatment	159 adults
		Kimura 2009	Parallel	4 weeks	10 mg/d	This study permitted the use of moisturisers	28 adults
Olopatadine	1	Kuniyuki 2009	Parallel	8 weeks	10 mg/d	Moisturisers were permitted. This study also allowed topical corticosteroids	99 adults
Tazifylline LN 2974	1	Savin 1986	Cross‐over	variable (≥ 3 days)	30 mg/d	Unspecified routine topical treatment	10 adults
Terfenadine	4	Hjorth 1988	Cross‐over	2 weeks	120 mg/d	Not reported	30 adults
		Doherty 1989	Parallel	10 days	180 mg/d	Twice‐daily application of 0.05% clobetasone butyrate ointment and aqueous cream as a soap substitute	30 adults
		Berth Jones 1989	Cross‐over	1 week	240 mg/d	Unspecified steroids and emollients	28 adults
		Nuovo 1992^a	Cross‐over	2 weeks	240 mg/d	Concomitant therapy with topical corticosteroid	1 adult

Study ID	Primary outcome 1	Primary outcome 2	Secondary outcome 1	Secondary outcome 2	Secondary outcome 3
Berth Jones 1989	VAS pruritus (0 to 10)	Adverse events	Severity of excoriations	Not assessed	Not assessed
Cambazard 2001	Pruritus as part of SCORAD but only total SCORAD reported	Adverse events	SCORAD	Not assessed	Amount of topical corticosteroid used
Diepgen 2002	Pruritus as part of SCORAD but only total SCORAD reported	Adverse events	SCORAD	Not assessed	Use of a variety of topical and systemic medications including oral use of H1 antihistamines
Doherty 1989	VAS pruritus (0 to 100)	Not assessed	Number of participants for whom treatment helped itching (physician‐ assessed)	Not assessed	Not assessed
Falk 1993	Pruritus by Likert scale (scaling unclear)	Not assessed	Combination of 5 signs and symptoms (severity of diseased skin, area affected, erythema, lichenification, and pruritus) to a total score	Not assessed	Not assessed
Frosch 1984	Pruritus by VAS (0 to 100)	Adverse events	Number of participants with overall improvement, no overall improvement or overall worsening	Not assessed	Amount of betamethasone used in grams
Hannuksela 1993	Pruritus as part of SCORAD (0 to 100)	Adverse events	Total symptom score	Not assessed	Amount of local rescue therapy (emollient or 1% hydrocortisone)
Henz 1998	Pruritus on 4‐point Likert scale	Adverse events (but not reported)	Mean overall response rate (number of participants who responded to treatment)	Not assessed	Not assessed
Hjorth 1988	Pruritus severity (no further details given)	Not assessed	Not assessed	Not assessed	Not assessed
Iikura 1992	Not assessed	Adverse events	Complete physical examination	Not assessed	Not assessed
Jung 1989	Pruritus by 4‐point Likert scale	Adverse events	Percentage of improvement rated as "good or excellent"	Not assessed	Not assessed
Kawashima 2003	Pruritus 0 to 8 score	Adverse events	Investigator‐assessed change in the ratio of pruritus area to body surface area	Not assessed	Amount of 0.1% hydrocortisone butyrate cream used during the study
Kimura 2009	Pruritus by VAS (0 to 100)	Adverse events	SCORAD	Not assessed	Not assessed
Kircik 2013	Pruritus by VAS (0 to 100)	Adverse events	Not assessed	Not assessed	Not assessed
Kuniyuki 2009	Pruritus by VAS (0 to 100)	Adverse events	SCORAD	Not assessed	Topical steroid score
Langeland 1994	Pruritus by VAS (0 to 10)	Adverse events	Not assessed	Not assessed	Mean number of days with use of local steroids during the 6 treatment periods and severity of rash at the end of each treatment period
LaRosa 1994	Pruritus by diary (no further details given)	Adverse events	Assessment by clinical examination	Not assessed	Amount of disodium cromoglycate, procaterol, steroids
Leon 1989	Pruritus by 4‐point Likert scale	Not assessed	Not assessed	Not assessed	Not assessed
Monroe 1992	Pruritus percentage score	Adverse events (but not reported)	Not assessed	Not assessed	Not assessed
Munday 2002	Pruritus by 4‐point Likert scale	Adverse events	Composite score consisting of 5 symptoms (erythema, excoriation, dryness, lichenification, exudation and crusting)	Not assessed	Amount of 1% hydrocortisone used in grams
Nuovo 1992	Pruritus on 7‐point Likert scale	Adverse events	Not assessed	Not assessed	Number of daily applications of the topical steroid triamcinolone
Ruzicka 1998	Pruritus by VAS (0 to 10)	Adverse events	Number for whom treatment success was judged as good or very good	Not assessed	Not assessed
Savin 1986	Pruritus by VAS (no further details given)	Not assessed	Not assessed	Not assessed	Not assessed
Simons 2007	Not assessed	Adverse events	Not assessed	Not assessed	Not assessed
Tharp 1998	Pruritus (no further details given)	Adverse events	Clinical signs and symptoms	Not assessed	Use of triamcinolone acetonide 0.1% cream (corticosteroid)

