Cyclosporine decreases skin lesions and pruritus in dogs with atopic dermatitis: a blinded randomized prednisolone-controlled trial

During the last decade, oral cyclosporin (CsA) has proven to be effective, in randomized controlled trials, for the treatment of atopic dermatitis (AD) in human patients. The purpose of this blinded randomized controlled trial was to test the hypothesis that CsA was successful in reducing the gravity of clinical signs of AD in dogs. Thirty dogs with nonseasonal AD were randomly allocated to receive an oral solution of either NEORAL CsA (5 mg kg-1) or prednisolone (0.5 mg kg-1) once daily for 6 weeks. Before, and 3 and 6 weeks after therapy, skin lesions were graded by clinicians using the Canine AD Extent and Severity Index (CADESI). Pruritus was assessed by the owners using a visual analog scale (PVAS). In both groups, CADESI and PVAS values were significantly lower at 6 weeks post treatment than before the initiation of therapy (Friedman test, P < 0.0004). The percentage reductions in CADESI and PVAS values from baseline were not statistically different between groups (Mann-Whitney test, P > 0.3). In this experiment, the tolerability and safety of oral CsA and prednisolone appeared similar. One-fifth of dogs given oral CsA occasionally developed diarrhoea or soft stools. One dog that was given CsA developed a generalized papillomatous skin eruption during the second half of the trial. Our study provides randomized controlled trial evidence that CsA reduces the severity of clinical signs in dogs with nonseasonal AD. Moreover, the anti-allergic efficacy of CsA appears comparable with that of prednisolone. We propose that oral CsA should be considered as a valuable alternative to glucocorticoid therapy in dogs with AD.     

Treatment of localized lesions of canine atopic dermatitis with tacrolimus ointment: a blinded randomized controlled trial

This investigator-blinded randomized controlled trial was designed to determine whether tacrolimus ointment (Protopic, Fujisawa Healthcare) decreased the severity of localized lesions of canine atopic dermatitis (AD). Twenty dogs with AD were enrolled if they exhibited lesions on both front metacarpi. Each foot was randomized to be treated with 0.1% tacrolimus or placebo (vaseline) ointment twice daily for 6 weeks. Before, and every 2 weeks during the study, erythema, lichenification, oozing and excoriations each were graded on a 10-point scale (maximal total score: 40). The primary outcome measures were the percentage reduction from baseline of lesional scores and the number of subjects whose scores had decreased by 50% or greater at study end. Intention-to-treat analyses were used. At study onset, lesional scores were not significantly different between sites treated with tacrolimus or placebo. After 6 weeks, the percentage reduction from baseline scores was higher for tacrolimus-treated sites (median: 63%; 95% confidence interval: 39-67) than for placebo-treated feet (median: 3%; confidence interval: -2-13) (Wilcoxon test; P = 0.0003). When tacrolimus was applied, lesions decreased by 50% or greater in 15/20 dogs (75%); these dogs were those that completed the study. In contrast, this benchmark was not reached for any placebo-treated feet (Fisher's test; P < 0.0001). Adverse drug events consisted of minor irritation in some lesional areas treated with tacrolimus. Results of this trial suggest that the application of 0.1% tacrolimus ointment is useful for reducing the severity of localized skin lesions of canine AD.     

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.     

Tepoxalin reduces pruritus and modified CADESI-01 scores in dogs with atopic dermatitis: a prospective, randomized, double-blinded, placebo-controlled, cross-over study

Thirty dogs with atopic dermatitis were given tepoxalin (Zubrin®, Intervet/Schering-Plough Animal Health, Boxmeer, the Netherlands) or placebo once daily for 4 weeks, followed by a wash-out period of 1 week before reversing the treatments. Pruritus was scored by the owners using the Edinburgh Pruritus Scale and one investigator employed a modification of the Canine Atopic Dermatitis Extent and Severity Index-01 (mCADESI-01) to score the physical lesions. After administration of tepoxalin there was a ≥ 50% reduction in pruritus and mCADESI-01 scores in 36% and 25% of the dogs, respectively, whereas following administration of the placebo there was a ≥ 50% reduction in pruritus and mCADESI-01 scores in only 25% and 16% of the dogs, respectively. Analysis of pooled data indicated that tepoxalin resulted in a significant reduction in pruritus ( P  = 0.012) and mCADESI-01 ( P  = 0.002) scores but there was no significant change after placebo. The median pruritus scores before and after tepoxalin were 2 (range 1–5) and 1 (range 0–5), respectively, and before and after placebo were 2 (range 0–4) and 2 (range 0–4), respectively. The median mCADESI scores before and after tepoxalin were 23 (range 0–68) and 16 (range 0–72), respectively, and before and after placebo were 18 (range 3–79) and 24 (range 0–65), respectively. At the dose used in this study (10.0–19.1 mg kg⁻¹), tepoxalin was well-tolerated and no adverse effects were noted.     

