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Abstract

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

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 efficacy 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 evidence 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 masitinib, with a need for monitoring for protein-losing nephropathy. Finally, we uncovered low-quality evidence of efficacy 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 interventions with highest evidence for efficacy and relative safety for treatment of canine AD.

Résumé

Contexte –  La gestion de la dermatite atopique canine (AD) repose principalement sur des méthodes de réduction du prurit et des lésions cutanées.

Objectifs –  Fournir une analyse critique des études cliniques récentes rapportant l’efficacité et l’innocuité des traitements de la dermatite atopique canine.

Méthodes –  Une revue systématique des études randomisées contrôlées (RCTs) publiées, présentées ou complétées entre 2008 et 2011, qui enrôlent les chiens atopiques. La recherche a été faite à partir de bases de données électroniques, de résumés de congrès publiés et par envoi de questionnaires sur des listes d’emails professionnels. Ont été sélectionnés les essais rapportant l’efficacité des interventions visant à traiter, prévenir ou réduire l’usage des glucocorticoïdes chez les chiens atopiques.

Résultats –  Vingt et un RCTs ont été inclues. Nous avons trouvé peu de preuves de qualité moyenne de l’efficacité et de l’innocuité des glucocorticoïdes oraux et de la ciclosporine pour le traitement de la dermatite atopique canine. Il y avait des preuves supplémentaires de qualité moyenne de l’efficacité des sprays corticoïdes topiques contenant de l’acéponate d’hydrocortisone. Un niveau de preuve faible a été trouvé pour l’efficacité et l’innocuité d’interférons recombinants injectables, de budésonide topique, d’une nano-émulsion topique de ciclosporine et de féxofénadine orale. Il y a un faible niveau de preuve de l’efficacité du masitinib oral avec la nécessité de surveiller la perte protéique liée à une néphropathie. Enfin, nous avons découvert un niveau de preuve faible de l’efficacité d’un régime industriel comme intervention d’épargne corticoïde et d’un spray corticoïde comme mesure de retard de crise. Un très faible niveau de preuve a été trouvé pour l’efficacité des autres interventions.

Conclusion et importance clinique –  Les glucocorticoïdes topiques et oraux ainsi que la ciclosporine orale restent les interventions avec le niveau de preuve d’efficacité et d’innocuité relative le pus élevé pour le traitement de la dermatite atopique canine.

Resumen

Introducción –  el manejo de la dermatitis atópica (AD) en perros se basa principalmente en la practica de tratamientos para reducir el prurito y las lesiones de piel.

Objetivos –  proporcionar un análisis crítico de ensayos clínicos recientes que indican eficacia y la seguridad de tratamientos para el manejo de la AD canina.

Métodos –  revisión sistemática de ensayos controlados seleccionados al azar (RCTs) publicados, presentados o terminados entre 2008 y 2011, que incluían perros con AD. La búsqueda fue hecha usando bases de datos electrónicas, evaluando resúmenes de conferencias científicas y enviando preguntas a listados profesionales de correo electrónico. Se seleccionaron aquellas pruebas que indicaban la eficacia de intervenciones para tratar, prevenir o reducir el uso de glucocorticoides en perros atópicos.

Resultados –  se incluyeron veintiún RCTs. Encontramos evidencia adicional de moderada calidad acerca de la eficacia y seguridad del uso de glucocorticoides orales y de ciclosporina para el tratamiento de AD canina. Se encontró evidencia adicional de moderada calidad indicando la eficacia de un aerosol con glucocorticoides tópico que contenía aceponato de hidrocortisona. Se obtuvo evidencia de baja calidad acerca de la eficacia y seguridad en el uso de interferones recombinantes inyectables, un acondicionador de budesonide, una nano-emulsión tópica de ciclosporina y fexofenadine por vía oral. También hay evidencia de baja calidad indicando la eficacia de masitinib por vía oral, con la necesidad de supervisar para posible nefropatía con perdida de proteínas. Finalmente, obtuvimos evidencia de baja calidad indicando eficacia de una dieta comercial para disminuir la dosis de glucocorticoides y de un aerosol de glucocorticoides para retrasar los empeoramientos clínicos. Se encontró evidencia de muy de baja calidad indicando eficacia de otras intervenciones.

Conclusiones e importancia clínica –  los glucocorticoids tópicos u orales y la ciclosporina oral continúan siendo los tratamientos mas eficaces y relativamente seguros para el control de la AD canina.

Zusammenfassung

Hintergrund –  Das Management der atopischen Dermatitis (AD) beim Hund beruht hauptsächlich auf dem Ergreifen von Maßnahmen, die den Juckreiz und die Hautveränderungen reduzieren.

Ziele –  Das Ziel dieser Studie war es, eine kritische Analyse jüngster Studien, die über die Wirksamkeit und die Sicherheit von Maßnahmen bei der caninen AD berichten, durchzuführen.

Methoden –  Es wurde eine systematische Review zufälliger kontrollierter Studien (RCTs), bei denen Hunde mit AD verwendet wurden und die zwischen 2008 und 2011 publiziert, präsentiert oder fertig gestellt wurden, durchgeführt. Die Suche wurde mit elektronischen Datenbanken, mittels Durchsicht publizierter Abstracts von Konferenzen und mittels Fragebögen an professionelle e-mail Listen durchgeführt. Es wurden Studien, welche über die Wirksamkeit von Eingriffen, die auf die Behandlung, die Vermeidung oder die Reduktion von Glukokortikoiden bei atopischen Hunden berichteten, ausgewählt.

Ergebnisse –  Es wurden einundzwanzig RCTs inkludiert. Wir fanden Evidenz von moderater Qualität und Sicherheit für die Verwendung von Glukokortikoiden und Ciclosporin für die Behandlung von caniner AD. Es bestand zusätzlich Evidenz von moderater Qualität im Bezug auf die Wirksamkeit von topisch angewandtem Glukokortikoid-Spray, der Hydrocortison Aceponat enthält. Eine Evidenz niedriger Qualität wurde für die Verwendung von injizierbaren rekombinanten Interferonen, einen Budesonid Leave-on Conditioner, eine Ciclosporin Nano-Emulsion zur topischen Anwendung und ein per os zu verabreichendes Fexofenadin gefunden. Es besteht Evidenz von geringer Qualität für die Wirksamkeit von Masitinib per os, was die Überwachung einer Protein-losing Enteropathie notwendig macht. Letztendlich deckten wir Evidenz niedriger Qualität für die Wirksamkeit einer kommerziellen Diät als Glukokortikoid-sparende Maßnahme sowie für die Verwendung eines Glukokortikoid Sprays als Maßnahme zur Verhinderung von Juckreizschüben auf. Wirksamkeit von sehr niedriger Qualität wurde für alle anderen Maßnahmen gefunden.

Schlussfolgerungen und klinische Bedeutung –  Die Maßnahmen mit der höchsten Evidenz im Bezug auf Wirksamkeit und relativer Sicherheit bei der Behandlung caniner AD bleiben topisch angewandte und per os verabreichte Glukokortikoide sowie per os verabreichtes Ciclosporin.

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Introduction

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

Atopic dermatitis (AD) is a common allergic skin disease of dogs that is currently defined as a genetically predisposed inflammatory and pruritic skin disease, with characteristic clinical features and an association with IgE antibodies most commonly directed against environmental allergens.1 This disease has recently been shown to have a strong impact on the quality of life of both affected dogs and their owners2,3 and, as such, it is probably one of the most important chronic skin diseases of dogs.

Recent international practice guidelines have highlighted the need for a multifaceted line of attack for the management of canine AD.4 Approaches to consider currently 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 systematic reviews of interventions to treat dogs with AD. The first review, published in 2003,5 analysed results of clinical trials testing pharmacological interventions, whether the trials were randomized or not; it did not discuss studies evaluating the efficacy of essential fatty acid (EFA) formulations or allergen-specific immunotherapy, and it was limited to clinical trials published in peer-reviewed journals.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 trials 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

Objectives

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

To determine the efficacy of interventions to treat or prevent skin lesions and/or pruritic manifestations of canine AD, we carried out a systematic review of 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 systematic reviews and meta-analyses set up by the latest 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.7

Methods

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

Protocol and registration

With minor changes in outcome measures and study selection criteria, 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 systematic 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 published, 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 Willemse10, Prélaud 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 done in our preceding systematic review,6 RCTs were categorized 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 assessment of the extent and/or intensity of pruritus 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 proportion 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 baseline of investigator-graded lesional (secondary outcome 2a) or owner-rated pruritus scores (secondary outcome 2b). In the absence of universally 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 outcome 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 studies, we used different outcome measures that appeared to be more clinically relevant for these unique study designs. These ad hoc outcome measures were the glucocorticoid dosage at study end and the time to relapse, respectively.