Study ID	Trial registration number
Berth Jones 1989	unable to obtain or not registered respectively
Cambazard 2001	a protocol number was provided (MPCE97B2501/lV ‐11 Dec. 97 Amdt 1 (29.01.98) / Amdt 2 (06.03.98)), but we could not find it
Diepgen 2002	unable to obtain or not registered respectively
Doherty 1989	unable to obtain or not registered respectively
Falk 1993	unable to obtain or not registered respectively
Frosch 1984	unable to obtain or not registered respectively
Hannuksela 1993	unable to obtain or not registered respectively
Henz 1998	unable to obtain or not registered respectively
Hjorth 1988	unable to obtain or not registered respectively
Iikura 1992	unable to obtain or not registered respectively
Jung 1989	a protocol number was provided (PCE87F291), but we could not find it
Kawashima 2003	unable to obtain or not registered respectively
Kimura 2009	unable to obtain or not registered respectively
Kircik 2013	NCT00884325 Management of pruritus with Xyzal in atopic dermatitis
Kuniyuki 2009	unable to obtain or not registered respectively
Langeland 1994	unable to obtain or not registered respectively
LaRosa 1994	unable to obtain or not registered respectively
Leon 1989	unable to obtain or not registered respectively
Monroe 1992	unable to obtain or not registered respectively
Munday 2002	unable to obtain or not registered respectively
Nuovo 1992	unable to obtain or not registered respectively
Ruzicka 1998	unable to obtain or not registered respectively
Savin 1986	unable to obtain or not registered respectively
Simons 2007	NCT00152464 Prevention of Asthma With Levocetirizine 18 Month Treatment in Infants (12 ‐ 24 Months) Suffering From Eczema (Atopic Dermatitis) and Sensitized to Grass Pollen and/or House Dust Mite (HDM)
Tharp 1998	unable to obtain or not registered respectively

