Clinical Guidelines for the Use of Antipruritic Drugs in the Control of the Most Frequent Pruritic Skin Diseases in Dogs

Pruritus is a common clinical sign in many skin disorders and is currently the main complaint in canine dermatology. Pruritic skin diseases can affect the quality of life of dogs and their owners. Several families of antipruritic drugs are available to help control pruritus in dogs. The aim of this review is to help practitioners select the most appropriate symptomatic treatment in the most frequent situations of dermatological pruritus in dogs. The molecules reviewed here are systemic and topical glucocorticoids, antihistamines, ciclosporin, oclacitinib and lokivetmab. A level of evidence (1, 2 or 3) has been established according to a detailed algorithm for each individual study in the literature published between 1990 and March 2021. The guidelines result from evidence grading using the strength of recommendation taxonomy (SoRT) and clinical recommendations using a thorough methodology.


Introduction
Pruritus is defined as an unpleasant sensation that provokes the desire to scratch [1]. Pruritus is a common clinical sign of many skin disorders and is the most common complaint in canine dermatology. Pruritic skin diseases can affect the quality of life (QoL) of dogs and their owners [2]. The first indication for the use of antipruritic drugs is, of course, allergies, notably canine atopic dermatitis (AD). However, in pruritic infections or parasitic dermatoses, the speed of action and the level of efficacy of etiological treatments vary and, to improve the QoL of both the dog and the owner, the use of an additional symptomatic antipruritic drugs in addition to etiological treatment sometimes makes sense after obtaining a clear diagnosis.
The most common causes of pruritus are allergies, parasites and bacterial or fungal infections. Diagnosis requires a methodical workup, and successful treatment depends on the identification of the underlying causes. Antiparasitics, antibiotics and/or antifungals are the first step in the control of pruritus. The high prevalence of pruritus and its impact on animals should encourage veterinarians to carefully consider the appropriate symptomatic treatment. In 2007, in humans, members of the International Forum for the Study of Itch proposed an etiological classification of pruritus [3]. An adaptation of this classification for dogs was recently proposed, with six distinct origins: dermatological,

Inclusion Criteria
The following types of study were initially selected: randomized controlled trials, clinical trials, cohort studies, and case series studies. The authors elected to search the data from the original studies and to exclude meta-analyses unless a clear level of heterogeneity with a Q statistic test or an I 2 index was established [9].

Exclusion Criteria
During the screening step, reviewers independently excluded studies for the following reasons: not a full-length article; duplicate study; article with no link with our topic, articles in a language other than English or French.

Clinical Situations
In addition to establishing a definitive diagnosis and an etiological treatment of the pruritus, the goal of this review was to establish the levels of evidence and the advice that can be given for the use of antipruritic drugs in: • Flares in canine atopic dermatitis (AD); • Long-term treatment of canine AD; • Allergen-specific immunotherapy treatment (ASIT) of canine AD; • Surface and superficial infectious skin disease (bacterial or Malassezia overgrowth, bacterial superficial pyoderma) with canine AD; • Sensitization tests (e.g., intradermal skin test (IDST)) and elimination diet period; • Parasitic skin diseases; • Animals with neoplastic diseases (mast cell tumor, histiocytoma, and lymphoma) or chronic diseases (hepatic diseases, renal failure, urinary tract infection, and diabetes mellitus).
Deep infectious dermatoses are not addressed in this review. However, if a deep infectious dermatosis is already present or if one appears, the expert panel recommends that the infectious problem is treated before any antipruritic treatment is started.

Presentation of the Results
For each molecule and for each of the two sections "level of evidence" and "recommendations", the following presentation scheme was selected: • In atopic dogs, excluding the induction period of ASIT: • Speed of action and efficacy; • Reduction in the dose/frequency of administration; • Combination of antipruritic molecules; • Use in superficial bacterial pyoderma or microbial overgrowth; • Adverse reactions.

•
In atopic dogs, during the induction period of ASIT.

•
In atopic dogs, during dietary trials.

Combination of Antipruritic Molecules
Administration of prednisolone 1 mg/kg sid for seven days and then eod for the next 14 days, and ciclosporin 5 mg/kg sid for 28 days, resulted in better control of pruritus after two weeks (72.8%-23 dogs) than ciclosporin alone at the same dose (24.7%-25 dogs) (LoE2) [20].
Supplementation with a combination of borage and fish oils in 30 dogs receiving oral prednisolone significantly reduced pruritus and lesion scores by day 64 of supplementation, compared with a group of 30 dogs receiving prednisolone alone, and reduced the doses of prednisolone required over 12 weeks, although the difference was not statistically significant (LoE1) [35]. In an open-label study of 11 dogs receiving oral prednisolone (0.22-0.58 mg/kg at 48 h intervals) for several weeks or months, the addition of essential fatty acids (fish oil and evening primrose oil) resulted in a 24-100% reduction in the dose of prednisolone in eight out of 11 dogs after 12 weeks of supplementation (LoE2) [27]. The addition of a supplement containing zinc methionine, fatty acids and biotin to 11 atopic dogs receiving background treatment with oral glucocorticoids resulted in a reduction in clinical and pruritus scores in 6 out of 11 dogs (55%) after 12 weeks of glucocorticoid dose reduction (LoE2) [33].

Use in Superficial Bacterial Pyoderma or Microbial Overgrowth
There are no published studies on the subject.

Adverse Reactions
Where specified, adverse events were reported in between 10% (LoE2) [18] and 100% (LoE1) [11,24] of treated dogs. Polyphagia and polyuria-polydipsia syndrome were among the most common (LoE1) [22,24,26], (LoE2) [15]. Other reported adverse events were digestive disorders (vomiting, diarrhea, loose stools) (LoE1) [22,23,26], superficial pyoderma in 10 (LoE1) [23] to 41% (LoE2) [33] of cases. A summary is given in Table 2. No data were available to assess the efficacy of systemic glucocorticoids in atopic dogs during the induction period of ASIT. However, oral prednisolone at a dose of 1 mg/kg was effective in controlling the adverse effects of rush immunotherapy in eight dogs (LoE2) [37]. The dose of methylprednisolone given in months 5 and 6 was reduced by 58% compared with the amount given during the first two months (LoE2) [36]. Furthermore, in the long term, a reduction in the dose of prednisolone from 1-2 mg/kg/week to 0.4 mg/kg/week was possible (LoE2) for 22 dogs out of 117 dogs undergoing ASIT that were monitored for 48 months [38].

