Glucocorticoids show a broad anti-inflammatory effect. Interestingly, in all RCTs where both lesions and pruritus are evaluated, a concurrent reduction of pruritus and skin lesions is normally seen, thereby indicating that glucocorticoids likely act via the inhibition of pro-inflammatory and pruritogenic cytokines, as well as nerve hypersensitivity secondary to inflammation. However, laboratory animal data suggest that a direct effect on sensory neurons also exists, as scratching induced by histamine, substance P, serotonin, and a PAR-2 agonist can be attenuated by topical administration of the strong dermocorticoid clobetasol propionate, even in mast cell-deficient mice (Sekine et al. 2012). There are few canine studies on the change in skin inflammatory mediators after glucocorticoid administration. In an experimental dog model of cutaneous late-phase reactions induced by anti-canine IgE antiserum, the mRNA expression of the cytokines IL-13, CCL2, CCL5, and CCL17 was suppressed by prednisolone (Pucheu-Haston et al. 2006). Recently, recombinant canine IL-31 was found to induce pruritus in dogs, and it is elevated in more than 50 % of dogs suffering from AD (Gonzales et al. 2013b). Prednisolone given 1 h before IL-31 injection to dogs does not reduce its induced pruritus, but it does so when given 2–10 h beforehand (Fleck et al. 2012).

Calcineurin inhibitors act mainly (but not exclusively) as T-cell inhibitors. By blocking the nuclear translocation of the nuclear factor of activated T-cell (NFAT) transcription factor, the secretion of cytokines such as IL-2 and interferon gamma is reduced in T cells. A direct effect of cyclosporine on canine T cells reveals that therapeutic doses of cyclosporine (5–10 mg/kg/day) reduce the expression of IL-2 and interferon gamma in in vitro stimulated T cells purified from peripheral blood mononuclear cells of orally treated dogs (Archer et al. 2011).

Specific studies on the influence of cyclosporine on mediators of itch have not yet been performed in dogs. As cyclosporine treatment in atopic humans is accompanied by a decrease of serum levels of IL-31 (Otsuka et al. 2011), the effect of cyclosporine A on canine serum IL-31 or in activated canine T cells and mast cells should be investigated.

The action of cyclosporine in atopic dermatitis (and itch) is most likely not restricted to that on T cells: the NFAT transcription factor is also found in other cells such as dendritic cells, eosinophils, mast cells, and keratinocytes, and cyclosporine is known to also affect the function of these cells (Fric et al. 2012). For instance, protease-induced secretion of GM-CSF was reduced in a canine keratinocyte progenitor cell line by cyclosporine (Kimura et al. 2013). Also the lipopolysaccharide-induced PGE₂ synthesis was significantly reduced by cyclosporine in primary canine keratinocytes (Baumer and Kietzmann 2007). On the contrary, a recently published study revealed that cyclosporine might enhance the response to Toll-Like receptor agonists Pam3CSK4 and staphylococcal peptidoglycan, as mRNA expression of TNFα and IL-8 was enhanced in canine keratinocytes (Hendricks et al. 2012). Future studies should focus on the recently published influence of cyclosporine and PAR-2-activated TSLP secretion in canine keratinocytes, as this could be a crucial inducer of itch in dogs, as shown recently in mice (Wilson et al. 2013).

There are several RCTs showing a significant reduction of pruritus in dogs suffering from AD after treatment with oral cyclosporine (Atopica, Novartis Animal Health) starting at 5 mg/kg once daily. Depending on the study, approximately 50–70 % of dogs exhibit a reduction of pruritus score equal or greater than 50 %. The maximal antipruritic effect is generally seen after 4–6 weeks, and the efficacy appears to remain stable even over longer treatment periods (Olivry et al. 2010; Olivry and Bizikova 2013; Steffan et al. 2006). Similar to that of glucocorticoids, the antipruritic effect of cyclosporine seems to be linked to the anti-inflammatory action of this drug, as the evolution of pruritus reduction appears to most often parallel that of the reduction in skin lesions. The concurrent use of oral prednisolone increases the speed of antipruritic action of cyclosporine (Dip et al. 2013).

