Of the 110 dogs diagnosed with atopic dermatitis in the study, the majority (84.5%) were of a defined breed. This finding is consistent with previously published data [7, 17], showing that dogs of many defined breeds are genetically predisposed to developing atopic dermatitis, likely due to a combination of genetic characteristics as well as certain environmental factors [3]. The most frequent breed represented in the present study was shih tzu, which is the most popular dog breed in Brazil [18]. Body weight of the animals ranged from 2.5 to 39.8 kg (mean 13.8 kg), with more than half of the dogs each weighing between 2.5 and 10 kg, demonstrating a current predominance of miniature and small client-owned dogs in Brazil [18]. Approximately 60% of the dogs in this study were females. Earlier studies do not predict a predisposition for the disease according to sex [5, 13]. Although there were more female dogs than male dogs presented with atopic dermatitis in the present study, no conclusions were drawn regarding this observation.
A limitation of this study is the absence of a control group. Initially, the study was to be carried out as a randomized clinical trial with a test group (lokivetmab) and a negative (placebo) or positive (corticosteroids) control group. However, with regard to a negative control group, we faced an ethical dilemma when we determined there was a severe degree of pruritus and lesions from itching and rubbing. Thus, it was decided that it would be very difficult to convince the owners that their dog might only receive a placebo for its severe infection. The other option of using a corticosteroids as a positive control treatment could be problematic for dogs with a long history of using prednisolone or other steroid treatments associated with adverse reactions.
Based on American laboratory dose titration and clinical dose determination studies with different dosages [4, 12], the minimum effective dosage was determined to be 2 mg/kg. Pharmacokinetic studies also predicted the 2 mg/kg dose would have mAb concentrations above EC50 for 28 days [12]. In the present study, enrollment of animals with more severe AD (VAS ≥7 and CADESI-4 ≥20) provided an opportunity to evaluate the level of efficacy over the 30-day period for these cases, noting that many other therapeutic options do not provide prolonged efficacy, as demonstrated by the daily administration of cyclosporine over 28 days of evaluation, compared with a single SC administration of lokivetmab on day 0 [13]. The 30-day efficacy period also provides a sensible, convenient period for dog owners to increase treatment adherence and compliance.
The time it takes for treatment to demonstrate its effect is an extremely important factor. In the present study, the mean VAS on day 0 was 7.68, which demonstrated a significant reduction within 2 days after treatment, remaining stable at the improved level throughout the study. Similarly, there was a satisfactory reduction in severity of lesion scores. CADESI-4 scores at baseline were reduced by 55% on day 30, in agreement with the study by Michels et al [4] where CADESI-4 scores were improved as early as 7 days after treatment.
There was relatively high variability among the animals in the severity of lesions at baseline. Despite the heterogeneity of lesion severity, the enrollment criteria required each dog to have a CADESI-4 score ≥20; therefore, none of the dogs had a skin condition on day 0 that would be considered mild. When evaluating Spearman's correlation between VAS and CADESI-4, there was a positive and significant correlation between these 2 variables, which indicates that as the pruritus improved, so did the skin lesions. This phenomenon probably occurs due to an indirect anti-inflammatory effect of lokivetmab which, despite specifically blocking IL-31 (pruritic) rather than targeting other agents of the inflammatory cascade, its role in reducing self-trauma from scratching is reduction of inflammation. This therapeutic aspect of lokivetmab was also highlighted by Moyaert et al. [13].
Associated with clinical improvements, there was also a reduction in Staphylococcus spp infections present on day 30. However, 7 dogs developed Malassezia spp infections despite the use of the antiseptic shampoos, and 2 animals developed a mixed infection of Staphyloccocus spp and Malassezia spp). Lokivetmab treatment appeared to facilitate a reduction of the bacterial infection, but not for the fungal infection. The reduction in bacterial infections was likely due to the reduction in the act of scratching, but no a plausible explanation for the appearance of Malassezia infections. Future studies will include evaluations to attempt to determine the role of AD and treatment, if any, in the development of these fungal infections.
The adverse events observed following administration of lokivetmab were mild and required no additional treatment or drug intervention. Of the 4 patients that were withdrawn from the present study by the owner, only 1 was due to diarrhea and severe vomiting on day 0, following administration of lokivetmab. The appearance and incidence of vomiting, diarrhea, or lethargy reported in the present study are similar to those reported previously in randomized clinical trials of efficacy and safety of lokivetmab in client-owned dogs, including one large safety study in dogs with reported comorbidities and only minimal restrictions for concurrent medications during the study [4, 13, 14]. As stated in the conclusions of the researchers in those earlier controlled studies, we found that lokivetmab demonstrated a good safety profile when administered by SC injection to dogs with atopic dermatitis.
OGATE is a relevant, but subjective, tool in assessing adherence and success of the therapeutic regimen [19]. In our sample, 75% of the dog owners rated the treatment as good to excellent, indicating a high level of satisfaction. Despite the majority of positive responses and the significant clinical improvement of pruritus and lesion scores achieved in this study, flares related to exposure to allergens are common and may cause some owners to feel that treatment did not provide the expected response [17]. In their development of a core outcome set for evaluating and comparing outcomes of treatments administered to dogs with atopic dermatitis, Olivry and others acknowledge the subjective nature of OGATE, but advise that it is a useful criterion when assessed in concert with results of clinical assessments [19].
It may be possible to provide acceptable efficacy, perhaps with even fewer adverse reactions, with lower dosages of lokivetmab. Results of one clinical study indicated that lokivetmab at 0.5 mg/kg provided significant reductions in lesion scores, although the treatment effect was observed later, and the duration of efficacy was shorter than for the dogs treated with lokivetmab at 2 mg/kg [4]. Future studies may be undertaken to determine whether lower doses will provide adequate efficacy against the clinical effects of AD for dogs in Brazil.