In Atopic Dogs, during Allergologic Tests
Administration of prednisolone to 15 dogs at 1.1 mg/kg for seven days then eod for 14 days had no influence on the results of serological tests (allergen-specific IgE) performed at day 21 compared with the results obtained at day 0 (LoE2) [39]. There were highly significant effects of prednisolone at a dose of 1 mg/kg in inhibiting the skin reactivity against histamine and Dermatophagoides farinae after one week, as compared with placebo. Skin reactions increased again on the 14th day, although there was still a statistically significant difference to baseline. Prednisolone should be discontinued at least two weeks prior to IDST (LoE2) [40].

In Atopic Dogs, during Dietary Trials
Prednisolone, at a dose of 0.5 mg/kg sid or bid for three days, followed by 0.5 mg/kg daily for 5-17 days, then eod for 6-8 days, reduced the duration of the exclusion diet regime to 4-6 weeks instead of the usual eight weeks (LoE2) [41,42].

In Pruritic Ectoparasitic Dermatoses
No published data are available for the antipruritic use of systemic glucocorticoids in dogs with ectoparasites.

With Vaccines
No published data are available for the effect of the antipruritic use of systemic glucocorticoids on vaccinations.

Topical Glucocorticoids
Nine studies were included. Data were mainly available for hydrocortisone aceponate. Table 3 summarizes the articles reviewed according to the LoE of each individual study. The efficacy of hydrocortisone aceponate on pruritus and skin inflammation at 14 days compared with the final efficacy at 28 days was 27% and 82%, respectively (LoE1) [45].

Reduction in the Dose/Frequency of Administration
The frequency of administration of hydrocortisone aceponate could be progressively decreased without loss of efficacy in the majority of treated dogs: after 28 days with an eod application in 38% of dogs, and after 56 days with an eod to biweekly application in 54% (LoE2) [47]. After 70 days of treatment, only 14% of dogs needed a daily application, 33.3% needed an eod treatment, and 33.3% a twice weekly application (LoE1) [45].
Another study showed that an initial treatment period with a daily application of hydrocortisone aceponate enabled maximum efficiency: after 21 days of one application daily, CADESI was reduced by 29.2% compared with 14.8% when an intermittent regimen (three days on/four days off) was used (LoE2) [48]. In the study using 0.015% triamcinolone acetonide solution, the results were obtained with a decrease in the frequency of application by stages bid for seven days, then sid for seven days, and finally eod for two weeks [49] (LoE1).

Combination of Antipruritic Molecules
In association with oclacitinib (see Section 3.5.1), applications of hydrocortisone aceponate sid for seven days then eod for 21 days prevented the rebound effect observed when oclacitinib administration frequency was reduced from bid to sid (LoE1) [44]. After 28 days, a 54.1% and 56% reduction in pruritus and CADESI scores, respectively, was observed in the aceponate hydrocortisone + oclacitinib group versus 30.8% and 30.5% in the oclacitinib group (LoE1) [44].

Use in Superficial Bacterial Pyoderma or Microbial Overgrowth
There are no published studies on the subject.

Adverse Reactions
Short-term, self-resolving adverse events (diarrhea, pyrexia, vomiting and persistent estrus) were reported with hydrocortisone aceponate ( Table 2) but were thought not to be related to treatment (LoE1) [45]. Skin atrophy (clinical and histopathological examination) was reported after 14 days of treatment (LoE3) [50]. One study reported that post ACTH stimulation, the cortisol level decreased (by 36%) after three weeks of daily application of hydrocortisone aceponate, but not if the frequency of application was reduced (LoE2) [48].

In Atopic Dogs, during the Induction Period of ASIT
There are no published studies on the subject.

In Atopic Dogs, during Allergic Testing
After seven days of daily applications of hydrocortisone aceponate on the skin of a colony of ten laboratory atopic dogs, skin reactivity decreased after skin injection of proinflammatory molecules (histamine, anticanine-IgE polyclonal antibodies) with a return to normal reactivity after a wash-out period of 14 days (LoE3) [50].

In Atopic Dogs, during Dietary Trials
There are no published studies on the subject.

In Pruritic Ectoparasitic Dermatoses
Hydrocortisone aceponate rapidly relieved pruritus and skin lesions in experimentally induced flea bite hypersensitivity (FBH) in dogs treated with nitempyram. Pruritus was reduced by 94% in the treatment group versus 24% in the control group in terms of cumulative time, and by 86% versus 34% in terms of frequency. After three days, the clinical score was reduced by 23% in the treatment group versus 0% in the control group and by 43% versus 15% after seven days (LoE2) [51].

With Vaccines
There are no published studies on the subject.

Antihistamines
Twenty-seven studies were included. Table 4 summarizes the retrieved articles according to the level of evidence of each individual study. The majority of studies were conducted over short periods (10 to 14 days) and reported the effectiveness of the molecules, tending to suggest the antihistamines acted rapidly (LoE1) [63], (LoE2) [57]. However, some studies reported that the effect was only observed or was greater over longer periods (three to six weeks) (LoE2) [17,64].
Oxatomide (2 to 3 mg/kg/day) was reported to be effective for pruritus in 33% of allergic dogs in an open trial (LoE2) [64].
With dimetindene (1 mg/10 kg), there was a 38% clinical improvement and a 22% pruritus improvement in 66% of the dogs (statistical difference from the placebo group) (LoE1) [63]. In contrast, there was no difference between the treated group and the placebo in the rate of animals improved by more than 50% (LoE1) [63]. The benefit seemed to vary with the dog and was considered to be animal-dependent, and hence not predictable (LoE1) [63].

Reduction in the Dose/Frequency of Administration
None of the listed studies tested a reduction in the dose or frequency of antihistamine administration.
Therapy combined with essential fatty acids was also studied and showed that a possible synergism further improved the clinical signs and management of pruritus (LoE2) [58,60].

Use in Superficial Bacterial Pyoderma or Microbial Overgrowth
One article reported the lack of impact of infections on the efficacy of antihistamines (LoE2) [61]. However, no data are available on the impact of antihistamines on the management of infections.