A topical nanoencapsulated cyclosporine formulation was reported recently to be capable of reducing pruritus in atopic dogs to an extent similar to that of orally administered cyclosporine (Puigdemont et al. 2013).

The classic H1 antihistamines are competitive inhibitors at the H1 receptor (Simons and Simons 2011). Histamine binds to four different G protein-coupled receptors. These are widely distributed in the body: to simplify, the H1R is found on smooth muscle, endothelial, as well as immune cells, and it plays a role in the genesis of immediate-type hypersensitivity reactions; the H2R plays a role in gastric acid production, whereas the H3R is mainly found in the central nervous system and on peripheral neurons. Interestingly, the H4R is mainly expressed on hematopoietic cells (neutrophils, eosinophils, monocytes, dendritic cells, Langerhans cells, T lymphocytes, basophils, mast cells), fibroblasts, endocrine cells, and neurons, and this leads to a suspected role in allergy and inflammation (Zampeli and Tiligada 2009). Importantly, histamine-induced pruritus in mice seems to be mediated via the histamine H1 and H4 receptors, while the H3R appears to have a negative regulatory role (Rossbach et al. 2011). Typical H1 antihistamines like diphenhydramine, cetirizine, loratadine, and hydroxyzine have only low binding affinity to the H2R, H3R, or H4R (Lim et al. 2005). With regard to pruritus, it might be important to distinguish centrally acting antihistamines (first-generation antihistamines like diphenhydramine) from those that lack (or have a vastly reduced) central action, as these hardly cross the blood-brain barrier (loratadine).

There are several clinical trials that tested the efficacy of both first- and second-generation H1R antihistamines in dogs with AD [reviewed in Olivry et al. (2010), Olivry and Bizikova (2013) and Olivry and Mueller (2003)]. In general, the quality of these trials was found to often be poor, and most RCTs did not document a clinically relevant efficacy of this class of drugs (Olivry et al. 2010; Olivry and Bizikova 2013; Olivry and Mueller 2003; Eichenseer et al. 2013). The main limitations of these studies are a short duration of action and, possibly, inappropriate dosages, as these are often extrapolated from those used in humans without further dog-specific pharmacokinetic/pharmacodynamic justification. In spite of the lack of consistently supportive RCT results, many clinicians anecdotally report a low to medium efficacy of H1R antihistamines to control pruritus in dogs with AD (Dell et al. 2012). To date, there has been no trial-based evaluation of the possible benefit of H4R (or combined H1R and H4R) antihistamines to control AD-associated itch in dogs.

The Janus kinase (JAK) family encompasses four intracellular tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce signals of numerous cytokine and chemokine receptors via the STAT signaling pathway (O’Shea and Plenge 2012). Oclacitinib (Apoquel, Zoetis) is a novel JAK inhibitor shown to principally inhibit the function of JAK1-dependent cytokines involved in allergic inflammation (IL-2, IL-4, IL-6, IL-13); it appears to have minimal activity against JAK2-dependent cytokines involved in hematopoiesis or those associated with the innate immune response (Gonzales et al. 2013a). Oclacitinib reduces IL-31-induced pruritus in dogs, likely because of its interference with the IL-31 receptor signal transduction.

A recent RCT documented the rapid efficacy of oclacitinib (0.4–0.6 mg/kg twice daily) to decrease itch, as well as skin lesions, in dogs with allergic skin diseases (Cosgrove et al. 2013). Oclacitinib significantly reduced pruritus compared to placebo as early as the first day, and approximately 60 % of treated dogs had at least a 50 % reduction in pruritus as early as 4 days of treatment (placebo 23 %) (Cosgrove et al. 2013).