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