Cetirizine 0.5 mg/kg/d compared with placebo for eczema
Patient or population: children with eczema Settings: secondary Intervention: cetirizine 0.5 mg/kg/d Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Cetirizine  0.5 mg/kg/d
Primary outcome 1. Mean change in patient‐assessed symptoms Pruritus was assessed once as part of SCORAD Follow‐up: 18 months	See comment	See comment	‐	‐	‐	This outcome was assessed as part of the SCORAD assessment, but the data were not presented separately for pruritus. Thus, no data for analysis of this outcome were available from this study.
Primary outcome 2. Proportion of participants reporting adverse effects and serious adverse events throughout the study period Follow‐up: 18 months	Study population		RR 0.68 (0.46 to 1.01)	795  (1 study)	⊕⊕⊕⊝  moderate^a	The difference was non‐significant and most reported symptoms and events were mild and were attributed to intercurrent respiratory or gastrointestinal infection or exacerbations of allergic disorders.
	136 per 1000	93 per 1000 (63 to 138)
Secondary outcome 1. Mean change in physician‐assessed clinical signs Measured by SCORAD Follow‐up: 18 months	See comment	See comment	‐	795  (1 study)	⊕⊕⊕⊝  moderate^a	No evidence for a treatment‐related reduction in SCORAD scores between baseline and the final visit was observed by study authors, as the difference between groups was reported to be non‐significant (from 24.9 to 15.2 in the cetirizine group and from 25.1 to 15.7 in the placebo group). Data could not be analysed because standard deviations were missing.
Secondary outcome 2. Mean change in quality of life	See comment	See comment	‐	‐	‐	No study addressed this outcome.
Secondary outcome 3. Number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications’ Follow‐up: 18 months	See comment	See comment	‐	795  (1 study)	⊕⊕⊕⊝  moderate^a	This outcome assessed the use of a variety of topical and systemic medications including oral use of H1 antihistamines. No significant difference between groups was observed, with 1 exception: participants in the placebo group were more likely to have used H1 antihistamines (P = 0.035). No data for analysis were available from the study. In other words, the intervention probably makes little or no difference in the use of additional H1 antihistamines to prevent flares.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; SCORAD: SCORing Atopic Dermatitis index.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Cetirizine 10 mg/d compared with placebo for eczema
Patient or population: adults with eczema Settings: secondary Intervention: cetirizine 10 mg/d Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Cetirizine  10 mg/d
Primary outcome 1. Mean change in patient‐assessed symptoms Pruritus was assessed once as part of SCORAD and once by patient case report form (CRF) Follow‐up: 4 weeks	See comment	See comment	‐	84  (1 study)	⊕⊕⊝⊝  low^a	Pruritus as part of SCORAD: no significant differences were observed between the intervention group and the placebo group Pruritus by patient CRF: according to study authors, no significant difference was observed between groups. It is of note that values reported in Table 2 of the publication actually increased from baseline to last visit, although the legend states that "lower values indicate less pruritus". We tried to contact the study authors to inquire about this but did not succeed in doing so.
Primary outcome 2. Proportion of participants reporting adverse effects and serious adverse events throughout the study period Follow‐up: 4 weeks	Study population		RR 1.11 (0.50 to 2.45)	84  (1 study)	⊕⊕⊝⊝  low^b	Non‐significant difference between groups in the occurrence of at least 1 adverse event. Most side effects pertained to sedation, others to skin‐related problems, respiratory symptoms or headache.
	214 per 1000	238 per 1000 (107 to 524)
Secondary outcome 1. Mean change in physician‐assessed clinical signs Total sum of 4 symptoms (signs) scores, each measured on 4‐point Likert scale (0 = absent; 3 = severe) Follow‐up: 4 weeks	See comment	See comment	‐	84  (1 study)	⊕⊕⊝⊝  low^c	It was reported that the total symptom/signs score decreased in both groups but there was no significant difference between groups.
Secondary outcome 2. Mean change in quality of life	See comment	See comment	‐	‐	‐	No study addressed this outcome.
Secondary outcome 3. Number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications’ Follow‐up: 4 weeks	See comment	See comment	‐	84  (1 study)	⊕⊕⊝⊝  low^c	No difference in amount of local rescue therapy (emollient or 1% hydrocortisone) nor in the number of applications was observed among groups.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; CRF: case report form; RR: risk ratio.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Fexofenadine 120 mg/d compared with placebo for eczema
Patient or population: adults with eczema Settings: secondary Intervention: fexofenadine 120 mg/d Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Fexofenadine  120 mg/d
Primary outcome 1. Mean change in patient‐assessed symptoms This outcome was measured as the mean change in patient‐assessed pruritus (range 0 to 8) between baseline and the night of day 6 Follow‐up: 1 week	Mean change was ‐0.5	Mean change was 0.25 lower (0.43 lower to 0.07 lower)	‐	400 (1 study)	⊕⊕⊕⊝  moderate^a	A significantly larger reduction was observed in the fexofenadine group compared to the placebo group. However, the effect observed appeared to be small.
Primary outcome 2. Proportion of participants reporting adverse effects and serious adverse events throughout the study period Follow‐up: 1 week	Study population		RR 1.05 (0.74 to 1.50)	411  (1 study)	⊕⊕⊕⊝  moderate^a	No significant difference between groups. The most frequent adverse events referred to somnolence and headache.
	221 per 1000	232 per 1000 (164 to 332)
Secondary outcome 1. Mean change in physician‐assessed clinical signs This outcome was assessed as investigator‐assessed change in the ratio of pruritus area to body surface area Follow‐up: 1 week	See comment	See comment	‐	Number of participants not reported  (1 study)	⊕⊕⊕⊝  moderate^a	It was stated that in terms of investigator‐assessed change in the ratio of pruritus area to body surface area, significantly more patients in the fexofenadine group than in the placebo group experienced a reduction in pruritus (P = 0.007). No further numerical data were provided.
Secondary outcome 2. Mean change in quality of life	See comment	See comment	‐	‐	‐	No study addressed this outcome.
Secondary outcome 3. Number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications’ Amount of 0.1% hydrocortisone butyrate cream used during the study Follow‐up: 1 week	See comment	See comment	‐	Number of participants not reported (1 study)	⊕⊕⊕⊝  moderate^a	Study authors reported no significant difference between the 2 groups in the amount of 0.1% hydrocortisone butyrate cream used during the study. No data for analysis could be extracted from this study.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Loratadine 10 mg/d compared with placebo for eczema
Patient or population: male and female adults aged 15 years and older with eczema Settings: secondary Intervention: loratadine 10 mg/d Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	No additional treatment	Loratadine 10 mg/d
Primary outcome 1. Mean change in patient‐assessed symptoms Reduction in pruritus on 100‐mm VAS from baseline Follow‐up: 4 weeks	Mean reduction was 29.4	Mean reduction was 2.30 lower (20.27 lower to 15.67 higher)	‐	28  (1 study)	⊕⊕⊝⊝  low^a	The difference was non‐significant. However, baseline differences were not adjusted for.
Primary outcome 2. Proportion of participants reporting adverse effects and serious adverse events throughout the study period Follow‐up: 4 weeks	Study population		RR 0.25 (0.01 to 5.76)	28  (1 study)	⊕⊕⊝⊝  low^a	There was only 1 event (folliculitis) in the placebo group and 0 events in the intervention group.
	83 per 1000	21 per 1000 (1 to 480)
Secondary outcome 1. Mean change in physician‐assessed clinical signs SCORAD Follow‐up: 4 weeks	Mean reduction was 16.9	Mean reduction was 4.1 lower  (13.22 lower to 5.02 higher)	‐	28 (1 study)	⊕⊕⊝⊝  low^a	The difference was non‐significant.
Secondary outcome 2. Mean change in quality of life	See comment	See comment	‐	‐	‐	No study addressed this outcome.
Secondary outcome 3. Number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications’ Follow‐up: 4 weeks	See comment	See comment	‐	‐	‐	No study addressed this outcome.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; SCORAD: SCORing Atopic Dermatitis index; VAS: visual analogue scale.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Mean change in patient‐assessed symptoms: VAS pruritus 7 days after baseline adjusted for baseline score as covariate	1	23	Mean Difference (IV, Random, 95% CI)	‐11.40 [‐29.44, 6.64]
2 Secondary outcome 1. Physician‐assessed clinical signs: number of participants for whom treatment helped itching	1	27	Risk Ratio (M‐H, Random, 95% CI)	2.69 [1.12, 6.49]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 2. Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Cetirizine 5 mg/d	1	62	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.11, 3.27]
1.2 Cetirizine 10 mg/d	1	65	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.18, 3.70]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 2. Proportion of participants reporting adverse effects and serious adverse events throughout the study period	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 10 mg/d vs placebo	1	84	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.50, 2.45]
1.2 20 mg/d vs placebo	1	87	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.70, 3.00]
1.3 40 mg/d vs placebo	1	89	Risk Ratio (M‐H, Random, 95% CI)	2.38 [1.25, 4.53]

