DJDeBoer- InnovativeTherapies 1
DouglasJ.DeBoer,D.V.M.,Diplomate A.C.V.D.Schoolof VeterinaryMedicineUniversityof Wisconsin-Madison
Mars el la e t al ., J Am Vet Med As soc. 2012 Ju l 15;241(2):194-207
CurrentViewofPathogenesis
• ADhasaverycomplexpathogenesis• Treatmentapproachesmustcombineseveral
modesoftherapyor“tools”
• Everypatientisdifferentandwillrequireadifferentcombinationof“tools”toprovideeffective,affordable,convenient,andsafetreatmentoveraverylongtime.
• Staphylococcalinfection• Malasseziadermatitis
“Porter”•3yearoldfemaleTerriercrossbreddog•Historyofchronicprurituswithintermittentlesionsforthepastyear•Treatedwith>6coursesofcephalexinoverthepastyear
“Porter”•Methicillin-resistantStaphylococcuspseudintermediusalsoresistanttonearlyallothersystemicantibiotics
Adjuncttreatment(withantibiotics)
Asprimarytreatment
SuperficialpyodermaMildtomoderateinextent/severityDailyapplicationfor3-6weeksConsiderfrequentshampooingplusleave-ontopicalonthenon-shampoodays
Chlorhexidine
•Various formulations available• 2-4%concentrations• With orwithout Tris• With orwithout antifungal
•Various ways todeliver• Shampoo• Spray• Wipes• Mousse or leave-onproduct
DJDeBoer- InnovativeTherapies 2
Gc
Gc
Gc
Gc
Gc
Gc
Gc
Gc
Gc
Gc Glucoco rtico id
Forreliefof“troublespots”likepedalpruritus…Fortemporaryorseasonaluseinatopicdermatitis
PotentCorticosteroidSprayAdviseowner:donotusepotenttopicalsteroidsformorethan2-3weeks
Cs Cyclo sporine
C s
C s
C s
C sC s
• Greatefficacy• Long-termsafety
• Slowonsetofaction• Expensive• Adverseeffects
AdverseeffectsGIdisturbances(~25%)Usuallytransient
Maropitant citrate(Cerenia)NK-1antagonist,controlsvomitingcentrallyUseonlyifnecessaryUseforfirst5+daysoftreatmentwithCsA
• CsA 5mg/kg/d• Pred 1mg/kg/dx7dthentaperx7d• DonotusePred +CsA longterm!!!
• Weakanti-inflammatoryeffects• Possibleeffectsonepidermal
barrierfunction
• Synergisticwithothermedications• Antihistamines(improvedefficacy)• Corticosteroids(dose-sparingeffect)• Ciclosporin(canuse25%less)
DJDeBoer- InnovativeTherapies 3
• EPA+GLA+DHA:>25mg/kg/d• ProbablyforalldogswithAD• Supplementsorindogfood• Nota“quickcure”
• Cautionwith“petstore”supplements• Salmonoil, coconutoil,etc…
• Abasicwaythatcellsregulatemanydifferentcellsignalingprocesses
• Somearepartofareceptor–the“triggering”mechanismthattransmitsasignalfromoutsidetoinsidecell
• Importanttargetfornewdrugs
• 4JAKsinmammals• JAK1,JAK2,JAK3,TYK2• Associatewithreceptorsinpairs
Janus
Examples ofreceptorsusingJAKs
O’Sheaetal.,Immunity 2012;36:542
mRNA
J AK (J anus k inase)
1. Cy tok ine binds rec eptor
3. STAT phos phory la tion
4. STAT dimeriz ation
Cel l membrane Nuc leus
6. Trans lationof mRNAproduc esprote ins
7. Cel l func tion c hanges:A. ↑ IgE produc tionB. Ly mphoc y te pro l i feration C. ↑Cy tok ine produc tionD. ↑Cy tok ine rec eptor
ex pres s ion E. ↑Chemok ine produc tion
2. Rec eptor dimeriz ationand J AK phos phory la tion
STAT
DNA
Ribos ome
Phos phates
5. RNA poly meras etrans c rip tion of DNA
Janus Kinase (JAK) Signaling Summary
J AK (J anus k inase)
1. J AK inh ib i tors bind J AK
2. Cy tok ine binds rec eptor
3. Rec eptor dimeriz ation
J AK inh ib i tor
J AK inh ib i tor
3. JAK inhibitors block downstreamactivity in the cell
JAK inhibitors only work to block the activ ity in cells where activ ity is mediated by cytokines that work through JAK.