Adverse Reactions
Sedation was the main but infrequently reported side effect (LoE1) [53,63] (Table 2). This effect was observed more frequently with the first generation of antihistamines and could be modulated by reducing the dose, sometimes without affecting the effectiveness of the molecule (LoE1) [63].

In Atopic Dogs, during the Induction Period of ASIT
One article reported the absence of association between the response to antihistamines and the response to ASIT (LoE2) [61].

In Atopic Dogs, during Dietary Trials
There are no published studies on the subject.

In Pruritic Ectoparasitic Dermatoses
Pruritus caused by some cases of flea bite hypersensitivity and sarcoptic mange seemed to be managed by terfenadine in seven to ten days (LoE3) [66][67][68].

With Vaccines
There are no published studies on the subject.

Association of Antipruritic Molecules
A three-month EFA supplementation (ratio 3.75/1, omega-3/6), in dogs already receiving ciclosporin for two months, made it possible to reduce ciclosporin by 0.85 mg/kg/day (LoE1) [76]. As previously stated (Section 3.1.1), the initial combination of ciclosporin (5 mg/kg/day) and prednisolone at 1 mg/kg/day, then eod for 14 days, accelerated clinical improvement (LoE1), the only observed effect being lethargy (17.4%) [20]. After seven days, the combination reduced pruritus by 64.4% compared with 14.5% with ciclosporin alone [20]. In healthy dogs, the combination of ciclosporin (5 mg/kg/day) and oclacitinib over three weeks did not alter any clinical or biochemical side effects compared with oclacitinib used alone (LoE2) [86]. To our knowledge, responses to anti-infectious agents used alone or with ciclosporin or another antipruritic drug have never been compared.

In Atopic Dogs, during the Induction Period of ASIT
There is no clinical evidence of an impact of ciclosporin on the efficacy of desensitization.

In Atopic Dogs, during Allergologic Tests
According to the only available study, IDST or Immunoglobulin E assays are not modified by ciclosporin (LoE1) [96].

In Atopic Dogs, during Dietary Trials
There are no published studies on the subject.

In Pruritic Ectoparasitic Dermatoses
There are no published studies on the subject.

With Vaccines
There are no published studies on the subject.

Oclacitinib
Seventeen studies were included. Table 6 summarizes the retrieved articles according to the level of evidence of each individual study. The recommended dose is 0.4-0.6 mg/kg bid for 14 days then 0.4-0.6 mg/kg sid. The reduction in pruritus, assessed using the pruritus Visual Analog Scale (pVAS), was very rapid, with a reduction observed as early as four hours post-administration (LoE1) [23,74,[100][101][102][103]. The reduction then slowed downed markedly until day 14, increased slightly at day 28, and pruritus then continued to decrease moderately (LoE1) [74,101]. The longest study showed a 57.8% reduction in pruritus at day 630 (LoE2) [102].
Some experimental models of canine AD were developed to study oclacitinib efficacy and showed that oclacitinib could delay the development of clinical lesions after allergen contact (LoE2) [105] and increase hydration (LoE2) [32], but no conclusive results were found concerning transepidermal water loss (TEWL) evaluation (LoE2) [32,105].
QoL was assessed in recent studies and demonstrated that more than 91% of owners were confident that treatment with oclacitinib was effective and improved QoL (LoE2) [102].

Reduction in the Dose/Frequency of Administration
A moderate exacerbation of pruritus [101,103] and a slight increase in or stabilization of clinical lesions scores [74,101] were observed when tapering oclacitinib therapy bid in dogs after day 14 to sid.

Association of Antipruritic Molecules
Hydrocortisone aceponate spray applied at the same time as oclacitinib prevented the relapse of pruritus and clinical lesions after tapering oclacitinib (mean reduction from the baseline of the hydrocortisone aceponate spray and oclacitinib-treated group was significantly higher than that observed in the oclacitinib and placebo spray-treated group for the PVAS and CADESI-4 on D21 (59.9% versus 27.6%, p = 0.0216) and D28 (56.0% versus 30.5%, p = 0.0109), respectively) (LoE2) [44].
Supplementation with SF68 Enterococcus faecium was associated with no difference in oclacitinib dose reduction versus placebo in 21 client-owned dogs with canine AD. Clinical disease scores did not differ between the groups upon completion of the study. There was no significant change in PVAS from the baseline in either group at any time point (LoE2) [108]. Treatment with oclacitinib alone or concomitantly with ciclosporin was not associated with adverse events, except diarrhea in two healthy dogs receiving both treatments (LoE2) [86]. Oclacitinib therapy combined with hydrocortisone aceponate spray was not associated with adverse events (LoE2) [44].

Use in Superficial Bacterial Pyoderma or Microbial Overgrowth
No available studies evaluated the impact of the use of oclacitinib on infectious dermatosis. However, one study compared the use of antibiotics in allergic dogs treated with oclacitinib versus allergic dogs treated with another antipruritic drug and reported that the use of antibiotics was reduced in dogs with allergic skin disease treated with oclacitinib compared with treatment with other antipruritic drugs (LoE2) [106].
3.5.2. In Atopic Dogs, during the Induction Period of ASIT Oclacitinib was used in 33 dogs during subcutaneous immunotherapy (fast-escalation or conventional regimen). No specific information is available to determine if oclacitinib inhibits or reduces the severity of adverse events in subcutaneous-immunotherapy-treated dogs (LoE2) [19].

In Atopic Dogs, during Allergologic Tests
In experimental canine models of AD epicutaneously sensitized with house dust mites, Dermatophagoides farinae, no statistically significant difference in allergen-specific IgE was found between treated (oclacitinib) and placebo groups and over time (LoE2) [105].

In Atopic Dogs, during Dietary Trials
Oclacitinib was able to shorten the elimination diet trial time with a provocation starting after four weeks and diagnosis within six weeks in most cases (LoE2) [42].

In Pruritic Ectoparasitic Dermatoses
Oclacitinib, associated with systemic antiparasitic drugs, allowed a significant decrease in pruritus within 24 h, provided rapid relief from pruritus, and reduced inflammation in dogs with sarcoptic mange (LoE2) [110]. In other ectoparasitic diseases, no studies have been conducted to assess the progression of clinical signs with oclacitinib.