Methods	Study design: randomised controlled trial Study grouping: cross‐over
Participants	Baseline characteristics Terfenadine Number of participants randomised: 28 Losses to follow‐up: 4 Age: M = 28.6 years Duration of condition: not reported Severity of condition: not reported Male/Female: not reported Placebo Number of participants randomised: 28 Losses to follow‐up: 4 Age: M = 28.6 years Duration of condition: not reported Severity of condition: not reported Male/Female: not reported Inclusion criteria: (1) diagnostic: eczema as defined by Hanifin and Rajka (1980); (2) severity of condition: not specified; (3) duration of condition: not specified; (4) site evaluated (e.g. face/back): physician‐assessed over entire body Exclusion criteria: not reported Group differences: cross‐over study
Interventions	Intervention characteristics Terfenadine Presentation: tablets Dose and frequency: 120 mg twice daily Total dose: 240 mg/d Duration given for: 1 week Supplier and trade name if relevant: not reported Placebo Presentation: matched Dose and frequency: matched Total dose: matched Duration given for: matched Supplier and trade name if relevant: not reported
Outcomes	Primary outcome: patient‐assessed symptoms: pruritus VAS (0 to 10) Outcome type: continuous outcome Reporting: fully reported Direction: lower is better Data value: endpoint Primary outcome 2: adverse events Outcome type: adverse event Secondary outcome 1: physician‐assessed clinical signs Outcome type: continuous outcome Notes: severity of excoriations at end of treatment; no exact numbers given nor results of significance tests
Identification	Sponsorship source: not stated Country: UK Setting: secondary Comments: not specified, presumably outpatient hospital (i.e. secondary care), probably Leicester Royal Infirmary as affiliation of main study author Author's name: Berth‐Jones, John, Dr. Institution: Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust Email: johnberthjones@aol.com Address: Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: study authors merely state 'in randomised order'. Insufficient information about the sequence generation process to permit judgement of low risk or high risk
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement of low risk or high risk
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Comment: Although study authors state that they report "the results of a double‐blind, placebo‐controlled" study, whether the placebo was identically matched to the terfenadine tablets remains unclear
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Comment: apart from stating "double‐blind", information is insufficient to permit judgement of low risk or high risk
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: loss to follow‐up: 4/28; no ITT analysis. Attrition less than 20%, so not substantial
Selective reporting (reporting bias)	Low risk	Comment: no comparison possible with protocol, as study protocol is not available, but it is clear that the published report includes all expected outcomes, including those that were prespecified
Other bias	Unclear risk	Comment: there may be further risk of bias but information is insufficient to judge whether additional bias exists (e.g. no conflict of interest statement provided, no provision of information regarding origin of drugs, Was study initiated by pharmacological company? Did study authors receive funding from any source?)

Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Cetirizine 0.25; 0.50; 0.75 mg/kg bw/d Number of participants randomised: not reported Losses to follow‐up: not reported Age: not reported Duration of condition: not reported Severity of condition: not reported Male/Female: not reported Placebo Number of participants randomised: not reported Losses to follow‐up: not reported Age: not reported Duration of condition: not reported Severity of condition: not reported Male/Female: not reported Total Number of participants randomised: 223 Losses to follow‐up: not reported Age: M = 30.8 months (range 11 to 71 months) Duration of condition: not reported Severity of condition: not reported Male/Female: 59% male Inclusion criteria: (1) diagnostic: children, male or female, 1 to 5 years old, who suffer from atopic dermatitis, with written consent to participate in the trial obtained from parents/legal representatives, who satisfy all inclusion/exclusion criteria; (2) severity of condition: not reported; (3) duration of condition: not reported; (4) site evaluated (e.g. face/back): not reported Exclusion criteria: not reported Group differences: not reported
Interventions	Intervention characteristics Cetirizine 3 groups Presentation: oral drops Dose and frequency: 0.25; 0.50; 0.75 mg/kg bw/d Total dose: 0.50 mg/kg bw/d Duration given for: 8 weeks Supplier and trade name if relevant: UCB Pharma Placebo Presentation: oral drops Dose and frequency: matched Total dose: n/a Duration given for: 8 weeks Supplier and trade name if relevant: UCB Pharma
Outcomes	Primary outcome 1: mean change in patient‐assessed symptoms: not reported Primary outcome 2: adverse events Outcome type: adverse event Secondary outcome 1: physician‐assessed clinical signs: modified SCORAD Outcome type: continuous outcome Secondary outcome 3: number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications' Amount of hydrocortisone 1% and clobetasone cream in grams
Identification	Sponsorship source: UCB Pharma, Belgium Country: 26 centres: France (10), Russia (8), Germany (4), Belgium (2), The Netherlands (1), United Kingdom (1) Setting: secondary Comments: Author's name: F. Cambazard Institution: not reported Email: not reported Address: Professor F. Cambazard, 42055 Saint‐Etienne, France
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information about the sequence generation process insufficient to permit judgement of low risk or high risk
Allocation concealment (selection bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Information insufficient to permit judgement of low risk or high risk. Number lost to follow‐up not reported
Selective reporting (reporting bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Other bias	Unclear risk	Further risk of bias is possible, but information is insufficient to judge whether additional bias exists (e.g. no conflict of interest statement provided); also, the study was funded in part by UCB, SA (Brussels, Belgium), and study medication was provided by that company

Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Cetirizine Number of participants randomised: 398 Losses to follow‐up: 48 Age: M = 16.8 months (SD = 4.2) Duration of condition: not reported Severity of condition: SCORAD: M = 24.9 (SD = 14.7) Male/Female: 61.8% male Placebo Number of participants randomised: 397 Losses to follow‐up: 51 Age: M = 17.2 months (SD = 4.1) Duration of condition: not reported Severity of condition: SCORAD: M = 25.1 (SD = 14.0) Male/Female: 62.5% male Inclusion criteria: (1) diagnostic: AD, infants (1 to 2 years of age), at least 1 parent or sibling with history of AD, allergic rhinitis or asthma; (2) severity of condition: active symptoms; (3) duration of condition: at least 1 month; (4) site evaluated (e.g. face/back): not reported Exclusion criteria: infants with asthma, or with a history (beyond the age of 6 months) of 1 or more episodes of wheezing or nocturnal cough, as well as any conditions that might obscure the diagnosis of asthma (14), were excluded from the study. Further exclusion criteria were the following: weight below the third percentile, chronic pulmonary disease, severe neurological or psychological disorder, any third disease likely to interfere with the study drug, clinically relevant cardiac disease, any anomaly of the Q–T interval on electrocardiogram (ECG) tracing, history of sleep apnoea in the participant or in siblings, neonatal distress, prior desensitisation or immunotherapy, prior treatment with medicines interfering with the immune system, hypersensitivity to cetirizine or other piperazines or parabens, participation in a clinical study within 3 months before randomisation Group differences: groups were comparable at baseline according to study authors
Interventions	Intervention characteristics Cetirizine Presentation: oral solution Dose and frequency: 0.25 mg cetirizine per kg bodyweight twice daily Total dose: 0.5 mg/kg bw/d Duration given for: 18 months Supplier and trade name if relevant: UCB SA Pharma Sector (Brussels, Belgium) Placebo Presentation: matched Dose and frequency: matched Total dose: matched Duration given for: 18 months Supplier and trade name if relevant: UCB SA Pharma Sector (Brussels, Belgium)
Outcomes	Primary outcome 1: mean change in patient‐assessed symptoms: pruritus as part of SCORAD Outcome type: continuous outcome Notes: pruritus as a subscale of SCORAD was not individually reported Primary outcome 2: adverse events Outcome type: adverse event Reporting: fully reported Notes: data were obtained from Simons 1999: P = 0.053; NB: N in Simons 1999 slightly larger; any events occurring during the 18‐month study period, including potential side effects (adverse events), were carefully recorded by parents/guardians on diary cards and discussed with the investigator at each visit; serious adverse events (e.g. any hospitalisations) had to be reported immediately Secondary outcome 1: physician‐assessed clinical signs Outcome type: continuous outcome Reporting: fully reported Data value: change from baseline Notes: SCORAD by trained investigator Secondary outcome 3: number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications’ Outcome type: continuous outcome Notes: Table 2 ‐ some significant differences in numbers using other topical and systemic medications; Table 3 ‐ no significant difference in duration of use of variety of topical and systemic medications (apart from H1 AH; P = 0.035) between groups
Identification	Sponsorship source: UCB, SA, Pharma sector (Brussels, Belgium) Country: 12 European countries and Canada Setting: dermatological or paediatric centres in 12 countries (i.e. secondary) Comments: Author's name: Thomas L. Diepgen Institution: University Hospital Heidelberg Email: thomas.diepgen@med.uni‐heidelberg.de Address: not reported
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Informatio about the sequence generation process insufficient to permit judgement of low risk or high risk
Allocation concealment (selection bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: incomplete outcome data, as 817 were randomised but ITT population consists of only 795 participants. 12.45% further unaccounted attrition. However, attrition was less than 30% (long‐term trial) so was considered to be low risk
Selective reporting (reporting bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk. No comparison with protocol possible, as a study protocol is not available
Other bias	Unclear risk	There may be further risk of bias, but information is insufficient to judge whether additional bias exists (e.g. no conflict of interest statement provided); also, the study was funded in part by UCB, SA (Brussels, Belgium), and study medication was provided by that company

