The most effective systemic treatment in dogs with sarcoptic mange: a critically appraised topic

Background Sarcoptic mange is a common, pruritic parasitic skin disease of dogs. Due to its highly contagious character, it represents a potential veterinary and public health risk. Because of clinical similarity with other diseases, cross-antigenicity, and low sensitivity of available diagnostic methods, therapeutical trial is frequently used to confirm the disease. Considering the variety of available acaricidal molecules as well as the need to use the most effective treatment, the present paper reviews evidence comparing different types of systemic treatment of canine scabies. Results Analysis of the results showed that afoxolaner, fluralaner and sarolaner as well as several macrocyclic lactones such as selamectin, moxidectin and milbemycin oxime can lead to parasitological and clinical cure. Conclusion The similarity in the clinical and parasitological efficacy of these substances enhances the need for comparative studies, which could allow the identification of the most efficacious product.


Background
Canine sarcoptic mange is a highly pruritic, non-seasonal, contagious and potentially zoonotic parasitic skin disease caused by the mite Sarcoptes scabiei var.canis.Dogs worldwide can be affected and no breed, age or sex predisposition has been demonstrated so far [1].Contamination occurs through direct contact with an infested host or with a fomite, due to the capacity of the mite to survive and remain infective in the environment for up to 21 days [2,3].Clinical presentation is characterized by intense pruritus, alopecia, papules, erythema, scaling and crusting.The disease is often complicated by secondary pyoderma, which determines the extent of the lesions and contributes to the diversity of clinical presentation, ultimately complicating the diagnosis [2,4].Hypothetical diagnoses are based on the clinical presentation [1], while confirmation is obtained by demonstrating the presence of the parasite, its eggs or fecal pellets in skin scrapings [2] or positive serology [3] or a favorable response to a specific therapy [2,5].The diagnosis of sarcoptic mange may be complicated by several factors: the mites are difficult to find by skin scraping in early infections and in animals harboring low levels of parasitism, and therefore only 20 -50% of skin scrapings from infested dogs are positive [1].Serological diagnosis also has certain limitations : seroconversion occurs 3-5 weeks post infection or 1 to 3 weeks after the onset of the clinical signs, leading to false negative results if the animals are sampled too soon [2].Furthermore, cross-antigenicity between Sarcoptes scabiei, house dust mites and storage mites has also been documented [2,6].Hence, therapeutical trial is one of the most frequently used methods to confirm the diagnosis in cases with suggestive clinical presentation but negative test results.In this context, only the most effective molecules should be used to confirm the diagnosis and/or to treat the disease.While the efficacy of contact topical acaricidal has always been considered to be limited and influenced by several factors, systemically acting acaricides, orally or topically administered, are widely recognized as efficient molecules and consequently preferred for treatment of the disease [3].Macrocyclic lactones include several licensed molecules that have traditionally been used for the treatment of sarcoptic mange.More recently, other therapeutic options in the isoxazoline class have demonstrated their efficacy against S. scabiei.This paper critically reviews the literature on systemic treatments of canine scabies and uses available evidence to determine the most effective therapy, according to the relevant literature identified.The selected format is a critically appraised topic (CAT).

Clinical scenario
The patient is a four-year-old German wirehaired pointer presented for a chronic, generalized, highly intense pruritus.The dog is used for hunting and is in close contact with two other dogs, who had started to develop similar clinical signs.A dermatological examination revealed the presence of alopecic and erythematous plaques, with scales and crusts distributed mainly on the ear pinnae, hocks and elbows.Microscopical examination of multiple skin scrapes revealed the presence of S. scabiei mites, enabling confirmation of sarcoptic mange.Given the range of licensed therapeutic options, the question is, which systemic molecule provides the most rapid clinical and parasitological cure.

Clinical question
A population, intervention, comparison, outcome (PICO) question was formulated: "In dogs with sarcoptic mange, which systemic treatment is the most efficacious?"P (population) = dog with sarcoptic mange.I (intervention) = systemic treatment.C (comparison) = different systemic molecules.O (outcome) = clinical and parasitic resolution.
Preferred study type = clinical trials.

Search strategy
A literature review was conducted to identify different types of treatments using the following criteria: ((dogs OR canine) AND (scabies OR Sarcoptes scabiei OR sarcoptic mange) AND (treatment)).Two electronic databases were searched (PubMed and CAB), with no time limit up to 4 th October 2022.In this study we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) updated guideline for systematic review stated in 2020 [7].

