Emmanuel Bensignor

PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family.

Evidence-based veterinary dermatology: a systematic review of interventions for Malassezia dermatitis in dogs.

The aim of this systematic review was to evaluate the efficacy of antifungal treatments for Malassezia dermatitis in dogs and, when possible, to propose recommendation for or against their use. Electronic searches were carried out using PubMed MEDLINE(R), CABDirect and CONSULTANT database. The volumes of Advances in Veterinary Dermatology, the proceedings of ESVD/ECVD and AAVD/ACVD congresses were hand-searched for studies relevant to this review. All articles and book chapters discussing treatment of Malassezia dermatitis were scanned for additional citations. Lastly, a request was sent to the Vetderm Listserv to share recent clinical trials. The analysis evaluated study design, methodology quality, subject enrolment quality, type of interventions and outcome measures. The searches identified 35 articles, and 14 trials that fulfilled the following selection criteria: (i) in vivo clinical trials, (ii) dogs showing clinical lesions of Malassezia dermatitis and (iii) enrolment of at least five dogs. Among these, only eight studies fulfilled the following additional criterion: (iv) prospective in vivo clinical trials reporting clinical and mycological outcome measures. A total number of 14 different treatment protocols included four blinded, randomized and controlled trials (quality of evidence grade A), four controlled studies lacking blinding and/or randomization (grade B), five open uncontrolled trials (grade C) and one descriptive study (grade D). This systematic review allowed us to recommend, with good evidence, the use of only one topical treatment of Malassezia dermatitis (2% miconazole nitrate +2% chlorhexidine, twice a week for 3 weeks) and with fair evidence the use of two systemic treatments with azole derivatives (ketoconazole, 10 mg kg(-1) day(-1) and itraconazole, 5 mg kg(-1) day(-1) for 3 weeks).

A review of topical therapy for skin infections with bacteria and yeast.

BACKGROUND Cutaneous infections with bacteria and yeasts are common in small animal practice. Treatment with systemic antibiotics or antifungal agents may not be ideal, because of the increasing development of multiresistant organisms, the cost and the possible adverse effects. Topical antimicrobials may be used as adjunctive therapy to systemic treatment or as sole therapy instead of systemic treatment. OBJECTIVE This literature review evaluated studies on topical antimicrobial treatment of skin infections. METHODS In vitro and in vivo studies evaluating topical antimicrobial agents were identified using a number of electronic and manual searches of textbooks and articles. Studies were evaluated, and the evidence for or against the use of the topical agents was extracted. RESULTS There is good evidence for the efficacy of chlorhexidine and, to a lesser degree, benzoyl peroxide in canine bacterial skin infections. There is limited evidence for the efficacy of silver sulfadiazine and medical honey against bacterial skin infections in the dog, and for the efficacy of hydrogen peroxide and stannous fluoride in the horse. Good evidence supports the use of a combination of chlorhexidine and miconazole in dogs with cutaneous Malassezia infections. There is insufficient evidence to recommend any other topical therapy for use in cutaneous infections. CONCLUSIONS AND CLINICAL IMPORTANCE Although many antimicrobial topicals are marketed in veterinary dermatology, the efficacy has been reported for only a minority of agents. Randomized controlled trials evaluating various topical treatments are therefore urgently needed.