Whenever possible and to provide a better comparison of the efficacy 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 relevance 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.

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 outcome over treatment with placebo. The lower the NNT, the stronger the treatment effect over placebo.

Finally, in this review, we extracted and reviewed adverse events following each nonplacebo intervention.

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 Dermatology (ESVD) and European College of Veterinary Dermatology (ECVD) of 2009, 2010 and 2011, as well as those of the North American 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 Dipderm) requesting colleagues to provide information on recently completed studies. Finally, we contacted, by email, representatives of three companies known to the authors to have completed relevant RCTs.

Search

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 December 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.).

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/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 identification 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.

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. Discrepancies 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

Data items

The following parameters were extracted from each article and/or from information obtained from the authors: objective of the study (treatment or prevention of AD); study design (parallel or crossover); duration of the trial; type of duration (short or long term); characteristics 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 funding source.

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 ‘assessment 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 ‘inadequate 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.

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 available, 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).

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 compare 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 consistent with those employed in recent RCTs enrolling dogs with AD and if they appeared clinically relevant.

Additional analyses

Owing to the heterogeneity of interventions and study designs, sensitivity, subgroup and meta-regression analyses were not conducted.

Results

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

Study selection

The search of Medline, Web of Science and CAB Abstract databases yielded a total of 672 citations, while 406 congress 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 eliminated seven RCTs that had been presented at congresses and later published as full papers (Figure 1). Owing to insufficient data available for full review and analysis, we also removed one published and one presented RCT.19,20 The remaining 21 RCTs are reviewed herein.

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

Download figure to PowerPoint

Study characteristics

Details of study methodology, participants, interventions and funding sources can be found in Table 1.

Table 1.   Characteristics of included studies
First author (year)Methods (duration, month)ParticipantsInterventionsPrevention or treatment?Short or long term?OutcomesFundingComments
  1. Abbreviations: AD, atopic dermatitis; EFA, essential fatty acids; IGA, Investigator Global Assessment; ITT, intention to treat; OGA, Owner Global Assessment; QoL, quality of life.

Bensignor (2008)36Crossover, 2 × 1 month20 dogs with nonseasonal nonfood-induced ADCommercial or home-made fish and potato dietTreatmentShort-termChange in lesion and pruritus scoresProcter and Gamble Pet Care
Glos (2008) 34Parallel, 2 months50 dogs with nonseasonal ADFour different commercial dietsTreatmentShort-termChange in lesion and pruritus scores, coat quality and stool characteristicsProcter and Gamble Pet Care
Bryden (2008)21Crossover, 2 × 0.5 month10 dogs with nonseasonal AD and pedal lesionsHydrocortisone aceponate spray or placeboTreatmentShort-termChange in lesion and pruritus scores, IGA, OGAVirbacOnly affected feet treated
Willemse (2009)32Parallel, 9 months38 dogs with D. farinae sensitive AD D. farinae restricted subcutaneous immunotherapy or placeboTreatmentLong-termChange in lesion and pruritus scoresArtu BiologicalsDogs also had hypersensitivities other than D. farinae
Nuttall (2009) 26Parallel, 1 month29 dogs with nonseasonal AD and CADESI-03 > 50Hydrocortisone aceponate spray or placeboTreatmentShort-termChange in lesion and pruritus scores, OGAVirbacPart 1 RCT data only
Horvath-Ungerboeck (2009) 38Crossover, 2 × 1 month30 dogs with nonseasonal ADTepoxalin or placeboTreatmentShort-termChange in lesion and pruritus scoresIntervet/Schering-Plough Animal Health
Carlotti (2009) 35Parallel, 6 months31 dogs with ADRecombinant feline interferon-ω or ciclosporinTreatmentLong-termChange in lesion and pruritus scoresVirbac
Plevnik(2009) 37Parallel, 1.5 months30 dogs with ADMethylprednisolone or fexofenadineTreatmentShort-termChange in lesion and pruritus scoresGovernment of Republic of Slovenia
Noli (2009) 31Parallel, 6 months14 dogs with seasonal AD recurrent for at least 2 yearsBlackcurrant seed oil or placeboPreventionLong-termChange in lesion and pruritus scoresNBF Lanes
Yasukawa (2010)40Parallel, 2 months31 dogs with ADTwo different dosages of recombinant canine interferon-γTreatmentShort-termChange in lesion and pruritus scoresToray Industries
Schmidt (2010)27Parallel, 2 months22 dogs with nonseasonal moderate/severe ADMethylprednisolone + Phytopica herbal preparation or placeboTreatment (steroid-sparing effect)Short-termChange in lesion and pruritus scores, OGA, methylprednisolone dosageIntervet/Schering-Plough Animal Health
Singh (2010)33Parallel, 2 months30 dogs with AD >0.5 year durationPentoxifylline, EFA or placeboTreatmentShort-termChange in lesion and pruritus scoresUnclear
Ahlstrom (2010)28Crossover, 2 × 3 weeks29 dogs with ADBudesonide conditioner or placeboTreatmentShort termChange in lesion and pruritus scores, QoLDermcare-Vet
Kovalik (2011)39Parallel, 1.5 months20 dogs with ADGeneric ciclosporin or prednisoneTreatmentShort-termChange in lesion and pruritus scoresTeva Pharmaceuticals
Mueller (2011)29Parallel, 3 months21 dogs with AD Trichuris vulpis eggs or placeboTreatmentLong-termChange in lesion and pruritus scoresCanine Research Society
Sanchez (2011)23Parallel, 2 months22 dogs with nonseasonal nonfood-associated ADPrednisone and fatty acid-rich or commercial dietsTreatment (steroid-sparing effect)Short-termChange in lesion and pruritus scores, prednisone dosageAffinity Petcare
Gingerich (2011)22Parallel, 1.5 months11 dogs with nonseasonal AD >1 year durationTCR-Vß8.1 or placeboTreatmentShort-termChange in lesion and pruritus scoresImmulan BioTherapeutics
Nuttall (2012) 30Parallel, 3 months48 dogs with at least mild nonseasonal ADHydrocortisone aceponate spray or ciclosporinTreatmentLong-termChange in lesion and pruritus scores, OGAVirbac
Cadot (2011) 25Parallel, 3 months316 dogs with nonseasonal AD and CADESI-02 > 25Masitinib or placeboTreatmentLong-termChange in lesion and pruritus scores, IGA, OGAAB-Science306 dogs analysed (modified ITT)
Lourenço (2012) 24Parallel, variable41 dogs with ADHydrocortisone aceponate spray or placeboPreventionLong-termTime to relapse necessitating treatmentVirbac
Puigdemont (2012) UnpublishedParallel, 1.5 months32 dogs with moderate or severe nonseasonal ADTopical ciclosporin or placeboTreatmentShort-termChange in lesion and pruritus scoresAdvancell
Publication status.

All but one study included in this review were RCTs reported in English; one was in Italian. At the time of writing, 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 selection24 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, personal communication 2012).

Methods.

Of 21 RCTs, there were 17 that used a parallel design of two groups or more, while the remaining four were crossover 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 the trial,24 it clearly lasted more than 2 months.

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 peptide group22) and the highest was 202 (masitinib group25). 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 nonseasonal 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 enrolment criteria. One trial of allergen-specific immunotherapy (ASIT) selected only dogs with demonstrable hypersensitivity 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. Puigdemont, personal communication 2012).25–27 Finally, two trials needed dogs to have signs for a minimal duration before selection (6 months33 and 1 year22).

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 glucocorticoids.23,27 Finally, two RCTs examined the outcome of interventions aimed at preventing the recurrence of flares of AD (i.e. prevention studies).24,31

Outcome measures.