The effects of capsaicin topical therapy in dogs with atopic dermatitis: a randomized,double-blinded,placebo-controlled,cross-over clinical trial

Abstract The efficacy of twice daily topical application of capsaicin (0.025%) for the management of pruritus in dogs with atopic dermatitis (AD) was evaluated in double-blinded, placebo-controlled study. Twelve dogs with AD were randomly assigned to either 0.025% capsaicin or vehicle lotion applied twice daily for 6 weeks. After a 4-week wash-out period, treatments were switched. Significant improvement was reported by owners ( P  = 0.0006), but not by investigators. Owners noted temporary worsening of pruritus after the first week of capsaicin therapy. Overall capsaicin was well tolerated. Substance P (SP) concentrations in the skin did not correlate with the severity of the pruritus and did not change significantly over time and between treatments. Lesional skin had less SP than nonlesional skin ( P  = 0.03). These observations suggest that topical capsaicin should be further evaluated as an adjunctive antipruritic agent in dogs with AD.     

P‐48 Treatment of localized lesions of canine atopic dermatitis with tacrolimus ointment: a blinded,randomized, controlled trial

The purpose of this study was to determine whether tacrolimus ointment (Protopic) decreased the severity of localized lesions of canine atopic dermatitis (AD). Twenty dogs with AD were enrolled if they exhibited skin lesions localized to both front metacarpi. Each foot was randomized to be treated either with 0.1% tacrolimus or placebo (vaseline) ointment twice daily for 6 weeks. The nature of treatment for each foot lesion was concealed from the clinician. Before, and every 2 weeks during the study, erythema, lichenification, oozing and excoriations each were graded on a 10‐point scale (maximal total score: 40). The primary outcome measures consisted of the percentage reduction from baseline of lesional scores, and the number of subjects whose scores had decreased by 50% or greater by the end of the study. Intent‐to‐treat analyses were used. At the beginning of the study, lesional scores were not significantly different between treatment groups. After 6 weeks, the percentage reduction from baseline scores was higher for tacrolimus‐treated sites [median: 63% (95% CI: 39–67)] than for placebo‐treated feet [3% (‐2‐13)] (paired t‐test; P < 0.0001). When tacrolimus was applied, lesions decreased by 50% or greater in 15 dogs (75%), while this benchmark was not reached for any placebo‐treated feet (Fisher's exact test; P < 0.0001). Adverse drug events consisted of minor irritation in some dogs treated with tacrolimus. Results of this randomized, controlled trial suggest that the daily application of 0.1% tacrolimus ointment is useful for reducing the severity of localized skin lesions of canine AD. Funding: Self‐funded.     

Comparison of cyclosporine A with methylprednisolone for treatment of canine atopic dermatitis: a parallel,blinded, randomized controlled trial

Abstract The objective of this multicentre, parallel, blinded, randomized controlled study was to evaluate the efficacy and the safety of cyclosporine (CsA group, 117 dogs) in comparison with methylprednisolone (MP group, 59 dogs) in the treatment of atopic dermatitis for 4 months. Mean induction dose of both drugs (5 mg/kg CsA, 0.75 mg/kg MP) was tapered over time according to the clinical response. At the end of the study, the mean estimated percentage reduction from baseline (confidence interval) of lesion scores was 52% (44–59) and 45% (35–56), and the reduction in pruritus score was 36% (27–43) and 33% (23–43) in dogs in the CsA and MP groups, respectively. These percentages were not significantly different between groups. A significantly better overall assessment of efficacy was obtained in the CsA-treated dogs (76 vs. 63% responses excellent or good in the CsA compared with MP group). CsA-treated dogs presented a higher frequency of gastrointestinal disorders, mainly vomiting, but MP dogs tended to be more susceptible to infections. There was no remarkable change over baseline of the haematological and biochemical parameters in the two groups.     

Patch testing of experimentally sensitized beagle dogs: development of a model for skin lesions of atopic dermatitis

In humans with atopic dermatitis (AD), the epicutaneous application of allergens (atopy patch tests or APT) to which the patients are sensitized often results in the development of inflammation resembling that of spontaneous skin lesions. Dogs are affected with a natural homologue of human AD, but information on the induction of positive patch testing reactions is limited. The objectives of this pilot study were to determine the nature and cellular dynamics of inflammation occurring after APT in dogs hypersensitive to house dust mite and flea allergens. Laboratory Beagles were sensitized experimentally to Dermatophagoides farinae house dust mites (two dogs), Ctenocephalides felis flea saliva (one dog) or both (two dogs). Two other dogs served as nonsensitized controls. Both allergens and saline were applied epicutaneously. Macroscopic evaluations and skin biopsies were performed at 4, 24, 48 and 96 h after starting allergenic challenge. Biopsies were evaluated histologically and immunohistochemically with a panel of monoclonal antibodies specific for canine leucocyte antigens. Positive macroscopic reactions consisted of erythema, oedema and induration, and they occurred between 24 and 96 h after allergen application. Macroscopic and microscopic APT reactions developed only whenever serum IgE was present against tested allergens. Microscopically, positive APT was associated with epidermal hyperplasia, Langerhans' cell hyperplasia, and eosinophil and lymphocyte epidermotropism. Dermal inflammation was mixed and arranged in a superficial perivascular to interstitial pattern. Numerous IgE+-CD1+ dendritic cells and gamma-delta T-lymphocytes were observed. Macroscopically and microscopically, APT reactions in these experimentally sensitized animals resembled those seen in lesional biopsy specimens of dogs and humans with spontaneous AD. Therefore, APT in hypersensitive dogs provides a relevant experimental model to investigate the pathogenesis and treatment of both canine and human AD skin lesions.     