With Vaccines
There are no published studies on the subject.

Lokivetmab
Nine studies were included. Table 7 summarizes the retrieved articles according to the level of evidence of each individual study. Lokivetmab is administered subcutaneously at 28-day intervals at a dose of 1 or 2 mg/kg depending on the country.
Lokivetmab was effective on pruritus (LoE1) [112] with a ≥50% score reduction in owner pruritus VAS score for 57% of 2 mg/kg treated dogs. The reduction in pruritus score was noted 24 h after a subcutaneous injection at a mean dose of 2.2 (1.8-3.7) mg/kg in 56% of dogs (LoE3) [116], within one to three days in 39.7% of dogs, and after three days in 100% of dogs (LoE3) [116]. Lokivetmab, at a dose of 2 mg/kg, reduced the lesional score by 37% and 43%, seven and fourteen days after the injection, respectively (LoE1) [112].
The level and duration of the response are dose-dependent. The global efficacy of one lokivetmab injection, at a dose of 1 to 3.3 mg/kg by the owner and investigator, were 67.8% and 70.1%, respectively (LoE1) [113].
A reduction in pruritus was observed in 87.8% of the dogs after one injection at a mean dose of 2.2 (1.8-3.7) mg/kg (LoE1) [75] with a pVAS score reduction of ≥50% in 77% of the dogs (LoE1) [75].
Lokivetmab improved the skin condition of atopic dogs (LoE1) [75,112], (LoE2) [114,115]. The level and duration of the response increased with increasing dose. A lesional score reduction of ≥50% was observed in 46% and 57.3% of the dogs 28 days after an injection, at a dose of 2 mg/kg (LoE1) [112] and 1.32 mg/kg (1-2.2 mg/kg) (LoE2) [114], respectively. A ≥50% reduction in the lesional score was observed in 78.8% and 80.8% of the dogs after two and three monthly injections, respectively, at a dose of 1.32 mg/kg (1-2.2 mg/kg) (LoE2) [114]. The skin condition was considered normal in 36.6% of the dogs after two injections at an interval of one month, at a dose of 2 mg/kg (LoE3) [116], and in 59.3% of the dogs after eight injections (LoE3) [116].

Reduction in the Dose/Frequency of Administration
There are no published studies on the subject.

Association of Antipruritic Molecules
There are no published studies on the subject.

Use in Superficial Bacterial Pyoderma or Microbial Overgrowth
There are no published studies on the subject.

In Atopic Dogs, during the Induction Period of ASIT
Lokivetmab seemed to have no effect on the 15 dogs on ASIT, in neither fast-escalation subcutaneous immunotherapy nor a conventional subcutaneous immunotherapy regimen (LoE3) [109].

In Atopic Dogs, during Allergologic Tests
There are no published studies on the subject.

In Atopic Dogs, during Dietary Trials
There are no published studies on the subject.

In Pruritic Ectoparasitic Dermatoses
There are no published studies on the subject.

With Vaccines
There are no published studies on the subject.

Recommendations
The results are summarized in Tables 8 and 9. Table 8. Summary of antipruritic drugs that may be used, according to the clinical situation.

In Atopic Dogs, excluding the Induction Period of ASIT During Flares (Reactive Therapy)
Oral glucocorticoids (prednisolone, methylprednisolone (SoR A), prednisone (SoR B) and injectable dexamethasone (SoR C) are effective for the treatment of flares of canine AD. They can be administered initially at 0.5-1.0 mg/kg (prednisolone) or 0.4-1 mg/kg (methylprednisolone) per day (SoR A), in one or divided into two administrations (SoR A), using a dose that is maintained or that can be decreased after 3-7 days (SoR B) using either a standard protocol or based on the outcome (SoR B). A significant reduction in pruritus is obtained rapidly, in a few hours or in a few days (SoR B).
In Non-Flare Periods (Proactive Therapy) No data are available. Use of systemic glucocorticoids for long-term management of canine AD is not recommended (SoR C) or only with great care, if a low dose (SoR C) is administered at 48 or 72 h intervals. Adrenal insufficiency can be minimized by instituting therapy eod, but adrenal insufficiency may occur at any pharmacologically active dose. Adrenal insufficiency may be particularly obvious after the discontinuation of corticosteroid therapy. Dose reduction and discontinuation should be gradual to avoid precipitating adrenal insufficiency even temporarily (SoR C).
Adverse events are frequent in short-term treatments and mainly consist of polyuria, polydipsia, polyphagia (SoR A) and gastrointestinal disorders (SoR B).

In Dogs with Superficial Pyoderma or Microbial Overgrowth
Few data are available. Daily oral administration of 0.75 mg/kg prednisolone for one month did not alter the skin microbiome of six asymptomatic atopic dogs [118]. Neverthe-less, considering their potential pro-infectious characteristics, their use should be restricted in the case of secondary skin infections and infectious diseases (SoR C).

In Dogs with Specific Problems
Liver disorders Changes in liver parameters associated with the use of systemic glucocorticoids are commonly observed. In the case of long-term use, their detection by regular liver function tests is recommended. The use of glucocorticoids is not recommended in animals with liver failure (SoR C).
Renal disorders The use of glucocorticoids is not recommended in dogs with renal disorders (SoR C). Diabetes mellitus Glucocorticoids stimulate gluconeogenesis. Lipogenesis is enhanced in certain areas of the body and adipose tissue may be redistributed away from the extremities to the trunk (SoR C). The use of glucocorticoids is associated with an increase in serum insulin but not serum fructosamine concentrations in dogs with canine AD (SoR B). Since prolonged use of systemic glucocorticoids can lead to the development of diabetes, their use in a diabetic animal, even if controlled, is not recommended (SoR C).
Neoplastic diseases Long-term use can cause immunomodulation that can lead to the development of neoplasia (SoR C). The use of glucocorticoids is not generally recommended in dogs with cancers (SoR C) unless they are part of the chemotherapy regimen [119,120].
Urinary infections Routine urine cultures and assessment of bacteriuria by cystocentesis should be part of the monitoring for dogs on long-term glucocorticoids. Glucocorticoids should be used cautiously in dogs with occasional urinary tract infections and be avoided in dogs with recurrent urinary infections (more than two episodes in six months or more than three episodes per year) (SoR C) [121].