Methods	Study design: randomised controlled trial Study grouping: parallel group
Participants	Baseline characteristics Overall Number of participants randomised: 49 (acrivastine: n = 13; terfenadine: n = 16; placebo: n = 14 (as per protocol)) Losses to follow‐up: 5 (but 5 + 43 = 48, not 49) Age: M = 26.8 years (range 16 to 58 years) Duration of condition: not reported Severity of condition: not reported Male/Female: N = 49 (male = 20, female = 29) Inclusion criteria: (1) diagnostic: clinical diagnosis of AD; (2) severity of condition: not reported; (3) duration of condition: not reported; (4) site evaluated (e.g. face/back): not reported Exclusion criteria: not reported Group differences: not reported
Interventions	Intervention characteristics Acrivastine Presentation: oral Dose and frequency: 8 mg 3×/d Total dose: 24 mg/d Duration given for: 10 days Supplier and trade name if relevant: not reported Terfenadine Presentation: oral Dose and frequency: 60 mg 3×/d Total dose: 180 mg/d Duration given for: 10 days Supplier and trade name if relevant: not reported Placebo Presentation: oral Dose and frequency: 3×/d Total dose: n/a Duration given for: 10 days Supplier and trade name if relevant: not reported
Outcomes	Primary outcome 1: mean change in patient‐assessed symptoms: pruritus VAS Outcome type: continuous outcome Range: 0 to 100 Direction: lower is better Data value: change from baseline Primary outcome 2: adverse events Outcome type: adverse event Notes: adverse events not reported Primary outcome 2: adverse events: number of flares Outcome type: adverse event Notes: not reported Secondary outcome 1: physician‐assessed clinical signs: no. for whom treatment helped itching Outcome type: dichotomous outcome Direction: higher is better Data value: endpoint
Identification	Sponsorship source: not reported Country: UK Setting: secondary Comments: UK outpatient hospital Author's name: Valerie Doherty Institution: Royal Infirmary, Edinburgh Email: val.doherty@nhslothian.scot.nhs.uk. Address: Valerie Doherty, Consultant Dermatologist, Royal Infirmary, Edinburgh EH3 9YW
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Information about the sequence generation process insufficient to permit judgement of low risk or high risk
Allocation concealment (selection bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Apart from stating "double‐blind", information is insufficient to permit judgement of low risk or high risk
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: 'as‐treated’ analysis done with departure of the intervention received from that assigned at randomisation. Attrition (10.2%) and no statement of analysis based on ITT principles. Cases with missing data were deleted from analyses. However, attrition was below 20% and medium‐term duration intervention, so considered as low risk
Selective reporting (reporting bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk. No comparison with protocol possible, as a study protocol is not available
Other bias	Unclear risk	Further risk of bias is possible, but information is insufficient to judge whether additional bias exists (e.g. no conflict of interest statement provided, no provision of information regarding origin of drugs, Was study initiated by pharmacological company? Did study authors receive funding from any source?)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 2. Proportion of participants reporting adverse effects and serious adverse events throughout the study period	1	151	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.49, 1.82]
2 Secondary outcome 3. Amount of 1% hydrocortisone in grams used	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1 days 1 to 29 ages 1 to 5 years	1	61	Mean Difference (IV, Random, 95% CI)	‐1.30 [‐5.96, 3.36]
2.2 days 1 to 29 ages 6 to 12 years	1	90	Mean Difference (IV, Random, 95% CI)	1.60 [‐2.53, 5.73]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Mean change in patient‐assessed symptoms: mean pruritus difference (0 to 8) between baseline and night of day 6	1	400	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.43, ‐0.07]
2 Primary outcome 2. Adverse events	1	411	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.74, 1.50]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Mean change in patient‐assessed symptoms: VAS pruritus (difference in pruritus sum between day 0 and day 13)	1	72	Mean Difference (IV, Random, 95% CI)	‐1.10 [‐2.30, 0.10]
2 Secondary outcome 1. Physician‐assessed clinical signs: number of participants for whom treatment success was judged as good or very good 13 days after randomisation	1	74	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.73, 3.42]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Mean change in patient‐assessed symptoms: VAS pruritus (difference in pruritus sum between day 0 and day 13)	1	71	Mean Difference (IV, Random, 95% CI)	‐0.96 [‐2.01, 0.09]
2 Secondary outcome 1. Physician‐assessed clinical signs: number of participants for whom treatment success was judged as good or very good 13 days after randomisation	1	73	Risk Ratio (M‐H, Random, 95% CI)	2.04 [0.99, 4.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Mean change in patient‐assessed symptoms: VAS pruritus (difference in pruritus sum between day 0 and day 13)	1	72	Mean Difference (IV, Random, 95% CI)	‐1.41 [‐2.49, ‐0.33]
2 Secondary outcome 1. Physician‐assessed clinical signs: number of participants for whom treatment success was judged as good or very good	1	73	Risk Ratio (M‐H, Random, 95% CI)	2.04 [0.99, 4.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Patient‐assessed symptoms: VAS pruritus 4 weeks after randomisation	1	28	Mean Difference (IV, Random, 95% CI)	‐2.30 [‐20.27, 15.67]
2 Primary outcome 2. Adverse events	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.01, 5.76]
3 Secondary outcome 1. Physician‐assessed clinical signs: SCORAD after 4 weeks	1	28	Mean Difference (IV, Random, 95% CI)	‐4.10 [‐13.22, 5.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome 1. Mean change in patient‐assessed symptoms: VAS pruritus 7 days after baseline adjusted for baseline score as covariate	1	27	Mean Difference (IV, Random, 95% CI)	‐15.2 [‐33.03, 2.63]
2 Secondary outcome 1. Physician‐assessed clinical signs: number of participants for whom treatment helped itching (1 week after randomisation)	1	30	Risk Ratio (M‐H, Random, 95% CI)	2.19 [0.88, 5.44]