As indicated in Table 1 and per selection criteria, all studies reported one or more outcome measures of efficacy. In general, these included the evolution, over the duration of the tested intervention(s), of pruritus and/or skin lesions scores (Table 1). To these were added, in five RCTs (Table 1), owner- and/or investigator-assessed global assessment ratings.21,25–27,30 In one study, the evaluation of quality of life (QoL) was also added.28 The two studies on glucocorticoid-sparing effect logically included the evaluation of the reduction in the dosage of oral glucocorticoids.23,27 Finally, one of the two prevention studies used ‘time to relapse necessitating treatment’ as a logical and relevant outcome measure for that particular design.24

Of the RCTs that tested the evolution of skin lesions over time, the validated third version of the CADESI score was used in 10 studies,21–24,26,27,29,30,34,35 while five trials employed the second version of this scale, which had limited validation.25,31,33,36,37 Four trials employed unvalidated scales modified from the first, second or third versions of the CADESI – the so called ‘modified CADESI’ or ‘mCADESI’– having changed the type of lesions, the body sites and/or the severity rating used (A. Puigdemont, personal communication 2012).28,38,39 One trial employed a scale derived from the ‘six area six signs AD’ (SASSAD) used in human patients with AD even though this scale had not been validated beforehand for canine AD.32 Finally, one study used a simple but not validated six-point categorical scale.40

Of 20 RCTs that tested the efficacy of interventions on pruritus, 16 used the evolution of scores obtained on a visual analog scale (VAS), which varied between 5 and 20 cm; only three22,29,30 used the PVAS developed and validated by Hill and colleagues,15 even though it was first published in 2007 before some of these RCTs were designed. Finally, three trials used other ad hoc unvalidated pruritus scales.35,38,40

Funding.

One trial was funded by a grant from the government of the Republic of Slovenia,37 while all others were funded by pharmaceutical companies.

Risk of bias in individual studies

Details on each study’s randomization method, intervention masking, loss to follow-up, diagnosis certainty, baseline group comparison, compliance assessment and overall quality rating can be found in Table 2.

Table 2.   Assessment of study design
First author (year)Generation of randomization sequenceAllocation concealmentIntervention maskingLoss to follow-upDiagnosis certaintyGroups comparable at baselineAssessment of complianceQuality
  1. Abbreviation: ITT, intention to treat.

Bensignor (2008) 36Adequate (coin toss)AdequateInvestigator onlyITT not performedAdequateYesNot assessedIntermediate
Glos (2008) 34Adequate (randomization table)AdequateAdequateITT performedAdequateYesNot assessedHigh
Bryden (2008) 21Adequate (computer)AdequateAdequateITT on all data provided by authorAdequateYesNot assessedHigh
Willemse (2009) 32Adequate (computer)AdequateAdequateITT performedAdequateYesAdequateHigh
Nuttall (2009) 26Adequate (computer)AdequateAdequateITT performedAdequateYesAdequateHigh
Horvath-Ungerboeck (2009) 38Adequate (block)AdequateAdequateITT not performedAdequateYesNot assessedIntermediate
Carlotti (2009) 35Adequate (computer)AdequateAdequateITT not performedAdequateYesAdequateIntermediate
Plevnik (2009) 37InadequateInadequateInadequateITT on all data provided by authorAdequateYesNot assessedIntermediate
Noli (2009)31InadequateInadequateAdequateITT on all data provided by authorAdequateYesNot assessedIntermediate
Yasukawa (2010) 40Adequate (table)AdequateNot performedITT performedAdequateHigher pruritus in 5000 units group at baselineNot provided upon requestIntermediate
Schmidt (2010) 27Adequate (computer)AdequateAdequateITT performedAdequateYesAdequateHigh
Singh (2010) 33InadequateInadequateNot performedITT not performedAdequateYesNot assessedPoor
Ahlstrom (2010) 28Adequate (coin toss)AdequateAdequateITT performedAdequateCarry over of budesonide effect if given before placeboAdequateHigh
Kovalik (2011) 39InadequateAdequateInvestigator onlyITT performedAdequateYesUnclearIntermediate
Mueller (2011) 29Adequate (randomization table)AdequateAdequateITT performedAdequateYesAdequateHigh
Sanchez (2011) 23Adequate (table)AdequateAdequateITT performedAdequateYesNot assessedHigh
Gingerich (2011) 22Adequate (block)AdequateAdequateITT on all data provided by authorAdequateYesAdequateHigh
Nuttall (2012) 30Adequate (computer)AdequateInvestigator onlyITT performedAdequateYesAdequateHigh
Cadot (2011) 25Adequate (computer)AdequateAdequateModified ITT performedAdequateYesAdequateHigh
Lourenço (2012) 24AdequateAdequateAdequateITT performedAdequateYesAdequateHigh
Puigdemont (2012) UnpublishedAdequate (computer)AdequateAdequateITT performedAdequateYesAdequateHigh

In summary, out of 21 RCTs, only one had an overall quality rated as ‘poor’,33 seven were given an ‘intermediate’ rating,31,35–40 and the remaining 13 had the highest quality mark (Table 2). The most common reason for not attributing this ‘high-quality’ rating was a lack of performance of ITT analyses.33,35,36,38

Results of individual studies

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

As in our recent systematic review,6 individual trials will be discussed below in groups testing similar interventions within three larger subheadings: (i) treatment; (ii) glucocorticoid sparing; and (iii) prevention RCTs. Details on study design and quality assessment can be found in Tables 1 and 2, respectively.

Interventions for treatment of clinical signs

Glucocorticoids.

Two RCTs used an oral glucocorticoid as control for another intervention,37,39 while four tested the efficacy of a topical glucocorticoid (Table 3).21,26,28,30

Table 3.   Randomized controlled trials evaluating interventions for treatment effect
First author (year)InterventionPrimary outcome measure (NNT)Secondary outcome measure (NNT)Comments
1a1b1a1b2a2b3a3b4a4b
Percentage of dogs with good-to-excellent response (clinician)Percentage of dogs with good-to-excellent response (owner)Percentage of dogs in complete remission (>90% reduction lesions)Percentage of dogs in complete remission (>90% reduction pruritus)Percentage of dogs in partial remission (>50% reduction lesions)Percentage of dogs in partial remission (>50% reduction pruritus)Percentage of dogs with lesions in the range of normal dogsPercentage of dogs with pruritus in the range of normal dogsPercentage of dogs with lesions in the range of dogs with mild ADPercentage of dogs with pruritus in the range of dogs with mild AD
  1. Abbreviations: AD, atopic dermatitis; EFA, essential fatty acids; EPS, Edinburgh Pruritus Score; FEX, fexofenadine; HCA, hydrocortisone aceponate; ITT, intention to treat; MP, methylprednisolone; n.a., not available or not assessable; NNT, number needed to treat; n.p., not provided by authors upon request; p.o., per os; PTX, pentoxifylline; s.c, subcutaneousy; TCR, T-cell receptor; VAS, visual analog scale

