ch15[1].pdf

Advances in Veterinary Dermatology. Edited by Sheila M. F. Torres.

Published 2013 by John Wiley & Sons, Ltd.

To cite this article, please use DOI: 10.1111/j.1365-3164.2012.01088.x

4.2

A systematic review of randomized controlled trials for

prevention or treatment of atopic dermatitis in dogs:

2008–2011 update

Thierry Olivry and Petra Bizikova

Department of Clinical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina

State University, Raleigh, NC, USA

Correspondence: Thierry Olivry, Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine, 1060 William

Moore Drive, Raleigh, NC 27607, USA. E-mail: tolivry@ncsu.edu

Background – The management of atopic dermatitis (AD) in dogs relies mainly on the use of interventions to

reduce pruritus and skin lesions.

Objectives – To provide a critical analysis of recent clinical trials reporting the efﬁcacy and safety of interventions

for canine AD.

Methods – Systematic review of randomized controlled trials (RCTs) published, presented or completed

between 2008 and 2011, which enrolled dogs with AD. The search was done using electronic databases,

reviewing published meeting abstracts and sending queries to professional email lists. Trials reporting the efﬁ-

cacy of interventions aimed at treating, preventing or reducing glucocorticoid usage in atopic dogs were selected.

Results – Twenty-one RCTs were included. We found further moderate-quality evidence of efﬁcacy and safety

of oral glucocorticoids and ciclosporin for treatment of canine AD. There was additional moderate-quality evi-

dence of the efﬁcacy of a topical glucocorticoid spray containing hydrocortisone aceponate. Low-quality evidence

was found for the efﬁcacy and safety of injectable recombinant interferons, a budesonide leave-on conditioner, a

ciclosporin topical nano-emulsion and oral fexofenadine. There is low-quality evidence of efﬁcacy of oral masiti-

nib, with a need for monitoring for protein-losing nephropathy. Finally, we uncovered low-quality evidence of efﬁ-

cacy of a commercial diet as a glucocorticoid-sparing intervention and of a glucocorticoid spray as a ﬂare-delaying

measure. Very low-quality evidence was found for the efﬁcacy of other interventions.

Conclusions and clinical importance – Topical or oral glucocorticoids and oral ciclosporin remain the interven-

tions with highest evidence for efﬁcacy and relative safety for treatment of canine AD.

Recent international practice guidelines have high-

lighted the need for a multifaceted line of attack for the

management of canine AD. 4 Approaches to consider cur-

rently include the avoidance of ﬂare factors, an increase

in skin and coat hygiene and care, the control of skin

infections and the use of pharmacotherapy to alleviate

skin lesions and manifestations of pruritus. 4 To reduce

signs immediately during acute ﬂares of AD, topical

and ⁄ or oral glucocorticoids are suggested. 4 For long-term

pharmacological treatment of chronic or recurrent signs

of canine AD, oral and ⁄ or topical glucocorticoids, topical

tacrolimus, oral ciclosporin and injectable interferons are

currently recommended. 4 Finally, additional strategies are

also used to prevent the recurrence of clinical signs. 4

The recommendations for speciﬁc drugs included in

the 2010 guidelines derived principally from two system-

atic reviews of interventions to treat dogs with AD. The

ﬁrst review, published in 2003, 5 analysed results of clini-

cal trials testing pharmacological interventions, whether

the trials were randomized or not; it did not discuss stud-

ies evaluating the efﬁcacy of essential fatty acid (EFA) for-

mulations or allergen-speciﬁc immunotherapy, and it was

limited to clinical trials published in peer-reviewed jour-

Introduction

Atopic dermatitis (AD) is a common allergic skin disease

of dogs that is currently deﬁned as a genetically predis-

posed inﬂammatory and pruritic skin disease, with char-

acteristic clinical features and an association with IgE

antibodies most commonly directed against environmen-

tal allergens. 1 This disease has recently been shown to

have a strong impact on the quality of life of both affected

dogs and their owners 2,3 and, as such, it is probably one

of the most important chronic skin diseases of dogs.

Accepted 12 June 2012

Sources of Funding: This study was self-funded.

Conﬂict of Interest: From 2008 to 2011, Thierry Olivry partici-

pated in North Carolina State University-approved consulting

activities (C) for or has received a lecturing honorarium (LH) or

obtained research funding (RF) from the following companies

whose products are discussed herein: AB-Science (France; C),

Novartis Animal Health (Switzerland; C, LH and RF) and Virbac

(France; C and RF). Petra Bizikova has received research funding

from Virbac (France) via North Carolina State University.