In Atopic Dogs, during the Induction Period of ASIT
Systemic glucocorticoids can be used during ASIT (SoR B) and can be used in the case of an adverse event during ASIT rush therapy (SoR B).

In Atopic Dogs, during Allergy Testing
Systemic glucocorticoids do not interfere with specific allergen serology tests (SoR B). They should be stopped at least two weeks prior to IDST as they can interfere with cutaneous reactions (SoR B).

In Atopic Dogs, during Dietary Trials
Systemic glucocorticoids can be used during the initial period of an elimination diet (SoR C).

In Pruritic Ectoparasitic Dermatoses
No data are available. Long-term use may indirectly promote parasitic infestation while masking or reducing symptoms. With the exception of demodicosis (confirmed or previous), for which glucocorticoids should be avoided, a short course (five days maximum) of oral glucocorticoids would be acceptable when initiating the treatment of a highly pruritic sarcoptic mange, flea infestation or flea allergy dermatitis (SoR C).

With Vaccines
In the case of vaccination with live attenuated vaccines, an interval of two weeks should be observed before or after treatment (SoR C). In the guidelines for the vaccination of dogs and cats published in 2016, experts reported the suggestion that immunosuppressive glucocorticoid treatment, i.e., with higher doses than for allergic diseases, prior to or concurrently with vaccination, has no significant suppressive effect on antibody production in response to vaccines. However, revaccination is recommended two or more weeks after glucocorticoid therapy has ended, especially when treatment occurs during the administration of the initial series of core vaccines [122]. Topical glucocorticoids (hydrocortisone aceponate (SoR C), triamcinolone (SoR C)) are effective for the treatment of flares of canine AD, especially for localized lesions. At the time of writing (2022), the lack of data on the efficacy of topical glucocorticoids in the first two weeks of treatment does not allow a recommendation beyond SoR C. The optimal regimen is daily treatment followed by a reduction in the frequency of application on the skin based on outcome (SoR C).

Topical
In Non-Flare Periods (Proactive Therapy) Hydrocortisone aceponate can be recommended in non-flare periods (SoR A). The frequency of application can be reduced after one or two weeks of treatment, which reduces the risk of adverse reactions (SoR B). Twice weekly applications on previous lesional skin areas reduce relapses (SoR A). Skin thinning can be observed after 14 days of treatment (SoR B).
The use of triamcinolone is also possible and effective, although there may be an increase in side effects (SoR B). With the use of other topical glucocorticoid formulations, there may be variations in efficacy and safety depending on the strength of the glucocorticoid, the chemical structure, and the vehicle [123,124]. Most topical corticosteroids are absorbed in quantities that can produce both systemic and local adverse effects [125]. These marked adverse effects may be observed with prolonged or frequent use and are more rapidly observed, more frequent, and more severe with potent topical corticoids (SoR C).

In Dogs with Superficial Pyoderma or Microbial Overgrowth
No data are available but, for the same reasons as systemic corticosteroids, it is not recommended to use topical glucocorticoids in the case of secondary skin infections and infectious diseases (SoR C).

In Dogs with Specific Problems
No data are available, but hydrocortisone aceponate seems to be a safe molecule because of its particular metabolic pathway, i.e., in the skin with no systemic absorption (SoR C). Because of its potential local effect on skin (thinning), its use is not recommended in dogs suffering from other systemic diseases that have an impact on skin integrity (e.g., Cushing disease) (SoR C). Like with the use of other topical glucocorticoids, caution is required because systemic absorption, potencies and the risk of adverse reaction will vary with the glucocorticoid molecule (SoR C).
Liver disorders No data are available but as hydrocortisone aceponate does not cause changes in biochemical parameters, this molecule could be used in dogs with liver disorders (SoR C). Caution is required with other topical glucocorticoids (SoR C).
Renal disorders No data are available. Hydrocortisone aceponate does not cause changes in renal parameters so this molecule could be used in dogs with renal disorders, but regular biochemical tests are mandatory (SoR C).
Diabetes mellitus No data are available. Due to its mode of action, hydrocortisone aceponate could be used in dogs with diabetes mellitus, but regular biochemical tests should be performed (SoR C). Like with other topical corticoids, there is a risk of developing diabetes mellitus as in humans with the cumulative dose and cumulative duration of use (SoR C) [126].
Neoplastic diseases No data are available. Hydrocortisone aceponate could be used in dogs with neoplastic diseases after evaluation of the benefit/risk ratio by the responsible veterinarian (SoR C).
Urinary infections No data are available. Because of its mode of action, hydrocortisone aceponate could be used in dogs with urinary infection (SoR C).

In Atopic Dogs, during the Induction Phase of ASIT
No data are available, but topical glucocorticoids can be used during the induction period of ASIT (SoR C).

In Atopic Dogs, during Allergy Testing
Hydrocortisone aceponate and other topical glucocorticoids should be stopped at least two weeks prior to IDST as they can interfere with the cutaneous reactions (SoR B) [127,128]. No data are available but topical glucocorticoids should not interfere with specific allergen serology tests (SoR C).

In Atopic Dogs, during Dietary Trials
No data are available, but topical glucocorticoids can be used at the beginning of trials for localized lesions to relieve the animal (SoR C).

In Pruritic Ectoparasitic Dermatoses
Topical glucocorticoids can be used when initiating treatment for flea allergy dermatitis (SoR B). With the exception of demodicosis (confirmed or previous), for which topical glucocorticoids should be avoided, a short course of treatment would be acceptable when initiating the treatment of a flea-or sarcoptic-mange-induced pruritus (SoR C).

With Vaccines
No data are available, but because of the absence of a systemic impact, hydrocortisone aceponate can be used (SoR C). Caution is required with other glucocorticoids, depending on their potency, especially when using live attenuated vaccines (SoR C).