Bensignor (2008)36Commercial or home-made fish and potato dietn.a.n.a.Commercial, 0/16 (0%). Home-made, 0/16 (0%)Commercial, 0/16 (0%). Home-made, 0/16 (0%)Commercial, 0/16 (0%). Home-made, 0/16 (0%)Commercial, 2/16 (1%). Home-made, 1/16 (1%)n.a.n.a.n.a.n.a.Reported reduction in average pruritus and skin lesions scores while on commercial but not home-made diet
Glos (2008)34Diet A, Hill’s canine d/d salmon & rice. Diet B, Eukanuba FP fish and potato. Diet C, Royal Canin Hypoallergenic DR21. Diet D, Pedigree Complete Maxi chicken and ricen.a.n.a.A, 1/14 (7%). B, 2/12 (17%). C, 2/12 (17%). D, 1/12 (8%)A, 1/14 (7%). B, 1/12 (8%). C, 1/12 (8%). D, 0/12 (0%).A, 7/14 (50%). B, 9/12 (75%). C, 5/12 (42%). D, 6/12 (50%).A, 5/14 (36%). B, 6/12 (50%). C, 2/12 (17%). D, 4/12 (33%)A, 4/14 (29%). B, 10/12 (83%). C, 3/12 (25%). D, 7/12 (59%)n.a.A, 6/14 (43%). B, 1/12 (8%). C, 9/12 (75%). D, 5/12 (42%)n.a.Eight dogs also treated with prednisolone, 1 with ciclosporin; coat became more lustrous with diet A; outcome measures provided by authors
Bryden (2008)21HCA once daily for 7 days then every other day for 7 days or placebo topicallyHCA, 3/10 (30%). Placebo, 0/10 (0%)HCA, 3/10 (30%). Placebo, 0/10 (0%)n.a.n.a.n.a.n.a.HCA, 3/10 (30%). Placebo, 1/10 (10%) (erythema)HCA, 1/10 (10%). Placebo, 1/10 (10%)HCA, 5/10 (50%). Placebo, 1/10 (10%) (erythema)HCA, 7/10 (70%). Placebo, 1/10 (10%)Outcome measures calculated from raw data provided by authors
Willemse (2009)32 D. farinae specific subcutaneous immunotherapy (standard protocol)n.a.n.a.n.a.n.a.n.a.n.a.n.a.n.a.n.a.n.a.No significant differences in pruritus and lesion scores between immunotherapy and placebo groups
Nuttall (2009)26HCA once daily or placebo topicallyn.a.HCA, 6/15 (40%). Placebo, 2/13 (15%)HCA, 1/15 (7%). Placebo, 0/13 (0%)HCA, 4/15 (27%). Placebo, 0/13 (0%)HCA, 11/15 (73%). Placebo, 3/13 (23%)HCA, 7/15 (47%). Placebo, 1/13 (8%)HCA, 4/15 (27%). Placebo, 0/13 (0%)n.a.HCA, 7/15 (47%). Placebo, 5/13 (39%)n.a.Primary outcome 1b: grades 4 and 5 combined; other outcome measures provided by authors
Horvath-Ungerboeck (2009)38Tepoxalin 10 mg/kg once daily or placebo p.o.n.a.n.a.Tepoxalin, 1/28 (4%). Placebo, 2/25 (8%)n.a.Tepoxalin, 7/28 (25%). Placebo, 4/25 (16%)Tepoxalin, 10/28 (36%). Placebo, 4/25 (16%)n.a.Tepoxalin, 4/28 (14%). Placebo, 1/25 (4%)n.a.Tepoxalin, 11/28 (39%). Placebo, 5/25 (20%)Normal dog: EPS = 0; mild AD: EPS = 1
Carlotti (2009)35Recombinant feline interferon-ω 1–4 million units/injection s.c. or ciclosporin 50–200 mg/day p.o.n.a.n.a.Interferon, 3/18 (17%). Ciclosporin, 4/8 (50%)Interferon, 3/18 (17%). Ciclosporin, 2/8 (25%)Interferon, 9/18 (50%). Ciclosporin, 4/8 (50%)Interferon, 7/18 (39%). Ciclosporin, 5/8 (63%)Interferon, 4/18 (22%). Ciclosporin, 2/8 (25%)n.a.Interferon, 4/18 (22%). Ciclosporin, 2/8 (25%)n.a.
Plevnik (2009)37MP 0.5 mg/kg once daily for 5 days, then every other day. FEX 18 mg/kg once daily. Both p.o.n.a.n.a.MP, 0/15 (0%). FEX, 3/15 (20%)MP, 5/15 (33%). FEX, 4/15 (27%)MP, 12/15 (80%). FEX, 14/15 (93%)MP, 10/15 (67%). FEX, 12/15 (80%)n.a.n.a.n.a.n.a.Outcome measures calculated from raw data provided by authors
Yasukawa (2010)40Recombinant canine interferon-γ 2000 or 5000 units/kg three times weekly for 4 weeks, then once weekly for 4 weeks s.c.n.a.n.a.n.a.n.a.2000 units, 4/11 (36%). 5000 units, 9/14 (64%)2000 units, 5/11 (46%). 5000 units, 11/14 (79%)n.a.n.a.n.a.n.a.8 week per protocol data extracted from table; erythema and pruritus parameters only
Singh (2010)33PTX 20 mg/kg three times daily, PTX + EFA mix or placebo, all p.o.n.a.n.a.n.a.n.a.n.a.n.a.PTX, 3/11 (27%). PTX + EFA, 5/12 (42%). Placebo, 0/4 (0%)n.a.n.a.Data shown are dogs with 100% remission of both CADESI-02 and pruritus VAS; author reported no longer having access to study data 
Ahlstrom (2010)28Budesonide 0.025% conditioner once weekly or placebo topicallyn.a.n.a.Budesonide, 3/29 (10%). Placebo, 0/29 (0%)Budesonide, 6/29 (21%). Placebo, 5/29 (17%)Budesonide, 20/29 (69%). Placebo, 5/29 (17%)Budesonide, 19/29 (66%). Placebo, 9/29 (31%)n.a.n.a.n.a.n.a.Higher quality-of-life values after budesonide; ITT data sets
Kovalik (2011)39Ciclosporin 5 mg/kg once daily or prednisone 1 mg/kg once daily for 7 days then every other day, both p.o.n.a.n.a.Ciclosporin, 7/13 (54%). Prednisone, 2/7 (29%)Ciclosporin, 4/13 (31%). Prednisone, 0/7 (0%)Ciclosporin, 11/13 (85%). Prednisone, 6/7 (86%)Ciclosporin, 10/13 (77%). Prednisone, 6/7 (86%)n.a.n.a.n.a.n.a.
Mueller (2011)29 Trichuris vulpis 2500 embryonated eggs or placebo p.o.n.a.n.a. Trichuris, 0/11 (0%). Placebo, 0/10 (0%) Trichuris, 0/11 (0%). Placebo, 1/10 (10%) Trichuris, 4/11 (36%). Placebo, 1/10 (10%) Trichuris, 3/11 (27%). Placebo, 0/10 (0%) Trichuris, 7/11 (64%). Placebo, 6/10 (60%) Trichuris, 2/11 (18%). Placebo, 2/10 (20%) Trichuris, 2/11 (18%). Placebo, 2/10 (20%) Trichuris, 3/11 (27%). Placebo, 2/10 (20%)Outcome measures provided by the authors
Gingerich (2011)22TCR-Vß8.1 100 mg injected twice or placebo s.c.n.a.n.a.TCR, 0/5 (0%). Placebo, 0/6 (0%)TCR, 1/5 (20%). Placebo, 0/6 (0%)TCR, 4/5 (80%). Placebo, 1/6 (17%)TCR, 4/5 (80%). Placebo, 1/6 (17%)TCR, 2/5 (40%). Placebo, 3/6 (50%)TCR, 3/5 (60%). Placebo, 2/6 (33%)TCR, 2/5 (40%). Placebo, 1/6 (17%)TCR, 1/5 (20%). Placebo, 1/6 (17%)Two dogs treated with placebo had normal CADESI-03 at baseline and at study end
Nuttall (2012)30HCA once daily topically or ciclosporin 5 mg/kg once daily p.o.; frequencies decreased to every other day or twice weekly if effectiven.a.HCA, 19/24 (79%). Ciclosporin 10/21 (48%)HCA, 9/24 (38%). Ciclosporin, 8/21 (38%)HCA, 5/24 (21%). Ciclosporin, 5/21 (24%)HCA, 18/24 (75%). Ciclosporin, 18/21 (86%)HCA, 16/24 (67%). Ciclosporin, 12/21 (57%)HCA, 8/24 (33%). Ciclosporin, 9/21 (43%)HCA, 10/24 (42%). Ciclosporin, 7/21 (33%)HCA, 5/24 (21%). Ciclosporin, 2/21 (10%)HCA, 0/24 (0%). Ciclosporin, 1/21 (5%)Outcome measures provided by authors, ITT with last value carried forward
Cadot (2011)25Masitinib 12.5 mg/kg or placebo once daily p.o.Masitinib, 90/202 (45%). Placebo, 26/104 (25%) (NNT, 6)Masitinib, 80/202 (40%). Placebo, 31/104 (30%) (NNT, 11)n.p.n.p.Masitinib, 86/202 (43%). Placebo, 27/104 (26%) (NNT, 6)n.p.n.a.n.a.n.a.n.a.All outcome measures from modified ITT with missing data as failure
Puigdemont (2012) UnpublishedCiclosporin 2.25% nano-emulsion twice daily or placebo topicallyn.a.n.a.Ciclosporin, 5/17 (29%). Placebo, 1/15 (7%)Ciclosporin, 2/17 (12%). Placebo, 1/15 (7%)Ciclosporin, 11/17 (65%). Placebo, 4/15 (27%)Ciclosporin, 10/17 (59%). Placebo, 5/15 (33%)n.a.n.a.n.a.n.a.Outcome measures provided by authors; ITT with last value carried forward