108

ª 2013 The Authors. Journal compilation ª 2013 ESVD and ACVD

Therapy of canine atopic dermatitis

nals. 5 In 2010, an international collaboration published a

second systematic review using the more stringent

methodology and the support of the Cochrane Skin

Group. 6 That study was limited to randomized controlled

trials (RCTs), and there were no restrictions on publication

type and status, languages or types of interventions. 6 In

that review, database searches were done in 2005 for tri-

als from 1980 to 2004, and RCTs published in 2005, 2006

and 2007 were included in a prospective fashion. In all, 49

RCTs were scrutinized. 6

As done in our preceding systematic review, 6 RCTs were catego-

rized at ‘short-term’ if they lasted 8 weeks or less and ‘long-term’ if

their duration extended beyond 8 weeks. We also separated studies

aimed at preventing ﬂares of canine AD from those designed to

relieve existing signs (i.e. treatment sensu stricto).

Types of outcome measures.

As in our recent review, 6

included studies had to report an assess-

ment of the extent and

or skin lesions

after a preventive or therapeutic intervention. Trials solely reporting

the safety of an intervention were not reviewed further.

Primary outcome measures were similar to those used

recently, while secondary outcome measures were expanded from

previous ones. 6 Primary outcome measures consisted of the pro-

portion of dogs with a good-to-excellent improvement at study

end using a categorical global assessment scale assessed by

either investigators (primary outcome 1a) or dog owners (primary

outcome 1b).

As secondary outcome measures, we determined the percentage

of dogs with complete – or near complete – remission of signs, as

estimated by a reduction of 90% or more from baseline investigator-

graded lesional (secondary outcome 1a) or owner-rated pruritus

scores (secondary outcome 1b). We also extracted from the RCTs

the percentage of dogs with a 50% or greater reduction from base-

line of investigator-graded lesional (secondary outcome 2a) or owner-

rated pruritus scores (secondary outcome 2b). In the absence of uni-

versally accepted validated severity scales for evaluating skin and

pruritus in dogs with AD, the outcome measures listed above were

determined from values assessed with any scoring scheme used by

the study authors, but only if there were more than 10 possible

grades of severity in the scales utilized.

Furthermore, whenever RCTs employed validated scales, such as

the Canine Atopic Dermatitis Extent and Severity Index version 3

(CADESI-03) 13,14 and Hill’s Pruritus Visual Analog Scale (PVAS), 15,16

for which thresholds for normal dogs have been established, we

added four other secondary outcome measures. For these RCTs, we

calculated the percentage of dogs that, at trial’s end, had CADESI-03

values in the range of those of normal dogs (0–15; secondary out-

come 3a) or of dogs with mild AD (16–59; secondary outcome 4a).

Likewise, we determined the percentage of dogs with a PVAS in the

range of that of normal dogs (0–1.9; secondary outcome 3b) or dogs

with mild pruritus (i.e. the value anchored by the third lowermost

descriptor, 2–3.5; secondary outcome 4b). We also calculated these

outcome measures for other scales if there were clearly indicated

benchmarks for the absence of signs (or normal dog status) and ⁄ or

for mild AD.

Finally, for glucocorticoid-sparing effect trials and prevention stud-

ies, we used different outcome measures that appeared to be more

clinically relevant for these unique study designs. These ad hoc out-

come measures were the glucocorticoid dosage at study end and the

time to relapse, respectively.

Whenever possible and to provide a better comparison of the efﬁ-

cacy between different interventions tested in placebo-controlled

RCTs, we calculated numbers needed to treat (NNT) based on each

of the available outcome measures. However, to limit the lack of rele-

vance of NNTs because of a high random chance placebo effect in

RCTs with small group sizes, 17 NNTs were calculated only for large

trials with more than 50 dogs per group.

Each NNT was calculated as follows. 18

1 The average beneﬁt increase (ABI) of the intervention over

placebo equals the percentage of dogs with positive outcome in

the active intervention-treated group (i.e. the experimental

event rate) minus the percentage of dogs with positive outcome

in the placebo-treated group (i.e. the control event rate)

2 The NNT, which is the inverse (i.e. reciprocal) of the ABI, equals

one divided by the ABI.

3 The NNT was rounded up to the next integer.

⁄

or intensity of pruritus and

⁄

Objectives

To determine the efﬁcacy of interventions to treat or pre-

vent skin lesions and ⁄ or pruritic manifestations of canine

AD, we carried out a systematic reviewof recent RCTs that

had enrolled atopic dogs of any age and disease severity.