Methods	Study design: single‐patient randomised trial Study grouping: cross‐over single‐patient
Participants	Baseline characteristics Overall Number of participants randomised: 1 Losses to follow‐up: n.a. Age: 32 years Duration of condition: lifelong Severity of condition: not reported Male/Female: 1 male Inclusion criteria: (1) diagnostic: (2) severity of condition: not reported; (3) duration of condition: lifelong; (4) site evaluated (e.g. face/back): not reported Exclusion criteria: n.a. Group differences: n.a.
Interventions	Intervention characteristics Chlorpheniramine 16 mg/d Presentation: oral Dose and frequency: 8 mg chlorpheniramine twice daily Total dose: 16 mg/d Duration given for: 2 weeks Supplier and trade name if relevant: not reported Chlorpheniramine 24 mg/d Presentation: oral Dose and frequency: 12 mg chlorpheniramine twice daily Total dose: 24 mg/d Duration given for: 2 weeks Supplier and trade name if relevant: not reported Terfenadine 240 mg/d Presentation: oral Dose and frequency: 120 mg terfenadine twice daily Total dose: 240 mg/d Duration given for: 2 weeks Supplier and trade name if relevant: not reported Placebo Presentation: oral Dose and frequency: not reported Total dose: n/a Duration given for: 2 weeks Supplier and trade name if relevant: not reported
Outcomes	Primary outcome 1: mean change in patient‐assessed symptoms: pruritus assessed on 7‐point Likert scale Outcome type: dichotomous outcome Primary outcome 1: mean change in patient‐assessed symptoms: patient‐assessed severity of symptoms assessed on 7‐point Likert scale Outcome type: dichotomous outcome Primary outcome 2: adverse events (severity of drowsiness) on 7‐point Likert scale Outcome type: adverse event Secondary outcome 3: number of eczema flares/frequency of triamcinolone applications Outcome type: continuous outcome Data value: endpoint
Identification	Sponsorship source: the paper was supported by a grant (HS06006) from the National Center for Health Services Research‐OASH Country: USA Setting: secondary Comments: Author's name: James Nuovo Institution: Departments of Family Medicine, Pharmacy Practice, and Medicine, Schools of Medicine and Phannacy, University of Washington, Seattle Email: not reported Address: Department of Family Medicine, RF‐30, University of Washington, Seattle, WA 98195
Notes	‐
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "the order of treatment was determined by random allocation" Comment: no further information given (i.e. information about the sequence generation process insufficient to permit judgement of low risk or high risk)
Allocation concealment (selection bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "the patient and the investigator were blinded to the treatment sequence"; "A pharmacist prepared all study medications to appear identical as pink capsules and maintained the drug code" Comment: participants and personnel were blinded to study groups
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Comment: information insufficient to permit judgement of low risk or high risk
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: all data from the cross‐over trial were reported
Selective reporting (reporting bias)	Unclear risk	Information insufficient to permit judgement of low risk or high risk. No comparison with protocol possible, as a study protocol is not available
Other bias	Unclear risk	Further risk of bias is possible, but information is insufficient to judge whether additional bias exists (e.g. no conflict of interest statement provided, no provision of information regarding origin of drugs, Was study initiated by pharmacological company?) However, a source of funding was provided

Study	Reason for exclusion
Anton'ev 1988	Wrong study design: study not described as randomised
Balabolkin 1983	Wrong study design: study not described as randomised
Bogdaszewska 1968	Wrong study design: study not described as randomised
CastroTorres 1987	Wrong indication/wrong patient population: study included participants with different pruritic skin diseases, varying from insect bites to psoriasis. However, study authors did not give clear indications that the study included participants with eczema
Eberhartinger 1969	Wrong study design: study not described as randomised
Foulds 1981	Wrong comparator/wrong intervention: Cimetidene vs promethazine hydrochloride but not vs placebo
Furue 2009	Wrong study design: study not described as randomised
Grabner 1970	Wrong study design: study not described as randomised
Imaizumi 2003	Wrong study design: study not described as randomised
Kawakami 2006	Wrong comparator/wrong intervention: comparison of fexofenadine combined with emollient vs fexofenadine combined with steroid treatment
Kleine Natrop 1970	Wrong study design: study not described as randomised
Kori Lindner 1997	Review article
Korossy 1972	Wrong study design: study not described as randomised
Liu 2008	Wrong study design: study not described as randomised
Lutsky 1993	Wrong comparator/wrong intervention: comparison of loratadine vs terfenadine but not vs placebo
May 1966	Wrong study design: study not described as randomised
Mensing 1991	Wrong comparator/wrong intervention: comparison of loratadine vs dimethindene but not vs placebo
Mesquita 1994	Wrong comparator/wrong intervention: comparison of dimethindene vs astemizole but not vs placebo
Miller 1963	Wrong study design: study not described as randomised
Nitzschner 1970	Wrong study design: study not described as randomised
Ohsawa 2014	Review article
Ohtani 2004	Wrong comparator/wrong intervention: comparison of cetirizine vs epinastine hydrochloride vs vitamin B2 but not vs placebo
Pacor 1992	Wrong comparator/wrong intervention: comparison of oxatomide vs cromoglycate but not vs placebo
Patel 1997	Wrong comparator/wrong intervention: comparison of loratadine vs cetirizine but not vs placebo
Pfab 2012	Wrong study design: comparison of effects of several interventions on magnitude of experimentally induced itch
Rajka 1965	Wrong study design: study not described as randomised
Rajka 1968a	Wrong study design: study not described as randomised
Rajka 1968b	Wrong study design: study not described as randomised
Schmoeckel 1992	Wrong study design: observational drug safety study (i.e. study not described as randomised)
Sheng 2009	Wrong comparator/wrong intervention: comparison of mizolastine in combination with dyclonine cream vs cetirizine and dyclonine cream vs vitamin C and dyclonine cream
Simons 1984	Wrong comparator/wrong intervention: comparison of hydroxyzine 0.7 mg/kg 3 times daily vs hydroxyzine 1.4 mg/kg 3 times daily but not vs placebo
Sugai 2003	Wrong comparator/wrong intervention: comparison of tacrolimus ointment alone for 2 weeks followed by complementary use of cetirizine for another 2 weeks vs tacrolimus ointment and cetirizine for 2 weeks followed by tacrolimus alone for 2 weeks
Tarchalska 1988	Review article: a literature review
Veien 1995	Wrong patient population: sample consisted of patients with current hand eczema who had or previously had eczema
Voigtlander 1989	Wrong study design: study not described as randomised
Wahlgren 1990	Wrong study design: study not described as randomised
Wahlgren 1991	Wrong study design: study not described as randomised
Weitgasser 1967	Wrong comparator/wrong intervention: comparison of tavegyl vs another unspecified antihistamine
Wolfram 1967	Wrong study design: study not described as randomised
Zhang 1998	Wrong comparator/wrong intervention: comparison of oral terfenadine, injection of interferon gamma (up to 7 to 11 weeks), and rinse with calamine lotion vs cyproheptadine tablets and rinse with calamine lotion
Zhang 2010	Wrong comparator/wrong intervention: comparison of Qushi decoction oral and bathed vs oral chlorpheniramine 0.35 mg/kg 3×/d combined with Kangfu ointment
Zuluaga de Cadena 1989	Wrong study design: study not described as randomised

