2022 article
What can we learn from treating atopic itch in dogs?
Labib, A., Yosipovitch, G., & Olivry, T. (2022, August). JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol. 150, pp. 284–286.
author keywords: Atopic dermatitis; eczema; dog; pruritus; itch; JAK inhibitor; IL-31 inhibitor; oclacitinib; lokivetmab
MeSH headings : Animals; Dermatitis, Atopic / therapy; Dogs; Pruritus / therapy
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Added: December 5, 2022
Atopic dermatitis (AD) is a common, chronic skin disorder affecting up to 2.4% of the worldwide population. It negatively affects patients and their caregivers owing to the unrelenting itch, rash, and disturbed sleep. Not only does AD affect humans, but it is also very prevalent in domestic canines. Because of the extensive similarities in the phenotype and pathogenesis between human and canine AD, the latter serves as an excellent model to evaluate the use of novel antipruritic drugs. In this Paradigms and Perspectives article, we review the use of the Janus kinase (JAK) inhibitor (JAKinib) oclacitinib (Apoquel [Zoetis, Parsippany-Troy Hills, NJ]), and the anti–IL-31 mAb lokivetmab (Cytopoint [Zoetis]), which have been available to treat atopic dogs for years. This short synopsis aims to help physicians become more familiar with what to expect when treating human atopic patients with similar therapeutics. AD spontaneously affects dogs, likely owing to a combination of environmental and genetic factors, the latter supported by a strong breed predisposition to develop this disease. In dogs as in humans, the diagnosis of AD stems from the observation of erythema and self-induced lesions that follow an often severe itch at typical body locations (Fig 1); the phenotype of canine AD—like that of its human counterpart—varies among races (breeds). In both species, the pathogenesis of AD involves IgE sensitizations to allergens, a complex skin barrier dysfunction due to lipid and protein anomalies, a type 2 (ie, TH2 cell–predominant) immune cascade, a neuronal sensitization to itch, and a cutaneous microbial dysbiosis (reviewed in Nuttall et al1Nuttall T.J. Marsella R. Rosenbaum M.R. Gonzales A.J. Fadok V.A. Update on the pathogenesis, diagnosis and treatment of atopic dermatitis in dogs.J Amer Vet Med Assoc. 2019; 254: 1291-1300Crossref PubMed Scopus (14) Google Scholar). At this time, the main apparent difference between species is the current lack of reports of pathogenic mutations in filaggrin or other keratinocyte genes in canine AD, thus suggesting that the observed barrier dysfunction seen in dogs likely follows dermal inflammation. As in humans, the historical mainstay of AD pharmacotherapy in dogs has been topical and oral glucocorticoids, even though the dense coat of dogs limits use of the former. In the event of insufficient benefit of glucocorticoids or unacceptable adverse effects, immunosuppressants such as cyclosporine have historically been prescribed. The past decade saw the emergence of small molecules and biologic treatments specifically targeting the harmful effect of proallergic and pruritogenic cytokines. Among these are the JAKinib oclacitinib and the IL-31–inhibiting mAb lokivetmab, which were approved several years ago to treat canine AD; details on their efficacy and safety could be informative for the treatment of the human homologue. Approved by the US Food and Drug Administration in 2013 to treat AD and allergic dermatitis in dogs, oclacitinib is a first-generation, nonselective, yet JAK1-predominant JAKinib.2Gonzales A.J. Bowman J.W. Fici G.J. Zhang M. Mann D.W. Mitton-Fry M. Oclacitinib (Apoquel®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy.J Vet Pharmacol Ther. 2014; 37: 317-324Crossref PubMed Scopus (117) Google Scholar The treatment protocol is 0.4 to 0.6 mg/kg administered orally twice a day for 2 weeks, followed by a once-daily administration for maintenance therapy. Oclacitinib exhibits a remarkably rapid antipruritic effect in allergic dogs, with an effect noted within hours of administration, as with prednisolone.3Gadeyne C. Little P. King V.L. Edwards N. Davis K. Stegemann M.R. Efficacy of oclacitinib (Apoquel®) compared with prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in client-owned dogs in Australia.Vet Dermatol. 