In Atopic Dogs, Excluding the Induction Period of ASIT During Flares (Reactive Therapy)
Antihistamines are not recommended for the treatment of severe acute flare-ups of AD (SoR A). However, because their actions are animal-dependent and often mild, as they are relatively fast acting, mainly inexpensive and have few side effects, they can be used for mild AD flare-ups (SoR C).
In Non-Flare Periods (Proactive Therapy) Limited evidence-based clinical data are available concerning the antipruritic effect of antihistamines and there is a quasi-absence of knowledge concerning the doses and frequency of administration of antihistamines in dogs. Antihistamines could have a global moderate antipruritic efficiency with individual variation (SoR B). Their use for longterm management can be tested alone in the case of mild to moderate dermatosis or associated with other molecules for any degree of severity of dermatosis (SoR C). Indeed, antihistamines can be used in a multimodal approach to reduce the dose of other drugs, such as corticosteroids (SoR C).

In Dogs with Superficial Pyoderma or Microbial Overgrowth
Antihistamines can be used in dogs with superficial pyoderma or microbial overgrowth (SoR C).
In Dogs with Specific Problems Liver disorders No data are available. First-generation antihistamines mainly have a hepatic metabolism. In humans, a dose reduction is recommended in the case of hepatic insufficiency, but their use is not contraindicated [129,130]. So, these molecules could be used in dogs with liver disorders, perhaps at a lower dose (SoR C).
Renal disorders No data are available. Some antihistamines such as cetirizine have a renal metabolic route in humans, but the route is still not known in dogs [70]. In humans, in the case of renal insufficiency, a reduction in dose is recommended, but its use is not contraindicated [129,130]. Antihistamines could be used in dogs with renal disorders, perhaps at a lower dose (SoR C).
Diabetes mellitus No data are available. Antihistamines appear to be usable in dogs with diabetes mellitus (SoR C).
Neoplastic diseases No data are available. Antihistamines appear to be usable in dogs with neoplastic diseases (SoR C).
Urinary infections No data are available. Antihistamines appear to be usable in dogs with urinary infections (SoR C).

In Atopic Dogs, during the Induction Period of ASIT
Antihistamines can be used during desensitization in dogs (SoR C).

In Atopic Dogs, during Allergologic Tests
A therapeutic window of seven to ten days is necessary before performing an IDST (SoR A). There have been no studies on the impact of antihistamines on serological tests. The mode of action of antihistamines should not interfere with the measurement of allergenspecific IgE. Thus, the withdrawal of antihistamines does not appear to be needed.

In Atopic Dogs, during Dietary Trials
No data are available. Antihistamines are not contraindicated (SoR C) [131].

In Pruritic Ectoparasitic Dermatoses
Antihistamines can be used in cases of mild to moderate parasitic pruritus (SoR C).

During Vaccines
No data are available. The summaries of product characteristics of the available formulations do not limit the use of antihistamines during vaccination. Antihistamines can be used alongside vaccines (SoR C). Ciclosporin is partially effective at the beginning of treatment, and is fully effective after four to six weeks of treatment (SoR A); it is therefore not recommended for the treatment of flares (SoR A).

In Non-Flare Periods (Proactive Therapy)
Ciclosporin is recommended to manage canine AD in non-flare periods (SoR A). It is possible to reduce the frequency of administration after two to four months depending on the clinical response, while maintaining the efficacy of the molecule with treatment on alternate days or twice a week (SoR A). A decrease in the daily dose is also possible (SoR B).
At the beginning of treatment, the combination of ciclosporin (5 mg/kg/day) and prednisolone (1 mg/kg/day for 7 days, then eod for 14 days), accelerates the clinical response with no increase in severe adverse effects (SoR B), and with a threefold greater effect on pruritus in the first few days. The authors suggest modifying the protocol by rapidly reducing the prednisolone dose to 0.5 mg/kg/d (SoR C).
EFA supplementation in the plateau stage (after two months) could improve pruritus and clinical signs (SoR B) and reduce the dose of ciclosporin (from 0.85 mg/kg/day).
Gastrointestinal side effects, most often transient and moderate, are common (46% of cases) (SoR A) [99]. Neoformations are rare (SoR A). Papillomatous lesions are reported, usually not linked to the presence of papillomaviruses, but possibly in response to bacterial infections [132]. These lesions and gingival hyperplasia usually regress after stopping ciclosporin (SoR B).
Infections were present in 11% of treated animals [133]. As the infections were mostly cutaneous (68%), it is difficult to confirm a role for the molecule given the naturally high frequency of infections during CAD and in the absence of studies with control groups [134]. Bacterial urinary tract infections (30% of infections mentioned) are neither statistically more frequent than in untreated dogs, nor are they accompanied by clinical urinary signs [98]. A link between clinical urinary bacterial infection and the use of the drug has therefore not been established, although caution is recommended and regular urinary analyses may be required during long-term treatment (SoR B).

In Dogs with Superficial Pyoderma or Microbial Overgrowth
No available information indicates any adverse effects of ciclosporin in dogs with canine AD and superficial infections, and proper management will reduce the frequency of these infections. Ciclosporin is advisable for superficial bacterial infections in dogs with well-managed canine AD (SoR C).
In Dogs with Specific Problems Liver disorders Ciclosporin, even when used at high doses and for long periods, does not appear to be hepatotoxic in dogs [133], but no data are available in the case of pre-existing liver disorders. The molecule does not seem to be advisable in animals with hepatic disorders because of its mainly hepatic metabolism via cytochrome P-450 [135]. However, ciclosporin seems to be beneficial to hepatocytes during porto-cavity shunting and improves hepatic biochemical parameters during chronic idiopathic hepatitis [136,137].
Ciclosporin is not recommended for liver disorders, but the benefit-risk balance should be assessed (SoR C).
Renal disorders Unlike in humans, even when used at high doses and for long periods, ciclosporin does not appear to be nephrotoxic in dogs [133] and no adverse effects have been reported in studies on canine AD. No abnormalities in renal biochemical parameters were detected experimentally after two years of treatment in 38 dogs [87]. However, to the best of the authors' knowledge, no studies have been conducted on animals with renal failure. Ciclosporin seems to be suitable for use in dogs with renal disorders, but the benefit-risk balance should be assessed and regular biochemical tests performed (SoR C).
Diabetes mellitus Observations of diabetes mellitus in dogs monitored in studies are limited to one case of hyperglycemia and diabetes mellitus after three years of treatment with ciclosporin [12]. Clinical data suggest that treatment in West Highland white terriers is associated with increased incidence of diabetes mellitus [138]. Experimentally, ciclosporin may reversibly increase peripheral insulin resistance and decrease insulin secretion [139]. In a study of 16 dogs with canine AD, ciclosporin (5 mg/kg/day; six weeks) significantly increased glucose levels and decreased serum insulin concentrations, whereas fructosamine levels (statistically increased) remained within the normal range and no dog developed diabetes mellitus [93]. In diabetic dogs, the clearance of ciclosporin increased significantly and the half-life shortened compared with controls [134]. This led to the recommendation to avoid treating diabetic dogs with ciclosporin (SoR C).
Neoplastic diseases No increase in the prevalence of neoplasia has been reported in published clinical studies. One study of 51 dogs given ciclosporin for six to 30 months did not show increased neoplasia compared with the general population [87], and ciclosporin treatment in canine AD was not a risk factor for cutaneous lymphoma [140]. No articles analyzed the effect of ciclosporin in animals with neoplastic diseases. However, the immune effects and the potential impact on tumor progression led to the recommendation to avoid using ciclosporin in dogs with neoplasia or when neoplasia is diagnosed during treatment (SoR C).
Urinary tract infections Ciclosporin can be used in dogs with occasional urinary tract infections (SoR B) but is not recommended in dogs with recurrent episodes of bacterial cystitis (SoR C) [121].