These trials had to be completed, presented or published

between 2008 and 2011. This paper serves, therefore, as

an update of the previous systematic review. 6 This article

is written according to the reporting standards for system-

atic reviews and meta-analyses set up by the latest 2009

Preferred Reporting Items for Systematic Reviews and

Meta-Analyses (PRISMA) statement. 7

Methods

Protocol and registration

With minor changes in outcome measures and study selection crite-

ria, the protocol for this systematic review was nearly identical to that

of a recent publication. 6 Owing to the lack of availability of online

repositories accepting the advanced publication of veterinary system-

atic review protocols, it could not be published before this review

was conducted.

Eligibility criteria

Types of studies.

In this systematic review, we included solely RCTs of interventions

aimed at treating or preventing AD in dogs. As our latest systematic

review focused on trials published or presented from the early 1980s

until the end of 2007, 6 we limited our present analysis to trials pub-

lished, presented or completed between 2008 and 2011, both years

included. There were no language or publication status restrictions.

Finally, we excluded studies that had been presented at meetings

before 2007, and which had already been discussed in our 2010

review. 6

Types of participants.

As done previously, 6 dogs had to be diagnosed with AD based on (as

minimal criteria) the presence of characteristic clinical signs and the

exclusion of pruritic dermatoses of similar appearance. 8,9 The fulﬁlment

of published diagnostic criteria such as those of Willemse 10 , Pr ´ laud et

al. 11 or Favrot et al. 12 was considered acceptable if non-AD pruritic

diseases had also been excluded according to current standards. If the

RCT had enrolled dogs with different diagnoses (e.g. AD and other

diseases or pruritic dogs without further diagnostic characterization),

the study was excluded. We also eliminated four trials that enrolled

laboratory dogs with experimentally induced atopic skin lesions.

Types of interventions.

Randomized controlled trials had to report either the treatment or

prevention of manifestations of pruritus and

or skin lesions of canine

AD. There was no restriction on the route or type of intervention.

Comparators could either consist of a relevant placebo or an active

medication, be it a different dose of the same drug or an intervention

already recommended for treatment of canine AD. 4

⁄

As an example, in the context of this review, an NNT of ‘n’ could

be interpreted as follows: a veterinarian would have to treat ‘n’ dogs

with AD with the active intervention to obtain one additional positive

109

Olivry and Bizikova

outcome over treatment with placebo. The lower the NNT, the stron-

ger the treatment effect over placebo.

Finally, in this review, we extracted and reviewed adverse events

following each nonplacebo intervention.

duration of the trial; type of duration (short or long term); characteris-

tics of study participants (number of dogs, their age range, type of

AD etc.); type of intervention (treatment or prevention, including

dose, duration and frequency); type of outcome measure; and fund-

ing source.

Information sources

Studies were identiﬁed by searching three databases (Medline

via PubMed, Thomson Reuters’ Web of Science and CAB

Abstract via EBSCO Host) for the period between 1 January

2008 and 31 December 2011. Searches were done once on

2 January 2012.

Additionally, we searched online published abstracts from the

three leading veterinary dermatology international congresses: the

World Congress of Veterinary Dermatology (WCVD, 2008), the

annual joint congresses of the European Society of Veterinary Der-

matology (ESVD) and European College of Veterinary Dermatology

(ECVD) of 2009, 2010 and 2011, as well as those of the North Ameri-

can Veterinary Dermatology Forum (NAVDF) held annually between

2008 and 2011.

To identify RCTs that had not yet been published or presented, we

sent an email twice (18 December 2011 and 3 January 2012) to the

three main veterinary dermatology lists (Vetderm, DipECVD and Dip-

derm) requesting colleagues to provide information on recently com-

pleted studies. Finally, we contacted, by email, representatives of

three companies known to the authors to have completed relevant

RCTs.

Risk of bias in individual studies

To determine the validity of eligible RCTs, the adequacy of several

parameters known to affect bias was assessed as done previously. 5,6

The following parameters were rated as ‘none’, ‘adequate’, ‘unclear’

or ‘inadequate’: (i) method of generation of randomization

sequences; (ii) method of concealment of allocation to treatment

groups; (iii) masking of intervention for observers (e.g. clinicians) and

participants (e.g. dog owners); (iv) inclusion of cases lost to follow-up

in intention-to-treat (ITT) analyses; and (v) degree of certainty that the

participants were affected with AD, as judged by the author’s

description.

The parameters ‘comparison of groups at baseline’ and ‘assess-

ment of compliance’ were also added to the appraisal of study

design.

Three of the parameters above (randomization method, masking

and ITT) were used for an overall evaluation of study quality. When

these parameters had been rated as ‘adequate or performed’, the

RCT was graded as ‘high quality’; when they were all rated as ‘inade-

quate or unclear’, the study was graded as ‘poor’; and when only one

or two of three parameters was assessed as ‘inadequate or unclear’,

the RCT was graded as being of ‘intermediate’ quality.