2014; 25 (512-e86)Crossref PubMed Scopus (37) Google Scholar A caveat of oclacitinib is the transient rebound in pruritus scores that was reported in every trial (eg, in Cosgrove et al4Cosgrove S.B. Wren J.A. Cleaver D.M. Walsh K.F. Follis S.I. King V.I. et al.A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis.Vet Dermatol. 2013; 24 (587-e142)Crossref Scopus (85) Google Scholar) when its frequency of administration was reduced from twice to once daily after 2 weeks. Such a rebound is suspected to be caused by a persistent transcription of pruritogenic cytokines in lesional skin during the induction of JAKinib therapy.5Fukuyama T. Ganchingco J.R. Baumer W. Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib.Eur J Pharmacol. 2017; 794: 20-26Crossref PubMed Scopus (15) Google Scholar The concurrent application of topical glucocorticoids or a 4-day course of prednisolone at the onset of oclacitinib therapy (our submitted data, 2022) prevents or diminishes such a rebound. The benefit of oclacitinib in terms of decreasing skin lesions is generally noted within 1 to 2 weeks, which is slower than for itch; the lesion-reducing effect of oclacitinib is similar to that of cyclosporine.6Little P.R. King V.L. Davis K.R. Cosgrove S.B. Stegemann M.R. A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs.Vet Dermatol. 2015; 26 (23-e8)Crossref PubMed Scopus (46) Google Scholar The administration of oclacitinib to dogs is generally considered to be safe, as the proportion of minor adverse events mirrors that seen in dogs treated with placebo, prednisolone, or cyclosporine.3Gadeyne C. Little P. King V.L. Edwards N. Davis K. Stegemann M.R. Efficacy of oclacitinib (Apoquel®) compared with prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in client-owned dogs in Australia.Vet Dermatol. 2014; 25 (512-e86)Crossref PubMed Scopus (37) Google Scholar,4Cosgrove S.B. Wren J.A. Cleaver D.M. Walsh K.F. Follis S.I. King V.I. et al.A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis.Vet Dermatol. 2013; 24 (587-e142)Crossref Scopus (85) Google Scholar,6Little P.R. King V.L. Davis K.R. Cosgrove S.B. Stegemann M.R. A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs.Vet Dermatol. 2015; 26 (23-e8)Crossref PubMed Scopus (46) Google Scholar Occasionally, after weeks of treatment with oclacitinib, dogs develop demodicosis due to Demodex canis or papillomavirus infection, which is an unsurprising event inasmuch as these diseases are normally controlled by T cells in immunocompetent dogs (unpublished observation, 2018).4Cosgrove S.B. Wren J.A. Cleaver D.M. Walsh K.F. Follis S.I. King V.I. et al.A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis.Vet Dermatol. 2013; 24 (587-e142)Crossref Scopus (85) Google Scholar Such a potential immunosuppressive effect has restricted the US Food and Drug Administration's approval of oclacitinib to dogs older than 1 year on account of side effects seen in younger dogs with more immature immune systems (Freedom of Information summary; New Animal Drug Application no. 141-345). The long-term administration of oclacitinib to dogs might be of concern to some, as its immunosuppressive effect could be predisposing to malignancies. However, in a case-control study lasting longer than 2 years (a period corresponding to far longer than a decade in humans), there were no notable differences in the cumulative incidence of neoplasia between dogs with allergy treated with oclacitinib and those receiving other standard-of-care anti-allergic medications.7Lancelloti B.A. Angus J.C. Edginton H.D. Rosenkrantz W.S. Age- and breed-matched retrospective cohort study of malignancies and benign skin masses in 660 dogs with allergic dermatitis treated long-term with versus without oclacitinib.J Amer Vet Med Assoc. 