In Atopic Dogs, during the Induction Period of ASIT
No data are available. An increase in the population of regulatory T cells could play a role in desensitization [141]. Ciclosporin administration increases populations of regulatory T cells in humans [142], and has no effect in dogs [143], but never reduces this population. Ciclosporin could react in synergy or have no effect on desensitization. Ciclosporin is usable during desensitization in dogs (SoR C).

In Atopic Dogs, during Allergologic Tests
In addition to the sole published article, one other study showed that ciclosporin reduced reactivity to the skin tests, but not the IgE assay, in relation to an Ascaris allergen [144], whereas two abstracts, one from an experimental study and the other from a clinical study, reported no effect [145,146].
Ciclosporin can be used without a therapeutic window before these sensitization tests are performed (SoR B).

In Atopic Dogs, during Dietary Trials
Because ciclosporin is too slow-acting to control pruritus during the induction period of a hypoallergenic diet, and because of its persistent action several days after discontinuation, potentially masking the response to the challenge diet, this molecule is not recommended during a dietary trial (SoR C).

In Pruritic Ectoparasitic Dermatoses
External antiparasitics are rapidly effective, whereas ciclosporin is slow, so its use is not recommended (SoR C).

During Vaccines
There are no published effects of ciclosporin on the efficacy and hazards of vaccination. Only indications of the summary of the product characteristics of ciclosporin-containing drugs are available: do not vaccinate with a live vaccine during treatment or in the two weeks preceding or following treatment (SoR C).

In Atopic Dogs, excluding the Induction Period of Allergen-Specific Immunotherapy During Flares (Reactive Therapy)
Due to the rapid and efficient reduction in pruritus, oclacitinib (SoR A) is effective for the treatment of flares, with efficacy obtained in a few hours (SoR B) or a few days (SoR A). The dose of oclacitinib is 0.4-0.6 mg/kg twice a day orally for 14 days, thereafter reduced to 0.4-0.6 mg/kg once a day (SoR A). When tapering oclacitinib therapy, a slight rebound of pruritus is observed (SoR B).
When the molecule chosen for the control of canine AD is ciclosporin, oclacitinib can be used concomitantly at the beginning of the treatment to accelerate the reduction in pruritus (SoR B) during the flare.
Hydrocortisone aceponate can also be combined with oclacitinib to prevent the relapse of pruritus and skin lesion when reducing the frequency of administration of oclacitinib from bid to sid (SoR A).
In Non-Flare Periods (Proactive Therapy) Oclacitinib is safe and effective and is recommended for the long-term management of canine AD (SoR A). Adverse events associated with oclacitinib are uncommon (mainly gastro-intestinal) (SoR B).

In Dogs with Superficial Pyoderma or Microbial Overgrowth
Oclacitinib could be used when dogs are affected by these infectious diseases, provided the infectious component is concomitantly-or ideally previously-controlled (SoR C). No study has shown that administration of oclacitinib aggravates the clinical signs of bacterial overgrowth, superficial pyoderma or Malassezia dermatitis. Moreover, allergic dogs treated with oclacitinib received less antibiotics than allergic dogs treated with other anti-pruritic treatments [106].
In Dogs with Specific Problems Liver disorders No data are available. In one case of necrolytic migratory erythema syndrome, oclacitinib was effective as long-term therapy (12 weeks) in controlling pruritus [147]. No study reported adverse hepatic effects in atopic dogs treated with oclacitinib. It thus seems that this molecule can be used in dogs with hepatic troubles, but the benefit-risk balance should be evaluated and a biochemical follow-up test conducted regularly (SoR C).
Renal disorders No study reported adverse renal effects in atopic dogs treated with oclacitinib. It thus appears that this molecule can be used in dogs with renal troubles, but the benefit-risk balance should be evaluated and the biochemical profile checked regularly (SoR C).
Diabetes mellitus No study reported signs of diabetes mellitus in atopic dogs treated with oclacitinib. It thus seems that this molecule can be used in dogs with diabetes mellitus, but the benefit-risk equation should be evaluated and the biochemical profile checked regularly (SoR C).
Neoplastic diseases The summary of product characteristics prevents the use of this molecule in dogs with neoplastic diseases. The development of papilloma has also been reported in dogs. However, there is no association between the daily administration of oclacitinib and the odds of malignancies or benign skin masses [104]. Oclacitinib was a therapeutic option in one case of cutaneous epitheliotropic T-cell lymphoma [148]. Oclacitinib was well tolerated when administered in combination with carboplatin or doxorubicin in nine tumoral cases [149]. Oclacitinib was shown to modulate the production of interleukin-8 and monocyte chemoattractant protein-1 by certain canine MCT cell lines [150]. Oclacitinib appears to be able to reduce pruritus in dogs affected with cutaneous tumors (SoR B).
Urinary tract infections Some authors observed urinary tract infection/cystitis [100,102] but bacteriuria is not an expected adverse effect in dogs with no prior history of urinary tract infection or predisposed condition. Oclacitinib can be used in dogs with occasional urinary tract infections (SoR B), but it is not recommended for dogs with recurrent episodes of bacterial cystitis (SoR C) [121].