One study reported the efficacy of methylprednisolone (Medrol; Pharmacia, Luxemburg, Luxemburg),37 while the second used prednisone (Encorton; Polfa Pharmaceuticals, Lublin, Poland).39 In both studies, drug dosages and protocols corresponded to those employed and recommended in recent practice guidelines.4 In these two small trials, the frequencies of dogs that achieved positive outcomes (Table 3) are in the range of those found after similar interventions (reviewed by Olivry et al.6). The results suggest treatment efficacy even though the glucocorticoids were not compared with placebo but were used as positive comparators for another intervention. Adverse effects reported in the publications were those expected for oral glucocorticoids.37,39

Three RCTs reported efficacy data for the same novel diester glucocorticoid spray that contains 0.0584% hydrocortisone aceponate (Cortavance; Virbac, Carros, France),21,26,30 while one tested the effectiveness of a novel glucocorticoid leave-on conditioner containing 0.025% budesonide (Barazone; Dermcare-Vet, Springwood, Queensland, Australia; Table 3).28 Three studies were placebo controlled,21,26,28 while one used ciclosporin as the active control.30 One trial focused on pedal pruritus and skin lesions;21 two had a crossover design.21,28

In two studies, the hydrocortisone aceponate spray appeared to be more effective than placebo for nearly all outcome measures (Table 3 and Figures 2 and 3).21,26 The magnitude of the effect was dampened by the small size of each treatment group, this being shown by the very large confidence interval bracketing the relative risk (Figures 2 and 3). In the largest trial, the outcome measures of efficacy were comparable between the glucocorticoid spray and ciclosporin.30 The safety of this diester glucocorticoid spray was found to be acceptable, with the lack of report of relevant adverse drug events.21,26,30 Remarkably, skin thinning was not reported with this formulation, even after 3 months of usage at frequencies varying from once daily to twice weekly.30

image

Figure 2.  Forest plot of the primary outcome measure 1a: clinician global assessment of efficacy. In this figure, the event rate represents the number of dogs for which clinicians reported a good-to-excellent response at trials’ end. In these plots, the vertical line (‘1’) represents the ‘no effect’ line. The horizontal bar spanning the blue squares highlights the confidence interval of the risk ratio (i.e. treatment effect). In this graph, the size of the blue square was not made proportional to the size of the study. Interventions 1 and 2 are the ones listed in the second column. Abbreviations: CI, confidence interval; HCA, hydrocortisone aceponate; and M-H, Mantel–Haenszel test.

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image

Figure 3.  Forest plot of the primary outcome measure 1b: owner global assessment of efficacy. In this figure, the event rate represents the number of dogs for which owners reported a good-to-excellent response at trials’ end. In these plots, the vertical line (‘1’) represents the ‘no effect’ line. The horizontal bar spanning the blue squares highlights the confidence interval of the risk ratio (i.e. treatment effect). In this graph, the size of the blue square was not made proportional to the size of the study. Interventions 1 and 2 are the ones listed in the second column. Abbreviations: CI, confidence interval; HCA, hydrocortisone aceponate; M-H, Mantel–Haenszel test.

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A once-weekly application of the 0.025% budesonide leave-on conditioner appeared more effective than placebo for the achievement of outcome measures of partial (≥50%) but not complete (≥90%) reduction of pruritus and skin lesions (Table 3). In this crossover study, there was a carry-over effect of budesonide on skin lesions when it had been applied before placebo. Quality of life was reported to be significantly higher with the glucocorticoid conditioner than after placebo application.28 This conditioner was discussed as having a good-to-excellent tolerance, and there were no differences between placebo and actively treated dogs for scores of polydipsia, polyphagia and skin thinning.

Ciclosporin.

Oral ciclosporin (Atopica; Novartis Animal Health, Basel, Switzerland) was used in two RCTs as an active comparator for two other interventions (Table 3).30,35 In another trial, a generic microemulsified formulation of ciclosporin (Equoral; Teva Pharmaceuticals, Warsaw, Poland) was tested against prednisone (see glucocorticoid section above for details on the prednisone arm),39 and a fourth RCT evaluated the efficacy of a novel topical 2.25% nano-emulsion of ciclosporin (Cyclostopic-Vet; Advancell, Barcelona, Spain) versus placebo (A. Puigdemont, personal communication 2012). In trials were ciclosporin was used as a positive comparator,30,35 secondary outcome measures were found to be in the range of those reported in the previous systematic review that had analysed data from six RCTs (Table 3).6 Positive outcome measures obtained using the generic formulation of ciclosporin were also similar to those reported previously for the brand approved for the treatment of canine AD.6 This generic formulation also appeared to be of an efficacy equivalent to that of oral prednisone.39 In these three studies, adverse effects of ciclosporin were mainly the expected occurrences of mild, usually self-limiting vomiting, loose stools and diarrhoea.

Positive outcome measures were more frequently achieved after the twice-daily application of the novel topical ciclosporin nano-emulsion for 6 weeks than after that of placebo (Table 3). Adverse events were not seen.

Interferons.

There were two intermediate-quality-graded small RCTs testing the efficacy of recombinant interferons for the treatment of canine AD (Table 3).

In one study,35 dogs were treated with either injections of recombinant feline interferon-ω (Virbagen Omega; Virbac, Carros, France), a type I interferon, plus capsules of placebo, or they received oral ciclosporin capsules (Atopica; Novartis Animal Health, Basel, Switzerland) and placebo injections. Positive secondary outcome measures were seen more often after treatment with oral ciclosporin than with injectable feline interferon-ω (Table 3), but the improvement between groups was of the same order of magnitude. Relevant adverse events were not seen except for one dog that repeatedly exhibited increased pruritus 3 days after interferon injections.

In the second RCT, dogs received injections of one of two different dosages of recombinant canine interferon-γ (KT-100; Toray Industries, Tokyo, Japan) in a nonblinded fashion.40 For evaluation of skin lesions, we reviewed only data for the parameter ‘erythema’, because the other two lesions (‘excoriations’ and ‘alopecia’) were secondary to pruritus, which was evaluated separately. The reduction of erythema and pruritus was greater with the higher dosage of canine interferon-γ (5000 units/kg/injection; Table 3), even though the pruritus scores had been significantly higher in that group at baseline. Safety appeared excellent, except for one dog from the high dosage group that exhibited immediate allergic signs shortly after an injection.

Diets.

Two studies looked at the benefit of using commercial diets for treatment of canine AD.34,36

In the first RCT, which had a crossover design without washout, dogs with nonfood-induced AD were given either a home-made fish and potato diet or a commercially available diet with similar ingredients (Eukanuba FP dry; Iams, Procter & Gamble Pet Care, Schwalbach, Germany). The main difference between these two interventions was the lack of supplementation with EFA, minerals and vitamins in the home-made diet. The study authors reported that skin lesion and pruritus scores decreased more often after the commercial than the home-made diet, but there were no difference in rates of achievement of secondary outcome measures between the two interventions (Table 3). Adverse events were not discussed in this paper.

The second RCT compared the effect of three diets marketed for allergic dogs with that of a widely used commercial diet.34 Dogs were randomized to be fed Hill’s prescription diet Canine d/d Salmon & Rice (Hill’s Pet Nutrition, Hamburg, Germany), Eukanuba Dermatosis FP (Procter & Gamble Pet Care, Schwalbach, Germany) Royal Canin Hypoallergenic DR21 (Royal Canin, Köln, Germany) or the Pedigree Complete Maxi Chicken & Rice (Masterfoods, Verden, Germany) control diet (Table 3). Of importance is that enrolled dogs had not all been subjected to a dietary restriction–provocation test beforehand, and this could have affected treatment benefit if any dog had eaten a diet containing ingredients to which it was hypersensitive. In all, positive secondary outcome measures were reached in a highly variable percentage of dogs being fed the test or control diets, and these outcome measures were also inconsistently achieved within each diet group (Table 3). Clinically relevant and constant differences in benefit from any of the ‘allergic’ diets over the control diet were not found.

Miscellaneous.