Cel l membrane Nuc leus
Janus Kinase (JAK) Inhibition
CytokinesandItch
Nerve fibers in skin
Any direct mechanical or chemical stimulus thatstimulates nerve fibers in the skin, which transmitthe impulse to the CNS and creates the uncomfortablesensation of itch.
Many different chemical messengers cancreate itch, including cytokines.
Cellmembrane
IL-31 Receptor
And itusesoneoftheJAKpathways!• APOQUEL® (oclacitinibtablet)• AspecificinhibitorofJAK1indogs
• Indications• Controlofpruritusassociatedwithallergicdermatitis
• Controlofatopicdermatitis• Indogsatleast12monthsofage
DJDeBoer- InnovativeTherapies 4
Whatkindofpatientscanbenefit?SafetyandmonitoringTips,tricks,andcaseexamples
FleaAllergy FoodAllergy ContactAllergy AtopicDermatitis
APOQUELworksonallofthem!
Mean APOQUEL® Scores WereSignificantlyBetter Than PlaceboScores on EachAssessmentDay
NospecificlaboratorymonitoringrecommendationNoorgantoxicity
PotentialadverseeffectsOccasionalmildstomachupset(3-4%)??‘Immunosuppressive’category;possibleincreasedsusceptibilitytoinfectionsanddemodicosisDonotuseifpre-existingneoplasia
Formuchmoreinformationvisit:www.apoquel.com
0.4-0.6mg/kgtwicedailyforupto14days,thenoncedailythereafter,formaintenance
DoesnotinterferewithIDTorserologictestingOKwithnearlyallothermedicationsNoneedfor“washout”aftersteroidsorciclosporin
Anantipruritic,immunomodulatory drugNotreallyan“immunosuppressive”drug
Can’tbeusedinpemphigus,AIHA,etc.Notreallyan“anti-inflammatory”drug
Notusefulinswellingfromotitisexterna,etc.Apoquelisnotadrugfor“anydogwithskindisease”!!
VeryoccasionaldemodicosisVeryoccasionalloweredWBC(~3000)Recheckexamsat2months,6months,yearly
SkinscrapingsforDemodexBloodcountChemistriesnotnecessary(butoftenagoodidea)Urinalysisnotnecessary(butoftenagoodidea)Thoroughphysicalexaminationforcontraindications
MayNOTworkinpruritusassociatedwithbacterialoryeastskininfectionsShorthalf-life(4hr)– somepatientshaveincreaseinitchwhenswitchingtooncedaily
Consideraddinganantihistaminee.g.atnight
Bestaspartof‘multimodaltherapy’
Biologicalcompound (notachemical)Largeproteinorpeptidemolecule,madeinlaboratorycultureratherthanbychemicalsynthesisExample:monoclonalantibodytherapy
DJDeBoer- InnovativeTherapies 5
Humanexample:Humira®(adalimumab - AbbVie)
Mab againstTNF-αIndications:psoriasis,rheumatoidarthritis,Crohn’s diseaseOneSQinjectionevery2weeks
“Whatdoyouwanttogetridof?”AmicroorganismAtumorcellAcelloftheimmunesystemAcytokineorothersmallmolecule
Cellmembrane
IL-31 Receptor
IL-31isakeycytokineincaninepruritus.PreventingIL-31fromactingisavaluable treatmentmodality.
X Cellmembrane
IL-31 Receptor
IL-31isakeycytokineincaninepruritus.PreventingIL-31fromactingisavaluable treatmentmodality.
XX X• ADisamultifactorialdiseasewithacomplexpathogenesis
• Therapywillcontinuetobeindividualizedandmultimodal
• Newdrugsandnewtherapymodalitiesareenablingmoreeffectiveandsaferlong-termmanagement