Quantity and quality of evidence
The search produced 51 results in PubMed and 47 in CAB.The preferred language was English.Among the full-text potentially eligible articles, only 16 met the eligibility criteria, including relevance to our PICO question and multi-animal inclusion, and were included in our review, whereas case reports and case series articles were excluded (Fig. 1).
The data that highlight the quality of the evidence, such as the journals in which the articles were published, the number of enrolled subjects, and the type of study are summarized in Table 1.All the papers included in this study were published in international peerreviewed journals.The quality of evidence presented in the selected papers was very uneven.The main factors responsible were variable numbers of the enrolled subjects, as well as the study design.However, in all cases, the quality was considered sufficient to contribute to the conclusion of the PICO.
Positive skin scraping was the sine qua non inclusion criterion in all but five studies described in four articles [8][9][10]13] and was also the technique used to evaluate the efficacy of the parasitological cure.Animals enrolled and still present at the end of the study were declared parasitologically cured in 12 of the studies [3,4,8,11,12,[14][15][16][17][18][19][20].Interestingly, one study demonstrated that adding vitamin E and selenium to a protocol of a weekly subcutaneous administration of ivermectin improved efficacy from 82% to 100% by day 28 [16].Although the use of ivermectin may be preferred due to its low cost, the high probability of side effects in some breeds, the fact the product is not licensed in some countries, as well as the reported refractory cases should be taken into account [22].
The majority of substances tested led to a marked improvement in skin lesions and pruritus.Dogs were declared clinically cured in five of the studies, three of which tested macrocyclic lactones.In the first of these studies, 2 mg/kg of milbemycin oxime was administrated orally two or three times, either weekly or at two week intervals [9].However, the timing of the clinical evaluation relative to the time treatment was administered was not mentioned in the study, and what is more, a relapse of sarcoptic mange was reported in two dogs in the same study [9].In the second of the five studies, a topical 0.5% ivermectin solution was applied on day 1 and day 15 of the study, at a dose of 500 μg/kg.The dogs were evaluated as clinically cured by day 150 [10].The third study evaluated the efficacy of oral and/or subcutaneous weekly administration of moxidectin until clinical remission (3-6 weeks).Thirty-seven of the enrolled animals were evaluated as clinically cured within this 3-to-6-week time frame.Among the original total of 41 dogs, seven exhibited side effects, and in three animals, treatment was discontinued for this reason [13].The other two studies that reported a clinical cure tested molecules belonging to the more recently discovered isoxazoline class.The animals in the study using oral or topical fluralaner and oral sarolaner were considered clinically cured by day 84 [3] while animals treated with afoxolaner, and afoxolaner plus milbemycin oxime were declared cured by day 56 [21].A slightly more rapid disappearance of clinical symptoms was reported with the medication in which milbemycin oxime was added to afoxolaner, despite the fact that the dose of milbemycin oxime added in the tested product was below the therapeutic dose recommended for sarcoptic mange [20].These results are consistent with those obtained previously in a similar study [20], except that in the study that tested oral administration of milbemycin oxime, the dogs were followed up for longer, i.e. between 42 and 150 days.It has already been reported that resolution of alopecia in dogs with sarcoptic mange increases significantly after day 56, and that a period of four weeks between administration of the treatment and clinical evaluation is most likely too short to allow complete resolution of the lesions [20].A longer observation period would therefore improve the reliability of clinical cure.
Five studies tested the efficacy of selamectin and/ or imidacloprid plus moxidectin, and showed that two monthly applications of either of the two spot-on products can lead to parasitological and clinical cure.However, results differed regarding the time of the appearance of the parasitological cure, which varied between day 22 and day 60 [11,12,14,15].Moreover, the only study of the efficacy of a macrocyclic lactone against an isoxazoline showed that sarolaner was slightly more effective, reaching 100% efficacy by day 60, compared to 96% efficacy of the product containing imidacloprid plus moxidectin [17].
A single oral dose of fluralaner administered 10 to 20 minutes after food, or topically, was shown to lead to parasitological cure and to a significant improvement in skin lesions and pruritus by day 28 [4,19].All the other tests of isoxazolines, sarolaner, afoxolaner, and afoxolaner plus milbemycin oxime, demonstrated high efficacy against canine sarcoptic mange after a monthly dose, and all the products tested led to parasitological cure [16,17,19,20].
It is known that successful treatment of canine sarcoptic mange depends to a great extent on the product's ability to immediately eliminate all active mites.The effect must last long enough to prevent renewed contamination from eggs laid by hatched larvae, fomites or through contact with other infected animals [3].Interestingly, none of the studies we reviewed reported treatment of the environment.However, when required (multiple animals involved, with no possibility of housing them individually), in-contact dogs were also treated.
The main results of all the studies are summarized in Table 2.  Medium or small number of animals.
[11] The reason for the withdrawal from the study was not given for all the animals. [12] Oral or s.c.moxidectin.
4 dogs were withdrawn from the study (3 because of side effects).
7 dogs treated s.c.showed side effects.
Clinical cure in all remaining 37 dogs.
Five dogs were withdrawn due to events unrelated to treatment.Parasitological cure rate on D56 was 100% in both study groups and >96% of the dogs in both groups were clinically cured or improved.One dog treated with selamectin showed side effects.
Medium number of animals. [

Fig. 1
Fig. 1 Search strategy and selection process flow-chart

Table 1
Summary of the quality of evidence

Table 2
Summary of the key results