Seven trials evaluated the efficacy of a variety of interventions to treat dogs with AD. The tested interventions included D. farinae restricted immunotherapy in dogs hypersensitive to this plus other allergens,32 the cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase inhibitor tepoxalin (Zubrin; Intervet/Schering-Plough Animal Health, Boxmeer, The Netherlands),38 the type 1 histamine receptor inverse agonist (antihistamine) fexofenadine (Telfast; Sanofi-Aventis, Ljubljana, Slovenia),37 the phosphodiesterase inhibitor pentoxifylline with or without EFA (brands not specified),33 embryonated eggs of Trichuris vulpis,29 synthetic T-cell receptor V-β peptides,22 and the tyrosine kinase inhibitor masitinib (Masivet or Kinavet; AB-Science, Paris, France).25 Outcome measures are reported in Table 3. Except for fexofenadine and masitinib, whose results are discussed below, the evaluation of our standardized measures of efficacy did not suggest any clinical benefit of these interventions. In general, this lack of efficacy was due to an inconsistency between positive outcome measures,22,29,38 too low an effect compared with placebo,29,32,38 a lack of available data to assess33 and/or to a very small subject number per group, resulting in a study that was probably underpowered.22,29,33

One small RCT of intermediate quality suggested, for all outcome measures, a consistent benefit of the antihistamine fexofenadine (Telfast; Sanofi-Aventis), with an efficacy that was of the same magnitude as that of oral methylprednisolone (Medrol; Pharmacia, Luxemburg, Luxemburg).37 Unfortunately, there was no report of a power analysis done beforehand to justify such a small number of dogs in this noninferiority trial; this study was probably underpowered. Clinically relevant adverse effects of fexofenadine were not noted.

The largest RCT reviewed herein is a 3 month high-quality study that tested the efficacy of masitinib (Masivet or Kinavet; AB-Science, Paris, France) versus placebo in 316 dogs with nonseasonal AD, of whom 306 were retained for modified intention-to-treat analyses (202 masitinib and 104 placebo).25 In Table 3, we calculated outcome measures using the set of ‘missing data as failure’. Data for calculation of our standardized outcome measures were not provided upon request. Overall, the published outcome measures were satisfied more often after oral administration of masitinib than after placebo, and the confidence interval of the effect suggests a modest treatment benefit (Table 3 and Figures 2 and 3). The calculation of NNTs, which was done only for this large trial, is also consistent with a small treatment effect (i.e. between six and 11 dogs would have to be treated to gain one additional positive outcome over placebo). This modest efficacy over the control intervention was most likely due to an unusually large benefit seen in the placebo group, which was probably caused by the allowance of microbial infection control in this trial, as well as the enrolment of dogs with no pruritus or mild pruritus at baseline in both groups (see online supplemental information in the study by Cadot et al.25). The intake of masitinib led to a higher proportion of severe and nonfatal adverse events compared with placebo. In dogs receiving masitinib, a severe protein-losing nephropathy developed in two (1%), proteinuria in 12 (6%) and hypoalbuminaemia in five of 206 dogs (2%). If detected early, this urinary protein loss was reversible.

Interventions for glucocorticoid dose reduction.

Our search identified two small high-quality RCTs aimed at testing an intervention that, given along with oral glucocorticoids, was hoped to result in a decrease in glucocorticoid dosage (Table 4).23,27

Table 4.   Randomized controlled trials evaluating interventions for glucocorticoid-sparing effect
First author (year)InterventionPrimary outcome measure (NNT)Secondary outcome measure (NNT)Comments
1a1b1a1b2a2b3a3b4a4b
Percentage of dogs with good-to-excellent response (clinician)Percentage of dogs with good-to-excellent response (owner)Percentage of dogs in complete remission (≥90% reduction lesions)Percentage of dogs in complete remission (≥90% reduction pruritus)Percentage of dogs in partial remission (≥50% reduction lesions)Percentage of dogs in partial remission (≥50% reduction pruritus)Percentage of dogs with lesions in the range of normal dogsPercentage of dogs with pruritus in the range of normal dogsPercentage of dogs with lesions in the range of dogs with mild ADPercentage of dogs with pruritus in the range of dogs with mild AD
  1. Abbreviations: EFA, essential fatty acids; n.a., not available or not assessable; NNT, number needed to treat; p.o., per os.

Schmidt (2010)27Methylprednisolone 0.4 mg/kg once daily + Phytopica 200 mg/kg once daily or placebo, all p.o.n.a.Phytopica, 8/10 (80%). Placebo, 8/11 (73%)Phytopica, 0/10 (0%). Placebo, 1/11 (9%)Phytopica, 4/10 (40%). Placebo, 1/11 (9%)Phytopica, 10/10 (100%). Placebo, 9/11 (82%)Phytopica, 9/10 (90%). Placebo, 7/11 (64%)Phytopica, 0/10 (0%). Placebo, 0/11 (0%)n.a.Phytopica, 10/10 (100%). Placebo, 9/11 (82%)n.a.Dogs with 50% reduction of methylprednisolone dosage at day 56: Phytopica, 8/10 (80%); placebo, 4/11 (36%)
Sanchez (2011)23Prednisone 0.5 mg/kg once daily p.o. then decreased plus EFA-rich (Atopic Care) test or control (Brekkies Excel Complet) dietsn.a.n.a.Test diet, 6/11 (55%). Control diet, 1/11 (9%)Test diet, 8/11 (73%). Control diet, 0/11 (0%)Test diet, 11/11 (100%). Control diet, 6/11 (55%)Test diet, 11/11 (100%). Control diet, 8/11 (73%)Test diet, 7/11 (64%). Control diet, 2/11 (18%)n.a.Test diet, 4/11 (36%). Control diet, 6/11 (55%)n.a.Dogs on prednisone at study end: test diet, 0/11 (0%); control diet, 8/11 (73%); outcome measures provided by authors

In the first trial,27 dogs received daily oral methylprednisolone with a plant-derived extract (Phytopica; Intervet Schering-Plough Animal Health, Milton Keynes, UK) or placebo dry granules. Once daily, the owners were instructed to decrease the dose of methylprednisolone based on the dog’s pruritus levels assessed using a VAS. While there was a similar change in global efficacy rating and lesional and pruritus scores in both groups (Table 4), the decrease in methylprednisolone dose was significantly higher in dogs given Phytopica rather than placebo.27 Furthermore, after 2 months, twice as many dogs (80%) given the herbal supplement had had a 50% reduction in their dose of methylprednisolone compared with that taken at baseline (Table 4).27 Five of 21 dogs (24%) did not complete this trial, mainly because of adverse effects. These consisted principally of polyuria–polydipsia, which was seen equally in both groups, and soft stools mostly after Phytopica. To the best of our knowledge, this herbal supplement is no longer available commercially.

The second study employed a design similar to the one above.23 Dogs with nonseasonal nonfood-induced AD were given prednisone along with a novel EFA-rich diet (Advance Veterinary Diets Atopic Care; Affinity Petcare, Sant Cugat del Vallès, Spain) or a control commercial dog food (Brekkies Excel Complet; Affinity Petcare, Sant Cugat del Vallès, Spain) for 2 months, and the dose of the glucocorticoid was then reduced according to a predetermined protocol. Altogether, the EFA-rich test diet appeared to lead to a greater reduction in skin lesion and pruritus scores compared with the control diet. Moreover, at study end, eight of 11 dogs (73%) eating the control diet were still receiving prednisone, while none of the dogs given the EFA-rich test diet was given this medication (Table 4). Adverse effects of the diets were not discussed in either study abstract or poster transmitted by the authors.

Interventions for prevention of flares.

There are two studies that investigated if an intervention could prevent relapses of signs of canine AD (Table 5).24,31 The first RCT was a small intermediate-quality study enrolling dogs with recurrent seasonal AD.31 One to 2 months before the expected seasonal exacerbation, dogs were given a supplementation of either blackcurrant seed oil (Vegetable Seedoil Product, Paesi Bassi) or a non-oil placebo (brands not specified). Using the parameters set out in Table 5, recurrences were found to have occurred at comparable rates in dogs treated with blackcurrant seed oil or placebo. Adverse effects were not discussed in the paper.