Treatment of demodicosis in dogs: 2011 clinical practice guidelines

BACKGROUND AND OBJECTIVES These guidelines were written by an international group of specialists with the aim to provide veterinarians with current recommendations for the diagnosis and treatment of canine demodicosis. METHODS Published studies of the various treatment options were reviewed and summarized. Where evidence in form of published studies was not available, expert consensus formed the base of the recommendations. RESULTS Demodicosis can usually be diagnosed by deep skin scrapings or trichograms; in rare cases a skin biopsy may be needed for diagnosis. Immune suppression due to endoparasitism or malnutrition in young dogs and endocrine diseases, neoplasia and chemotherapy in older dogs are considered predisposing factors and should be diagnosed and treated to optimize the therapeutic outcome. Dogs with disease severity requiring parasiticidal therapy should not be bred. Secondary bacterial skin infections frequently complicate the disease and require topical and/or systemic antimicrobial therapy. There is good evidence for the efficacy of weekly amitraz rinses and daily oral macrocyclic lactones such as milbemycin oxime, ivermectin and moxidectin for the treatment of canine demodicosis. Weekly application of topical moxidectin can be useful in dogs with milder forms of the disease. There is some evidence for the efficacy of weekly or twice weekly subcutaneous or oral doramectin. Systemic macrocyclic lactones may cause neurological adverse effects in sensitive dogs, thus a gradual increase to the final therapeutic dose may be prudent (particularly in herding breeds). Treatment should be monitored with monthly skin scrapings and extended beyond clinical and microscopic cure to minimize recurrences.

Efficacy of a 0.0584% hydrocortisone aceponate spray in the management of canine atopic dermatitis: a randomised, double blind, placebo-controlled trial.

This study evaluated a 0.0584% hydrocortisone aceponate (HCA) spray (Cortavance; Virbac SA, Carros, France) in canine atopic dermatitis (AD). Initially, dogs with a canine AD extent and severity index (CADESI-03) >or= 50 were randomly allocated to receive HCA (n = 15) or placebo (n = 13) (two sprays from 10 cm away to treat an area of 100 cm(2)) once daily for 28 days. Twenty-one of the dogs then received HCA spray once daily, reducing to every other day or twice weekly over 42 days if improvement was maintained. CADESI, pruritus (14 cm visual-analogue-scale) and owner satisfaction (5-point scale) were recorded every 14 days. Haematology, biochemistry and adrenocorticotrophic hormone stimulation were performed at baseline, d28 and d70 (HCA n = 9; placebo n = 7). Intention-to-treat data were analysed. HCA spray significantly decreased CADESI (-61.4% versus -13.4%, P = 0.0069) and pruritus (-38.8% versus +57.6%, P = 0.0015) at d28 compared to placebo. Scores were significantly decreased at d14 (CADESI -50.5%, P < 0.0021) and d28 (CADESI P < 0.0001; pruritus P = 0.018) compared to baseline following HCA but not placebo. At d28 11 of 15 and 7 of 15 HCA dogs had >or= 50% reductions in CADESI and pruritus compared to 3 of 13 (P = 0.02) and 1 of 13 (P = 0.04) placebo dogs. Owner satisfaction scores were significantly higher in the HCA group (d28 P = 0.0001). Daily 3 of the 21 dogs required daily maintenance therapy, 7 every other day, 6 twice weekly and 5 dogs required additional therapy. Coat length did not influence the results. No adverse effects or changes to blood parameters were noted. HCA spray proved safe and effective up to 70 days. It is not, however, licensed for long-term treatment.

Validation of the Canine Atopic Dermatitis Extent and Severity Index (CADESI)-4, a simplified severity scale for assessing skin lesions of atopic dermatitis in dogs

BACKGROUND Severity scales are used to grade skin lesions in clinical trials for treatment of dogs with atopic dermatitis (AD). At this time, only two scales have been validated, namely the Canine Atopic Dermatitis Extent and Severity Index (CADESI)-3 and the Canine Atopic Dermatitis Lesion Index (CADLI). However, the high number of assessed sites makes the CADESI-3 impractical. HYPOTHESIS/OBJECTIVES The aim of this study was to develop and validate a fourth version of the CADESI that is simpler and quicker to administer. METHODS Body sites, lesions and severity grades were revised by members of the International Committee on Allergic Diseases of Animals (ICADA). The newly designed CADESI-4 was tested for its validity (i.e. content, construct and criterion), reliability (i.e. inter- and intra-observer reliability and internal consistency), responsiveness (i.e. sensitivity to change) and time to administer. Disease severity benchmarks were chosen using receiver operating characteristic methodology. RESULTS The CADESI-4 was simplified in comparison to its previous version to comprise 20 body sites typically affected in atopic dogs. Three lesions (erythema, lichenification and alopecia/excoriation) were scored from 0 to 3 at each site. The CADESI-4 had satisfactory validity, reliability and sensitivity to change. On average, the time to administer a CADESI-4 was one-third that of a CADESI-3. Proposed benchmarks for mild, moderate and severe AD skin lesions are 10, 35 and 60, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE The CADESI-4 is simpler to use and quicker to administer than its previous version. The ICADA recommends the CADESI-4 instead of the CADESI-3 to score skin lesions of AD in dogs enrolled in clinical trials.