The same search was done with the three electronic databases, with

the goal of having a simple yet very sensitive strategy that yielded a

maximum of species- and disease-speciﬁc citations. The terms

employed were as follows: (dog or dogs or canine) and (atopic and

dermatitis). We added a date limit from 1 January 2008 to 31 Decem-

ber 2012, but there were no language or publication type restrictions.

The search was done by one author (T.O.) and veriﬁed by the

co-author (P.B.).

Planned methods of analysis

As no two studies appeared to test similar interventions and

or used

sufﬁciently similar designs, pooling of data for meta-analysis was not

attempted. As a result, between-RCT variability (i.e. heterogeneity or

inconsistencies) was not calculated. Nevertheless, whenever avail-

able, we compared dichotomous primary outcome measures

between interventions using the Mantel–Haenszel (M-H) test; results

are presented as risk ratios (RRs) with 95% conﬁdence intervals (CIs)

in the ﬁgures. These analyses were done using RevMan 5.0 analysis

software (The Nordic Cochrane Centre, Copenhagen, Denmark).

⁄

Study selection

As done for our 2010 Cochrane-style systematic review, 6 the titles

of all electronic citations and meeting abstracts were ﬁrst scanned

for identiﬁcation of clinical trials. Then, abstracts and

Risk of bias across studies

In the absence of availability of published clinical trial protocols before

the ﬁnal results were eventually reported, the authors could not com-

pare whether the outcome measures published matched those

planned at study onset. However, the outcome measures reported in

the study methods were matched to those of the results section. We

also assessed whether the reported outcome measures were con-

sistent with those employed in recent RCTs enrolling dogs with AD

and if they appeared clinically relevant.

or article full

texts were assessed to determine whether or not the study was

an RCT, if it had enrolled solely dogs with AD, and if it had

reported efﬁcacy outcome measures. Furthermore, meeting

abstracts and electronic article citations were matched for the iden-

tiﬁcation of duplicate studies. The trial selection was not blinded,

but it was done independently by the two authors; disagreements

were resolved by consensus. Reasons

⁄

for exclusion were

recorded.

Additional analyses

Owing to the heterogeneity of interventions and study designs, sen-

sitivity, subgroup and meta-regression analyses were not conducted.

Data collection process

One of the authors ﬁrst assessed study characteristics and extracted

outcome measures, while the other assessed the risks of bias; then

they reversed roles and veriﬁed each other’s extracted data. Discrep-

ancies were identiﬁed and resolved by consensus.

When information was insufﬁcient to assess outcome measures

from the published or presented data, study authors were contacted

by email. In the event of a lack of reply within 2 weeks, a second

request was sent. When authors further declined to provide the

requested information or original data, the mention ‘not provided

upon request’ was added to the tables or the study was excluded

from review, depending upon the amount of information available for

analysis. The extracted data were entered in tables similar to those

of the 2010 review. 6

Results

Study selection

The search of Medline, Web of Science and CAB Abstract

databases yielded a total of 672 citations, while 406 con-

gress abstracts were available after examination of their

online publication (Figure 1). Five replies were received

from queries sent to the three veterinary dermatology

lists. Among all citations, there were 48 clinical trials with

atopic dogs, of which 18 were excluded because of lack

of fulﬁlment of inclusion criteria. We subsequently elimi-

nated seven RCTs that had been presented at con-

gresses and later published as full papers (Figure 1).

Owing to insufﬁcient data available for full review and

Data items

The following parameters were extracted from each article and

from information obtained from the authors: objective of the study

(treatment or prevention of AD); study design (parallel or crossover);

⁄

110

Therapy of canine atopic dermatitis

Figure 1. Flow diagram of study selection. Abbreviations: AD, atopic dermatitis; and RCTs, randomized controlled trials.

analysis, we also removed one published and one

presented RCT. 19,20 The remaining 21 RCTs are reviewed

herein.

Participants.

The number of subjects varied among RCTs (average, 42;

median, 30; range, 10–316; Table 1). The lowest number

of dogs in a treatment group was ﬁve (T-cell receptor pep-

tide group 22 ) and the highest was 202 (masitinib group 25 ).