The clinical and histopathological effects of prednisone on acute radiation-induced dermatitis in dogs: a placebo-controlled, randomized, double-blind, prospective clinical trial

This study evaluated and compared the clinical and histopathological effects of prednisone on acute radiation-induced dermatitis (ARID) in dogs treated with 48 Gray of fractionated irradiation targeted to the skin surface. The study was designed as a double-blind, randomized, placebo-controlled prospective clinical trial. Twenty-two otherwise healthy companion dogs completed the clinical study. Three dogs were excluded from complete histopathological analysis because the owner declined one (one dog) or both (two dogs) biopsies. The study duration for each dog was 36 days from the start of radiation therapy (RT) to the first re-examination post RT. Dogs were treated with either oral prednisone at 0.5 mg kg(-1) or sugar pill, daily. All dogs received 48 Gray of fractionated, standardized RT, beginning 2 weeks after tumour excision. Acute Radiation Morbidity Scores, Cutaneous Toxicity Extent and Severity scores, digital images, and impression cytology were carried out on days 1, 8, 15, 22 and 36. Four-millimetre skin specimens from days 15 (RT-11) and 36 (2 weeks after the last RT dose) were scored by a pathologist and a dermatologist, blind to specimen identity. A one-way analysis of variance for longitudinal data was used to compare scores between groups. Spearman's rho correlation coefficient was used to measure strength of association between clinical and histopathology scores (HPS). There was no significant difference in CUTES, AMS or HPS scores between groups. There was a strong correlation between clinical and HPS scores. Prednisone did not decrease ARID severity clinically or histopathologically.     

Interventions for atopic dermatitis in dogs: a systematic review of randomized controlled trials

The objective of this systematic review, which was performed following the guidelines of the Cochrane collaboration, was to assess the effects of interventions for treatment of atopic dermatitis (AD) in dogs. Citations identified from three databases (MEDLINE, Thomson's Science Citation Index Expanded and CAB Abstracts) and trials published by December 2007 were selected. Proceedings books from the major veterinary dermatology international congresses were hand searched for relevant citations. The authors selected randomized controlled trials (RCTs), published from January 1980 to December 2007, which reported the efficacy of topical or systemic interventions for treatment or prevention of canine AD. Studies had to report assessments of either pruritus or skin lesions, or both. Studies were selected and data extracted by two reviewers, with discrepancies resolved by a third arbitrator. Missing data were requested from study authors of recently published trials. Pooling of results and meta-analyses were performed for studies reporting similar interventions and outcome measures. A total of 49 RCTs were selected, which had enrolled 2126 dogs. This review found some evidence of efficacy of topical tacrolimus (3 RCTs), topical triamcinolone (1), oral glucocorticoids (5), oral ciclosporin (6), subcutaneous recombinant γ-interferon (1) and subcutaneous allergen-specific immunotherapy (3) to decrease pruritus and/or skin lesions of AD in dogs. One high-quality RCT showed that an oral essential fatty acid supplement could reduce prednisolone consumption by approximately half. Additional RCTs of high design quality must be performed to remedy previous flaws and to test interventions for prevention of flares of this disease.     

Azithromycin therapy of papillomatosis in dogs: a prospective, randomized, double-blinded, placebo-controlled clinical trial

Azithromycin, an azalide subclass macrolide antibiotic, is an effective, well-tolerated and safe therapeutic option for treatment of papillomatosis in humans. This study reports the clinical and histopathological results from a prospective, randomized, double-blinded, placebo-controlled trial of 17 dogs of various breeds with diagnosis of oral ( n = 12) and cutaneous papillomatosis ( n = 5) treated with azithromycin. Papillomas appeared as whitish, verrucous, hyperkeratotic papules 1–2.7 mm in size. The cases were randomly assigned to azithromycin ( n = 10) and placebo treatment groups ( n = 7). Both owners and investigators were blinded to the allocation to the groups. Azithromycin (10 mg/kg) was administered per os every 24 h for 10 days. Clinical evaluations were done by the same investigator throughout the trial. Azithromycin treatment significantly decreased clinical scores ( P  < 0.001), whereas there was no change seen in the placebo group. In the azithromycin treatment group, skin lesions disappeared in 10–15 days. One case in the placebo had spontaneous regression of its papillomas by day 41, but lesions were still evident at day 50 in the remaining six cases. There was no recurrence of papillomatosis in the azithromycin treated dogs (follow up 8 months). No adverse effects were seen in either group. In conclusion, azithromycin appears to be a safe and effective treatment for canine papillomatosis.