Comparable efficacy of a topical 0.0584% hydrocortisone aceponate spray and oral ciclosporin in treating canine atopic dermatitis

This study compared the efficacy of a 0.0584% hydrocortisone aceponate (HCA) spray (Cortavance(®); Virbac SA) and ciclosporin (Atopica(®); Novartis Animal Health) in canine atopic dermatitis in a single-blind randomized controlled trial. Dogs received HCA (two sprays/100 cm(2); n=24) or ciclosporin (5 mg/kg; n=21). Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03, pruritus (visual analog scale with grade descriptors) and owner scores (5-point scales) were recorded every 28 days for 84 days. Intention-to-treat data were analysed. CADESI-03 and pruritus significantly decreased over time (P<0.0001), but there was no difference between the treatment groups (P=0.91 and P=0.52, respectively). Similar proportions of HCA- and ciclosporin-treated dogs achieved ≥50% reductions in CADESI-03 and pruritus scores at 28 days (CADESI-03 58.3 and 57.1%, P=0.76; pruritus 33.3 and 38.1%, P=1.0), 56 days (CADESI-03 70.8 and 81.0%, P=1.0; pruritus 62.5 and 57.1%, P=1.0) and 84 days (CADESI-03 75 and 85.7%, P=0.72; pruritus 65.2 and 57.1%, P=0.76). The CADESI-03 and pruritus scores were close to equivalence (0.47 and 0.51, respectively). By 84 days, every-other-day or twice-weekly therapy was achieved in 13 of 24 HCA- and 12 of 21 ciclosporin-treated dogs (P=0.85). There were no significant differences in scores for efficacy (P=0.82), tolerance (P=0.62) and ease of administration (P=0.25). Scores for tolerance (0.49) and administration (0.46) were close to equivalence. The score for efficacy favoured HCA (0.68). Mild adverse events were noted in six of 21 ciclosporin and none of 24 HCA dogs (P=0.008). Five HCA-treated dogs and three ciclosporin-treated dogs were prematurely withdrawn (P=0.7). In conclusion, HCA and ciclosporin proved equally effective in treating canine atopic dermatitis for up to 84 days.

Treatment of canine generalized demodicosis with a ‘spot‐on’ formulation containing 10% moxidectin and 2.5% imidacloprid (Advocate®, Bayer Healthcare)

In this multicentre study, the efficacy of a spot-on formulation containing 10% imidacloprid and 2.5% moxidectin (Advocate, Bayer HealthCare) was evaluated for the treatment of dogs with generalized demodicosis. The spot-on was applied every 2 weeks. Secondary bacterial infections were diagnosed by clinical examination, cytology and bacterial culture as appropriate and treated with oral antibiotics. Improvement or deterioration was determined monthly by clinical scores and by assessing mite numbers on microscopy of skin scrapings. Seventy-two dogs were included in the study. Fifty-two dogs had juvenile-onset demodicosis (mean of 11 months, range 2-24 months) and 20 dogs were adults at onset of disease (mean of 8.6 years, range 3.5-14 years). Twenty-six dogs went into remission, three with adult-onset demodicosis, 23 with juvenile-onset. The latter group showed significantly higher remission rates (P = 0.0252). Time until remission varied from 4 to 32 weeks (mean of 12.5 weeks). Dogs with a clinical score of <45 at the beginning of the study showed a significantly better response to the treatment (P = 0.0004), with a remission rate of 71%. In contrast, only 24% of those dogs with a score >45 went into remission. Adverse effects were not observed. One of the dogs responding to treatment showed recurrence of the disease during a follow-up period of 12 months. This study shows a better success rate of Advocate in dogs with mild clinical signs, versus those with moderate to severe clinical signs.