Table 5.   Randomized controlled trials (RCTs) evaluating interventions for prevention effect
First author (year)InterventionPrimary outcome measure (NNT)Secondary outcome measure (NNT)Comments
Percentage of dogs with good-to-excellent response (clinician)Percentage of dogs with good-to-excellent response (owner)Percentage of dogs in complete remission (≥90% reduction lesions)Percentage of dogs in complete remission (≥90% reduction pruritus)Percentage of dogs in partial remission (≥50% reduction lesions)Percentage of dogs in partial remission (≥50% reduction pruritus)Percentage of dogs with lesions in the range of normal dogsPercentage of dogs with pruritus in the range of normal dogsPercentage of dogs with lesions in the range of dogs with mild ADPercentage of dogs with pruritus in the range of dogs with mild AD
1a1b1a1b2a2b3a3b4a4b
  1. Abbreviations: AD, atopic dermatitis; BSO, blackcurrant seed oil; HCA, hydrocortisone aceponate; n.a., not available or not assessable; p.o., per os; VAS, visual analog scale.

Noli (2009)31BSO 100 mg/kg once daily or placebo p.o.n.a.n.a.n.a.n.a.n.a.n.a.No recurrence (lesions): BSO, 4/7 (57%); placebo, 3/7 (43%)No recurrence (pruritus): BSO, 3/7 (43%); placebo, 2/7 (29%)n.a.n.a.No recurrence parameters: <10 (CADESI-02) or <2 (VAS)
Lourenço (2012)24HCA for two consecutive days per week or placebo topicallyn.a.n.a.n.a.n.a.n.a.n.a.n.a.n.a.n.a.n.a.Mean (range) number of days to relapse needing treatment: HCA, 115 (31–260); placebo, 33 (15–61)

The second trial was a high-quality RCT that employed a novel design.24 Dogs with AD were treated once daily, until remission of signs, with the 0.0584% hydrocortisone aceponate spray already discussed in the preceding section discussing glucocorticoids (Cortavance; Virbac, Carros, France). Once their disease was controlled, dogs were randomized to have previously lesional areas sprayed once daily for two consecutive days each week with either the active glucocorticoid or a placebo. The time to relapse needing treatment was found to be significantly longer after treatment with the glucocorticoid compared with the placebo spray (Table 5). Adverse drug events were not observed with this glucocorticoid proactive intermittent regimen.

Syntheses of results

In this updated systematic review, because study designs, interventions and outcome measures varied vastly, we focused on individual study description rather than pooling of results in meta-analyses. The summary of available evidence can be found in the first section of the Discussion below.

Risk of bias across study

As protocols were not made available publically beforehand, post hoc modifications of outcome measures at the time of publication/presentation could not be verified. In all trials, outcome measures were matched to those reported in the Results section. In only one study was one data set defined in the Methods (‘imputation of missing values according to the last observation carried forward’) neither reported in the results section of that study nor further discussed.25 In general, the outcome measures reported in the studies were consistent with those used in a recent systematic review.6 Additional outcome measures were added whenever relevant to the study design (e.g. the dosage of glucocorticoid at trial’s end in studies testing a steroid-sparing effect,23,27 or the ‘time to relapse needing treatment’ in a flare prevention study24). For the first time among previous RCTs with atopic dogs, authors evaluated a ‘quality-of-life’ outcome measure, albeit using an unvalidated scale.28 Whenever not reported in study abstracts or papers, authors were contacted to obtain needed outcome measures and/or raw data to allow their calculation. Authors complied with this request in 18 of 21 studies (86%). Of the three studies with missing data, two were eventually excluded because of insufficient information available for appropriate evaluation;19,20 missing outcome measures were replaced by ‘not provided upon request’ for the last study.25

Discussion

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

Summary of evidence

In the following paragraphs of this section, the quality of evidence was defined according to that proposed in the recent GRADE consensus (Box 1).41 Specific recommendations for usage will be made in the Conclusion of this review.

Table  Box 1. .   Quality of evidence and definitions according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system41
High qualityFurther research is very unlikely to change our confidence in the estimate of effect
Moderate qualityFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low qualityFurther 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 qualityAny estimate of effect is very uncertain

Herein, we found further moderate-quality evidence of efficacy of oral glucocorticoids and microemulsified ciclosporin (Atopica; Novartis Animal Health) at dosages comparable to those used in trials already included in an earlier systematic review.6 There is new low-quality evidence, based on a single small trial,39 that a generic microemulsified ciclosporin (Equoral; Teva Pharmaceuticals) has an efficacy in the range of that of the brand approved for use in canine AD (Atopica; Novartis Animal Health). Surprisingly, in spite of the large size of this molecule, there is low-quality evidence that a nano-emulsion containing 2.25% of ciclosporin (Cyclostopic-Vet; Advancell) might be effective topically (A. Puigdemont, personal communication 2012).

Based on one RCT each, there is low-quality evidence of the efficacy and safety of injectable recombinant feline interferon-ω (Virbagen Omega; Virbac),35 injectable recombinant canine interferon-γ (KT-100; Toray Industries)40 and oral fexofenadine (Telfast; Sanofi-Aventis)37 to treat canine AD. Likewise, there is low-quality evidence of the efficacy of oral masitinib (Masivet or Kinavet; AB-Science) for management of this disease, but there is a need for close monitoring for rare but potentially fatal protein-losing nephropathy after using this drug.25

There is only very low-quality evidence of the possible modest clinical effectiveness of synthetic T-cell receptor V-β peptides, this reduced evidence grade stemming principally from a very small number of subjects per treatment group.22

The clinical benefit of the other interventions [tepoxalin (Zubrin; Intervet/Schering-Plough Animal Health),38Trichuris eggs,29 single mite allergen immunotherapy32 and pentoxifylline with or without EFA]33 was not readily apparent in single trials only providing very low-quality evidence. The same conclusion was reached for the benefit of blackcurrant seed oil to prevent the recurrence of signs of seasonal canine AD.31

Finally, a new EFA-rich diet (Atopic Care; Affinity Petcare) seems promising as a glucocorticoid-sparing dietary intervention (low-quality evidence).23 Another intervention that would successfully permit the lowering of the dosage of required glucocorticoids, Phytopica (Intervet-Schering Plough Animal Health),27 might no longer be available commercially.

Limitations

In comparison with our two previous publications on interventions for canine AD, this review has fewer limitations.5,6 Our sensitive search method and lack of restriction of publication status and languages reduced publication bias. The finding that all RCTs now enrolled only dogs with better-defined AD is likely to permit a better extrapolation of study results to the wider population of dogs with AD. The award of a ‘high-quality’ study design rating for 13 of 21 RCTs (62%) is a marked improvement over older RCTs, given that only 12 of 49 (24%) had received this grade in the previous review.6 This higher quality of trials is intrinsically associated with a reduction of selection, detection and attrition biases.6 Importantly, the main reason for not obtaining the highest design quality rating was the lack of performance of ITT analyses. Future publications of RCTs should address this insufficiency and report either ITT alone (with included dogs having received at least one dose of the tested interventions and missing values reported as ‘last observed carried forward’). Alternatively, authors could report both ITT and ‘per protocol’ data sets, the latter including only dogs that finished the trial without deviation.

The main limitation of RCTs included herein is that many had very low numbers of subjects per group (15 or less). Moreover, power analyses to determine an appropriate subject number beforehand were performed in fewer than 30% of the trials. Without a power calculation, the selection of the number patients is arbitrary, and low numbers would likely render trials unable to determine anything but a marked treatment effect. It is likely that, in this systematic review, most studies were underpowered; small but real treatment effects were thus likely missed.

Given that there is currently no avenue and no requirement for investigators to publish their study protocol before a RCT is started, there is no possibility for reviewers to verify changes made in outcome measures and/or subgroup analyses after randomization codes are unblinded and results analysed statistically. This limitation might allow some authors to selectively choose more favourable outcome measures thereby potentially making low-potency interventions appear more effective and in a better light than they really are.

A second limitation of trials reviewed herein is the common usage of unvalidated novel or modified published severity scales. Furthermore, reported outcome measures varied greatly, and this made their extraction and standardization difficult. In this systematic review, and to allow the comparison with studies included in the preceding systematic review, we used a set of primary and secondary outcome measures similar to that reported previously.6 Traditionally, one has mainly evaluated the efficacy of an intervention for canine AD by determining the proportion of dogs achieving a ‘≥50% reduction’ in skin lesion and pruritus severity during the trial. The satisfaction of such a lesion reduction benchmark appears to be associated with a good-to-excellent evaluation of treatment response by dog owners.42 However, the validity of this reduction threshold for determining a satisfactory antipruritic effect has been questioned recently.16 As a result of this observation, and as suggested before,16 we added herein two new outcome measures. These consist of the evaluation of the proportion of dogs that, at trial’s end, have skin lesion and pruritus scores in the range of those of normal dogs or of dogs with mild AD. Those outcome measures could be an additional clinically relevant assessment of effective interventions.

