Canine Atopic Derma//s and the IL-31 Inhibitors Daniel O. Morris, DVM, MPH, DACVD Professor of Dermatology & Allergy School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Daniel O. Morris F004 - Compara,ve Dermatology: Cases at the Intersec,on of Human and Veterinary Dermatology and the One Health Paradigm DISCLOSURES I do not have any relevant rela/onships with industry.
Canine Atopic Derma//s (cad) A chronic, pruri/c inflammatory skin disease of dogs that is immuno-physiologically homologous to human AD, and mediated in part by stratum corneum barrier func/on deficits. The main difference: my pa/ents are covered in dense hair coats. cad is perhaps the strongest link between human and canine dermatology, in regards to a model for inves/ga/on of mechanisms and therapeu/cs.
Clinical features of cad Primarily affects areas where the hair is most sparse (axillae, groin, interdigital spaces) or where the surface microclimate remains moist (peri-orificial areas, external ear canals).
Clinical features, cont Generalized disease is not common, but may occur in pa/ents with non-seasonal disease/secondary infec/ons. The wide-spread distribu/on and density of the hair coat makes topical therapy nearly impossible for most pa/ents.
Clinical features, cont A major feature of cad is the high prevalence of recurrent infec/ons: Staphylococcal pyoderma (manifest primarily as folliculi/s +/- furunculosis).
Shaving the hair may be necessary to appreciate the full extent of lesions.
Overgrowth of Malassezia pachyderma0s (may also serve as a potent allergen to atopic pa/ents).
Bacterial and yeast o//s externa
Therapeu/c considera/ons For those pa/ents in which recurrent pyoderma and/ or o//s externa is a major feature, potent an/- inflammatory (in addi/on to an/-pruri/c) therapy is usually necessary. Steroids Cyclosporine A
A newer target: The IL-31 story IL-31 is produced by ac/vated Th2 cells and CLA+ skinhoming T-cells. Upon binding to its receptor, IL-31 ac/vates the Janus kinase signal transduc/on pathway for transcrip/on of various pro-inflammatory cytokine genes. Receptors for IL-31 are also expressed on kera/nocytes, macrophages, eosinophils, and a sub-set of small-sized nocicep/ve peripheral nerves and dorsal root ganglia.
Vet Immunol Immunopathol 2009;131:140-3. Vet Immunol Immunopathol 2014;157:42-8.
Oclaci/nib This compound was selected for its: High affinity for inhibi/ng JAK-1 enzyme-mediated ac/va/on of cytokine expression, including IL-31. Inhibi/on of neuronal pruritus mediated by IL-31. An/-inflammatory and an/-allergic ac/vity mediated by reduc/on of IL-2, IL-4, IL-6, and IL-13. Minimal ac/vity against JAK-2 cytokines (important in hematopoiesis).
Pharmacology of oclaci/nib Based on its MOA, both direct an/-pruri/c effect AND some an/-inflammatory ac/vity is expected. Extremely rapid onset of ac/on (within 4 hours). Label Dosing: 0.4 to 0.6mg/kg administered Q12h x 14 days, then Q24h for maintenance. Labeled contraindica/ons: history of neoplasia, presence of severe infec/on, age under 12 months (due to risk for generalized demodicosis). Clinical trials demonstrate an/-pruri/c efficacy equivalent to both prednisolone and cyclosporine.
Post-marke/ng experience with oclaci/nib Due to its extremely short half-life, some dogs cannot be maintained on Qd dosing. Many relapse with pruritus once finished with the loading phase.
Oclaci/nib is not an effec/ve maintenance therapy for most dogs with severe or recurrent furunculosis of the feet, face or pressure points, or for reduc/on of hyperplas/c o//s externa.
A recent case-control study showed its use to be associated with a higher incidence of his/ocytomas in older dogs (compared to use of cyclosporine).
Lokivetmab A mab which targets canine IL-31 Prevents binding of IL-31 to its neuronal receptor, thereby interrup/ng neurotransmission of itch. Rapid onset of an/-pruri/c ac/on (within 1 day for many dogs) which persists for 30 to 60 days. Labeled for sub-cutaneous injec/on at 2mg/kg Q30d (or as needed beyond 30 days).
Lokivetmab, cont A caninized mab: 95% canine gene/c sequence; 5% murine sequence. In clinical trials, 2.5% of dogs developed an/-lokivetmab an/bodies, which reduced circula/ng mab levels by up to 90% within 4-6 weeks. Clinically apparent as a pa/ent that has a waning response with subsequent injec/ons amer responding favorably to the first dose.
Post-marke/ng experience with Lokivetmab Effec/ve for some dogs that fail oclaci/nib. Not generally effec/ve for pruritus due to ectoparasites Variable effect when secondary infec/ons are present. Linle to no an/-inflammatory ac/vity; not an effec/ve approach for cases with recurrent secondary pyoderma.
Conclusions Systemic therapies are generally necessary for cad due to the wide-spread distribu/on of disease and dense hair coat of dogs. (Heavy reliance on topical therapy = poor compliance). Steroids and calcineurin inhibitors have long been the gold standards by which new therapies are judged. Equal efficacy with a reduced side-effect profile is the holy grail of our search for alterna/ves. The IL-31 inhibitors achieve this for a sub-set of pa/ents. Proper case selec/on and careful monitoring for secondary skin infec/ons are the keys to a successful outcome.