In Atopic Dogs, during the Induction Period of ASIT
No studies have assessed the impact of oclacitinib during desensitization. Some dogs were receiving oclacitinib while being desensitized, but the consequences were not assessed (SoR C) [109]. Because of its mechanism of action, oclacitinib seems usable during the induction period of ASIT with no negative impacts (SoR C).

In Atopic Dogs, during Allergy Testing
No studies have assessed the impact of oclacitinib during allergy testing in atopic dogs. One pilot study used experimental models of canine AD and showed no influence of oclacitinib on allergen-specific IgE results. Oclacitinib can be used during allergy testing (SoR C).

In Atopic Dogs, during Dietary Trials
No negative effect on dietary trials has been published and oclacitinib can be used (SoR C).

In Pruritic Ectoparasitic Dermatoses
With the exception of demodicosis (confirmed or previous), in which case oclacitinib should be avoided (SoR C), a short course of treatment would be acceptable when initiating the treatment of a highly pruritic sarcoptic mange or flea infestation (SoR C).

With Vaccines
No data are available. In the summary of product characteristics, oclacitinib administration was associated with an adequate immune response to modified live vaccine canine distemper virus and canine parvovirus vaccination, but a decreased serological response to modified live vaccine canine parainfluenza and inactivated rabies vaccine. Oclacitinib can be used depending on the vaccine type (SoR C). 4.6. Lokivetmab 4.6.1. In Atopic Dogs, excluding the Induction Period of ASIT During Flares (Reactive Therapy) Lokivetmab subcutaneous injection results in an impressive improvement in pruritus between 4 and 24 h (SoR A) and is effective for the treatment of flares of canine AD (SoR A). Reductions in the pruritus score and in the lesional score were significant 28 days after one injection (SoR B). The lokivetmab dose used in Europe is a minimum of 1 mg/kg, and 2 mg/kg in North America.
In Non-Flare Periods (Proactive Therapy) Lokivetmab is recommended for non-flare periods of canine AD (SoR A). The lesional score improved after the first injection and continued to improve after the second and the third injections (SoR C). Lokivetmab can delay disease flares in some atopic dogs (SoR C).

In Dogs with Superficial Pyoderma or Microbial Overgrowth
Lokivetmab can be recommended in dogs with canine AD and superficial pyoderma or microbial overgrowth (SoR C), even if, to date, no data are available to assess the efficacy of lokivetmab or the impact of lokivetmab on dogs with superficial pyoderma or microbial overgrowth. No data are available that suggest a pro-infectious role of lokivetmab when used in dogs suffering from allergic dermatitis (SoR C).

In Dogs with Specific Problems
Liver disorders No specific study has been performed, but lokivetmab does not cause changes in biochemical parameters (SoR C). Lokivetmab can thus be recommended in dogs with liver disorder (SoR C).
Renal disorders No data are available. Renal parameters are not modified by lokivetmab (SoR C). Lokivetmab thus seems to be usable in dogs with renal disorder (SoR C).
Diabetes mellitus No data are available. Lokivetmab does not stimulate gluconeogenesis (SoR C). Lokivetmab thus seems to be usable in dogs with diabetes mellitus (SoR C).
Neoplastic diseases Few data are available. A monthly injection of lokivetmab at a dose of 2 mg/kg was effective in resolving and maintaining pruritus remission over a period of 15 months in a dog with widespread cutaneous mastocytosis [151] (SoR C). Similarly, it was used at a dose of 1.25 mg/kg in a dog with cutaneous epitheliotropic lymphoma in combination with prednisolone and resolved pruritus [152] (SoR C). Lokivetmab can be used in dogs with mastocytosis or epitheliotropic lymphoma and for other neoplastic diseases; however, although its use seems to be safe, there are no data on the safety of lokivetmab in the presence of tumor (SoR C).
Urinary infections In clinical trials, lokivetmab does not induce urinary infections, or changes in biochemical, hematological, and renal parameters (SoR C). Lokivetmab can thus be recommended in dogs with urinary infections (SoR C).

In Atopic Dogs, during the Induction Period of ASIT
No negative effect on ASIT has been published and lokivetmab can be used during the induction period of ASIT (SoR C).

In Atopic Dogs, during Allergy Testing
No published data are available. Lokivetmab could be used during allergy tests without the need for the withdrawal of the drug before the tests are performed (SoR C).

In Atopic Dogs, during Dietary Trials
No negative effect on dietary trials has been reported and lokivetmab can be used (SoR C). However, due to its prolonged effect beyond six weeks in some dogs, the interpretation of the outcome of the eviction regime should be made with caution.

In Pruritic Ectoparasitic Dermatoses
No data are available. A single injection would be acceptable when initiating the treatment of a highly pruritic sarcoptic mange or FBH (SoR C).

With Vaccines
No data are available. The summary of product characteristics does not limit the use of lokivetmab during vaccination, except to recommend giving the injections at different time points. Lokivetmab can be used with vaccines (SoR C).

Discussion and Conclusions
The aim of this extensive review was not to rank the molecules for each specific clinical situation, but to provide clinicians with the information they need to make a choice, including information on the presence or absence of data on efficacy, as well as on adverse effects.
Moreover, guidelines should always be interpreted as general recommendations that are appropriate for a large majority of cases based on good clinical practice. The guidelines are established to improve the quality and safety of care but are not intended to describe the entire management of a disease, and cannot cover all clinical situations encountered in routine practice. They do not exempt the clinician from exercising discernment in their management of the patient. These guidelines should be considered as a basis for decision making with regard to which different or additional approaches may be used in certain cases and according to the owner's preferences. Additionally, it should be borne in mind that the owners have to bear the cost of treatment, especially in the case of chronic diseases such as atopic dermatitis.
In published papers, the number of dogs that did not respond to the antipruritic molecule evaluated is rarely given, which may lead to an overestimation of the efficacy of the molecule. Precise data on adverse effects are often missing and causality is often difficult to establish.
Finally, the use of these molecules must take into account the conditions of use (age, weight, and physiological state) and the relative risks due to drug interactions.