Conclusions

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References

Implications for practice

Adding the evidence summarized in this work to that discussed in the two preceding systematic reviews of treatments for canine AD permits the following updated recommendations.5,6

Multiple high-quality RCTs have now shown the consistent efficacy, with minor and predictable adverse effects, of the oral glucocorticoids prednisone, prednisolone and methylprednisolone, with a starting dosage of approximately 0.5 mg/kg once to twice daily to be tapered as needed. Several high-quality RCTs have also confirmed the efficacy of topical glucocorticoid formulations, with the strongest evidence existing for the novel 0.0584% hydrocortisone aceponate spray (Cortavance; Virbac). The potency of topical glucocorticoids is likely to vary between formulations and brands; skin thinning with prolonged daily usage is the major safety risk. Intermittent application of these topical formulations appears to prevent this problem, and it might delay the recurrence of flares if applied proactively (i.e. applied even if lesions are no longer seen) to previously affected areas.

Overall, multiple high-quality RCTs have established the efficacy and safety, apart from minor reversible adverse effects, of oral microemulsified ciclosporin given at a starting dosage of 5 mg/kg once daily and tapered after treatment effect is seen. The benefit appears comparable to, but slower to appear than, that of oral glucocorticoids.

In all, a small number of intermediate-quality RCTs has documented the efficacy of recombinant interferons for treatment of canine AD, but protocols for optimal benefit and safety are still unknown. The most favourable regimen (i.e. type of interferon, dosage and frequency of injections) and its cost–benefit have not yet been determined.

The previous evidence of allergen-specific immunotherapy was not strengthened by the RCT reviewed herein,32 because the protocol of this recent study employed a mite allergen-restricted formulation in dogs hypersensitive to this and other allergens. Such a strategy had not been employed before.

Implications for research

In light of the results of the studies discussed in the present review, additional high-quality RCTs are needed to confirm the efficacy and safety of oral masitinib (Masivet or Kinavet; AB-Science), oral generic or brand-named pentoxifylline at high dosages (i.e. >60 mg/kg/day), oral generic or brand-named fexofenadine, the injectable recombinant interferons (KT-100; Toray Industries; and Virbagen Omega; Virbac), the topical ciclosporin nano-emulsion (Cyclostopic-Vet; Advancell), the budesonide leave-on conditioner (Barazone; Dermcare-Vet) and T-cell receptor peptides. Likewise, the glucocorticoid-sparing effect of the new EFA-rich diet (Atopic Care; Affinity-Petcare) and the preventive effectiveness of topical glucocorticoids (i.e. proactive therapy) must be verified. A parallel study comparing generic and brand-named microemulsified (modified) ciclosporin is warranted.

Additional RCTs to test the efficacy and safety of oral microemulsified ciclosporin and glucocorticoids for the treatment of canine AD are unlikely to provide additional benefit unless these explore new treatment regimens (i.e. different dosages or frequencies of administration) or their efficacy in different subsets of patients (e.g. dogs with mild or severe AD, or those with severe pruritus but few lesions). Ciclosporin and oral glucocorticoids are, nevertheless, the active drugs to which other new interventions should be compared in future trials. As only ciclosporin, but not oral glucocorticoids, has been tested against placebo in previous RCTs, it should be the medication preferred as active comparator for noninferiority trials.43

There is a need to conduct high-quality RCTs to assess the efficacy of other commonly used interventions for the treatment of canine AD. For example, trials comparing the effectiveness and safety of different protocols of immunotherapy should be performed (e.g. subcutaneous versus sublingual routes, standard versus rush frequencies, specific versus ‘regional nonspecific’ formulations). The effectiveness of the plethora of commercially available topical formulations containing oatmeal, antihistamines, topical anaesthetics and lipids deserves more scrutiny and stricter testing. Importantly, the impact of using oral and/or topical antimicrobials (antibacterial or antifungal) has never been assessed as sole or concomitant therapy in dogs with AD.

Further studies aimed at preventing relapses of AD when signs are in remission are also needed. Determining whether additional diets or supplements possess a glucocorticoid-sparing effect would be of great help to patients. Interventions limited to subjects whose signs did not respond to glucocorticoids or ciclosporin would be important, but this research would be likely to benefit only few patients. Finally, studying the cost of all interventions compared with their benefit, safety and improvement in the quality of life of the patients would be likely to influence the care of dogs with AD.

To decrease the risk of perception of a positive treatment effect in placebo control groups, enrolled subjects must have, at baseline, at least mild AD skin lesions and pruritus; dogs with pruritus in normal ranges should not be included. To lower the risk of high placebo effect, further study designs should limit the number of hygiene and anti-infective interventions that could result in improvement of clinical signs. If the duration of the study (i.e. if it lasts 3 months or more) justifies the need for an active control of infections, then a noninferiority trial with a proven effective intervention – preferably oral ciclosporin, because it has been tested against placebo – might be better indicated.43 Such a trial would be likely to require a higher number of subjects, especially if small noninferiority margins are used.43

To enable a better comparison of efficacy among RCTs, and to permit the regrouping of these RCTs in meta-analyses, it is critical that outcome measures be standardized. Investigators are encouraged to use only validated severity scales, such as the third version of the CADESI13 and Hill’s PVAS.15,16 Furthermore, these two scales are currently the only ones for which AD severity thresholds have been determined.14,15 Importantly, these scales must be used without a single modification, because ad hoc‘modified CADESI’ are not validated scales, and the use of this specific denomination implies a scale tested for reliability and validity. Finally, unvalidated scales might not be precise enough to detect a small treatment effect, or they might not be reproducible enough to permit the detection of a lack of treatment efficacy.

In follow-up to the discussion in the ‘Limitations’ section above, we propose to set up primary outcome measures for future RCTs to be both investigator and owner global assessments of treatment efficacy (IGA-E/OGA-E). Clinically relevant benchmarks would be the frequency of dogs with AD having a subjective good-to-excellent global response to tested interventions. As pruritus and acute skin lesions (i.e. erythema) are not always evolving in parallel in dogs with AD,44 the separate evaluation of skin lesions and pruritus during treatment should serve as secondary outcome measures. We recommend first an assessment of the proportion of dogs with complete or near complete response to treatment [that is, one associated with a reduction ≥90% of the initial CADESI (CADESI90) or PVAS (PVAS90) values]. One could also add an evaluation of partial treatment responses (i.e. ≥50% reduction from baseline of severity scale values; CADESI50 and PVAS50). We also encourage further determination and reporting of the proportion of dogs which, at study end, have normal CADESI-03 (i.e.CADESInorm of 0–15) or PVAS values (i.e. PVASnorm of 0–1.9), as well as those that reach benchmarks of only mild AD (i.e. CADESImild,16–59; and PVASmild, 2–3.5). These benchmarks can only be calculated with these two unmodified and validated severity scales.13,15 The assessment of pre- and post-treatment quality-of-life scores using previously reported scales could also be of value to pet owners.2,3,45,46

For trials testing the glucocorticoid-sparing effect of interventions, the proportion of dogs without glucocorticoids at study end, as well as the final dosage of glucocorticoids, appears to be relevant outcome measures.23,27 Finally, for studies evaluating interventions aimed at preventing flares of canine AD, determining the ‘time to relapse’ seems to be an easily understood outcome measure, as long as such relapse is clearly defined, for example, when pruritus in the preceding day increases to above a ‘grade 2’ of Hill’s PVAS.

Concluding statement

This systematic review confirmed the previously shown benefit of oral and topical glucocorticoids and oral microemulsified ciclosporin for treatment of canine AD. Masitinib appears to have a promising effect, but further studies are needed to confirm its efficacy and safety. Protocols for using injectable interferons must be optimized. Likewise, the use of nutritional interventions for glucocorticoid-sparing effect must be studied further. Finally, other studies are needed to further document the effect of intermittent proactive applications of topical glucocorticoids to prevent flares of AD.

References

  1. Top of page
  2. RésuméResumenZusammenfassung
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Results of individual studies
  8. Discussion
  9. Conclusions
  10. References