Only six of 21 RCTs (29%) performed or reported a power

analysis to justify subject numbers in each treatment

group. 25–30 All but one trial enrolled dogs with nonseason-

al AD, while the last looked at the effect of an intervention

to prevent recurrence of signs in dogs with predeﬁned

seasonal AD. 31

Several studies added further limitations to their enrol-

ment criteria. One trial of allergen-speciﬁc immunotherapy

(ASIT) selected only dogs with demonstrable hypersensi-

tivity to Dermatophagoides farinae house dust mites. 32

One RCT selected only dogs with pedal lesions, 21 another

selected dogs with at least mild signs, 30 while four studies

enrolled dogs with moderate to severe AD (A. Puigde-

mont, personal communication 2012). 25–27 Finally, two tri-

als needed dogs to have signs for a minimal duration

before selection (6 months 33 and 1 year 22 ).

Study characteristics

Details of study methodology, participants, interventions

and funding sources can be found in Table 1.

Publication status.

All but one study included in this review were RCTs

reported in English; one was in Italian. At the time of writ-

ing, 16 trials had been published in full in peer-reviewed

journals, three were published only as abstracts, 21–23 one

was accepted for publication at the time of selection 24

and one had neither been published nor presented, but

study details were provided for our review in response to

an email request to the vetderm list (A. Puigdemont, per-

sonal communication 2012).

Methods.

Of 21 RCTs, there were 17 that used a parallel design of

two groups or more, while the remaining four were cross-

over trials (Table 1). Fourteen studies had interventions

that were shorter than 8 weeks, hence were categorized

as ‘short term’; the other seven lasted from 2 to

9 months (i.e. ‘long-term’ studies). While the abstract

from one relapse prevention study did not specify the

duration of

Interventions.

All but four studies tested the efﬁcacy – and safety – of

various types of topical, oral or injectable interventions for

treatment of canine AD (Table 1). Two trials investigated

the effect of dietary interventions for their potential

reducing effect on concurrently given oral glucocortic-

oids. 23,27 Finally, two RCTs examined the outcome of

the trial, 24

it clearly lasted more than

2 months.

111

Table 1. Characteristics of included studies

First

author

(year)

Methods

(duration,

month)

Prevention

or treatment?

Short or

long term?

Participants

Interventions

Outcomes

Funding

Comments

Bensignor

(2008) 36

Crossover,

20 dogs with

nonseasonal

nonfood-

induced AD

Commercial

or home-made

ﬁsh and

potato diet

Treatment

Short-term

Change in

lesion and

pruritus scores

Procter and

Gamble Pet

Care

—

1 month

Glos

(2008) 34

Parallel, 2

months

50 dogs with

nonseasonal

Four different

commercial

diets

Treatment

Short-term

Change in

lesion and

pruritus

scores, coat

quality and

stool

characteristics

Procter and

Gamble Pet

Care

—

Bryden

(2008) 21

Crossover,

2 · 0.5 month

10 dogs with

nonseasonal

AD and pedal

lesions

Hydrocortisone

aceponate

spray or

placebo

Treatment

Short-term

Change in

lesion and

pruritus scores,

IGA, OGA

Virbac

Only affected

feet treated

Willemse

(2009) 32

Parallel, 9

months

38 dogs with

D. farinae sensitive

D. farinae restricted

subcutaneous

immunotherapy

or placebo

Treatment

Long-term

Change in lesion

and pruritus

scores

Artu Biologicals

Dogs also had

hypersensitivities

other than D. farinae

Nuttall

(2009) 26

Parallel, 1

month

29 dogs with

nonseasonal AD

and CADESI-03 > 50

Hydrocortisone

aceponate spray

or placebo

Treatment

Short-term

Change in lesion

and pruritus

scores, OGA

Virbac

Part 1 RCT data only

Horvath-

Ungerboeck

(2009) 38

Crossover,

30 dogs with

nonseasonal AD

Tepoxalin or

placebo

Treatment

Short-term

Change in

lesion and

pruritus

scores

Intervet

⁄

Schering-Plough

Animal Health

—

1 month

Carlotti

(2009) 35

Parallel,

6 months

31 dogs with AD

Recombinant

feline interferon-

Treatment

Long-term

Change in

lesion and

pruritus

scores

Virbac

—

or ciclosporin

Plevnik

(2009) 37

Parallel,

1.5 months

30 dogs with AD

Methylprednisolone

or fexofenadine

Treatment

Short-term

Change in

lesion and

pruritus

scores

Government of

Republic of

Slovenia

—

Noli

(2009) 31

Parallel, 6

months

14 dogs with

seasonal AD

recurrent for

at least 2 years

Blackcurrant seed

oil or placebo

Prevention

Long-term

Change in

lesion and

pruritus

scores

NBF Lanes

—

Yasukawa

(2010) 40

Parallel, 2

months

31 dogs with AD

Two different

dosages of

recombinant

canine interferon-c

Treatment

Short-term

Change in lesion

and pruritus

scores

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