Masitinib decreases signs of canine atopic dermatitis: a multicentre, randomized, double‐blind, placebo‐controlled phase 3 trial

This study investigated the efficacy and safety of masitinib, a selective tyrosine kinase inhibitor capable of downregulating mast cell functions, for treatment of canine atopic dermatitis (CAD). Dogs with confirmed CAD received masitinib at 12.5 mg/kg/day (n = 202) or control (n = 104) for 12 weeks. A reduction in CAD Extent and Severity Index (CADESI-02) score of ≥ 50% at week 12 was observed in 61% of masitinib-treated dogs versus 35% of control dogs (P < 0.001), according to the modified intent-to-treat population. For dogs resistant to ciclosporin and/or corticosteroids (60% of the study population), CADESI-02 response rates were 60 versus 31%, respectively (P = 0.004). The mean reduction in pruritus score of severely pruritic dogs was 46 versus 29%, respectively (P = 0.045). Furthermore, 65% of owners with severely pruritic dogs assessed masitinib efficacy as good/excellent versus 35% control (P = 0.05). Overall, 63% of investigators assessed masitinib efficacy as good/excellent versus 35% control (P < 0.001). Premature discontinuations from the modified intent-to-treat population (28.2% masitinib versus 26.0% control) were mainly due to adverse events (13.4 versus 4.8%, respectively) or lack of efficacy (12.4 versus 18.3%, respectively). In total, 13.2% dogs presented with severe adverse events (16.0% masitinib versus 7.7% control). Masitinib showed a risk of reversible protein loss, although regular surveillance of blood albumin and proteinuria allowed for discontinuation of treatment while the dog was still clinically asymptomatic. Masitinib proved to be an effective and mostly well-tolerated treatment of CAD, including severe and refractory cases, with medically manageable adverse effects.

Efficacy of an essential fatty acid-enriched diet in managing canine atopic dermatitis: a randomized, single-blinded, cross-over study

Evidence suggests that high-quality diets enriched with essential fatty acids (EFA) and other nutrients can ameliorate canine atopic dermatitis (AD). This study compared such a diet (Eukanuba Veterinary Diets Dermatosis FP) with a home-cooked equivalent (fish and potato) in a randomised, single-blinded, cross-over trial. Twenty dogs with perennial AD were randomly assigned to receive either the test (group A) or the control diet (group B) for 1 month, followed by the contrasting diet for a further month. Canine Atopic Dermatitis Extent and Severity Index (CADESI version 2) and pruritus (visual analogue scale) scores were recorded at days 0, 30 and 60. Eight dogs in each group completed the study. CADESI scores significantly declined when dogs were fed the test diet (group A P < 0.01; group B P < 0.001), and increased (group A P < 0.05) or remained steady (group B) on the control diet. CADESI scores decreased in 15 of 16 dogs fed the test diet, but this was less than 50% in all cases. Pruritus scores also declined when dogs were fed the test diet compared to the control diet, but this was only significant for group A (P = 0.027). Pruritus was reduced in 11 of 16 dogs fed the test diet, but this was 50% or more in only two dogs. This trial provides evidence for the efficacy of Eukanuba Veterinary Diets Dermatosis FP in canine AD, although it is likely that most cases will require adjunct therapy. The mechanism is unclear, but may involve increased and balanced EFA levels.