Methods	Controlled clinical comparison of BP 400 vs placebo
Participants	200 patients with eczema and other pruritogenic skin conditions
Interventions	BP 400 (synonyms: 1‐methyl‐4‐thioxanthen‐9‐ylidene‐piperidine; 9‐(1‐methyl‐4‐piperidinylidene)thioxanthene; 9‐(N‐methyl‐4’‐piperidylene)thioxanthene; 9‐(N‐methyl‐4’‐piperidylidene)‐thioxanthene; BP 400S; CGA 123427; Calmixen; Mepithiathene; Pimetixene) vs placebo
Outcomes	Antiprurigogenic and sedative effects of treatment
Notes	Not clear whether this was a randomised study. We contacted study authors but received no response to our queries

PERMALINK

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

Uwe Matterne

Merle Margarete Böhmer

Elke Weisshaar

Aldrin Jupiter

Ben Carter

Christian J Apfelbacher

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

1. Glossary of terms.

Definition

Clinical features and symptoms

1.

Epidemiology and causes

Biology

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Trials registers

Searching other resources

Reference lists

Adverse effects

Conference proceedings

Correspondence

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Cross‐over trials

Studies with multiple treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' table

Results

Description of studies

Results of the search

2.

Included studies

2. H1 antihistamines under investigation in the included studies.

Design

Participants and sample sizes

Setting

Interventions

Duration of the interventions

Outcomes

3. Outcomes.

Primary outcome 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))

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

Secondary outcome 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), SCORing Atopic Dermatitis index (SCORAD) (ETFAD 1993))

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

Secondary outcome 3. Number of eczema flares, measured by, for example, ‘escalation of treatment’ or ‘use of topical anti‐inflammatory medications’ (Thomas 2015)

Declaration of interest and funding

Methods	Double‐blind placebo controlled trial; however, whether a random allocation took place remains unclear
Participants	48 patients with eczema (children) with a mean age of 73.67 months
Interventions	Oral loratadine (5 mL/30 kg bodyweight/d) vs placebo as add‐on to once‐a‐day topical mometasone fuorate 0.1% ointment
Outcomes	Severity of eczema as measured by SCORAD; physician global assessment of improvement; pruritus
Notes	Not clear whether this was a randomised study. We contacted study authors but received no response to our queries

Methods	This is a randomised controlled trial
Participants	8 patients with eczema; 40 with other dermatological conditions, mainly hay fever
Interventions	Oral primalan (mequitazine) (10 mg/d) vs placebo
Outcomes	Clinical signs of eczema
Notes	Although the study was also conducted in patients with eczema, results were not reported separately for these. We tried to contact study authors to request additional information but received no response

Trial name or title	Prednicarbat and cetirizine dihydrochloride in the treatment of acute stage of atopic eczema in children
Methods	Not reported
Participants	Children with eczema (age 2 to 11 years)
Interventions	Prednicarbat and cetirizine dihydrochloride
Outcomes	Not reported
Starting date	Not reported
Contact information	Not reported
Notes	‐

Trial name or title	Effect of long‐term treatment with the H1 ‐receptor antagonist cetirizine in the prevention of urticaria in children with atopic dermatitis
Methods	Not reported
Participants	Children with eczema (age 2 to 11 years)
Interventions	H1‐receptor antagonist cetirizine
Outcomes	Not reported
Starting date	Not reported
Contact information	Not reported
Notes	May be related to Simons 2007

Trial name or title	Hydroxyzine: pharmacokinetics and antipruritic effect in children with atopic dermatitis
Methods	Not reported
Participants	Children with eczema (age 2 to 11 years)
Interventions	Hydroxyzine
Outcomes	Not reported
Starting date	Not reported
Contact information	Not reported
Notes	‐

Trial name or title	Evaluation of the efficacy and the safety of DCL syrup in childhood atopic dermatitis
Methods	Not reported
Participants	Children with eczema (age range unclear)
Interventions	Desloratadine
Outcomes	Not reported
Starting date	Not reported
Contact information	Not reported
Notes	‐

Trial name or title	Impact of olopatadine hydrochloride (Allelock(R)) against scratching behavior of atopic dermatitis patients at night
Methods	This is a randomised controlled trial
Participants	Adults suffering from atopic dermatitis Inclusion criteria: Persons with severe or moderate disease severity classification defined by atopic dermatitis (Japanese Dermatological Association) 18 years of age or older (at the time of obtaining informed consent) Unquestioned gender Outpatient Persons with voluntary documented consent form With night itching
Interventions	Olapatadine versus placebo
Outcomes	Measurement of the scratching ratio and the depth of sleep  Measurement will be performed on days ‐2, ‐1, and 7 for patients with atopic dermatitis  Measurement on day 7 day can be extended up to 3 additional days, in case the participant is not available on day 7  VAS value of itch and dermatitis score (EASI, ELQI) are measured for patients with atopic dermatitis  Medication and measurement on day 7 will not be performed for healthy individuals
Starting date	18/02/2013
Contact information	Keiichi Yamanaka, MD, PhD; Mie University, Graduate School of Medicine; Department of Dermatology; 2‐174 Edobashi, Tsu, Mie 514‐8507, Japan
Notes	‐