2020; 257: 507-516Crossref PubMed Scopus (4) Google Scholar Altogether, oclacitinib is a remarkable advance in treating canine allergic skin diseases thanks to its potent and rapid efficacy—especially against itch—and its favorable safety profile. IL-31 is a TH2 cytokine that induces profound itch in several species, including humans and dogs; it is the cytokine most highly expressed after an epicutaneous allergen challenge in house dust mite–sensitized dogs. The caninized mAb lokivetmab prevents the binding of dog IL-31 to its receptor; its approved administration protocol is 2 mg/kg every 6 to 8 weeks in the United States and 1 mg/kg every 4 weeks in the European Union. In an experimental canine model of IL-31–induced itch, the onset of lokivetmab’s antipruritic effect was visible within 3 to 4 hours after challenge.8Fleck T.J. Norris L.R. Mahabir S. Walters R.R. Martinon O. Dunham S.A. et al.Onset and duration of action of lokivetmab in a canine model of IL-31 induced pruritus.Vet Dermatol. 2021; 32 (681-e182)Crossref PubMed Scopus (1) Google Scholar In dogs with spontaneous AD, its beneficial effect on itch was noted within the first day after injection, and nearly half of the dogs had itch visual analog scale values within the range of those of normal dogs after 2 months.9Moyaert H. Van Brussel L. Borowski S. Escalada M. Mahabir S.P. Walters R.R. et al.A blinded, randomized clinical trial evaluating the efficacy and safety of lokivetmab compared to ciclosporin in client-owned dogs with atopic dermatitis.Vet Dermatol. 2017; 28 (593-e145)Crossref PubMed Scopus (44) Google Scholar Although in the first month, the antipruritic effectiveness of lokivetmab was stronger and faster than that of cyclosporine, the 2 medications were equipotent in reducing atopic skin lesion scores.9Moyaert H. Van Brussel L. Borowski S. Escalada M. Mahabir S.P. Walters R.R. et al.A blinded, randomized clinical trial evaluating the efficacy and safety of lokivetmab compared to ciclosporin in client-owned dogs with atopic dermatitis.Vet Dermatol. 2017; 28 (593-e145)Crossref PubMed Scopus (44) Google Scholar The monthly administration of lokivetmab monotherapy to dogs with controlled AD prevented the occurrence of flares for up to 1 year in one-fourth of dogs10Tamamoto-Mochizuki C. Paps J.S. Olivry T. Proactive maintenance therapy of canine atopic dermatitis with the anti-IL-31 lokivetmab. Can a monoclonal antibody blocking a single cytokine prevent allergy flares?.Vet Dermatol. 2019; 30 (98-e26)Crossref Scopus (13) Google Scholar; in that study, however, the median time to flare was 63 days, suggesting that mediators other than IL-31 were driving AD relapses in most of these patients.10Tamamoto-Mochizuki C. Paps J.S. Olivry T. Proactive maintenance therapy of canine atopic dermatitis with the anti-IL-31 lokivetmab. Can a monoclonal antibody blocking a single cytokine prevent allergy flares?.Vet Dermatol. 2019; 30 (98-e26)Crossref Scopus (13) Google Scholar Although pretreatment with lokivetmab nearly abolished the itch that followed topical application of allergens in experimentally sensitized dogs, it had little effect in the prevention of acute lesional flares, thus indicating the minimal importance of IL-31 in the generation of acute atopic skin lesions.10Tamamoto-Mochizuki C. Paps J.S. Olivry T. Proactive maintenance therapy of canine atopic dermatitis with the anti-IL-31 lokivetmab. Can a monoclonal antibody blocking a single cytokine prevent allergy flares?.Vet Dermatol. 2019; 30 (98-e26)Crossref Scopus (13) Google Scholar Overall, lokivetmab injections are occasionally followed by mild and transient side effects that are similar in prevalence to those seen in placebo-receiving dogs. It can be used simultaneously with other treatments, it has a low risk of antidrug antibody development, and it has no major contraindications. Unlike oclacitinib, lokivetmab has no minimum age requirement, likely because it does not interfere with T-cell function but targets a single cytokine with little importance in physiology. In summary, it is noteworthy that the sole inhibition of IL-31 with lokivetmab can have such an immediate antipruritic effect in atopic dogs; this establishes a unique role of IL-31 in allergic itch. Although this Paradigms and Perspectives article has reviewed the treatment of canine AD with oclacitinib and lokivetmab, there is still much to learn. Nevertheless, the knowledge derived from treating atopic dogs with these drugs might prove of help to allergists and dermatologists in use of the new small molecules and biologics with similar modes of action that have recently been launched or are in the process of entering the market.
