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CurrentStrategiesforGoutandOtherTypesofMonoarticular
Arthritis
Andrew J. Gross, MDRheumatology Clinic Chief
Associate Clinical ProfessorUniversity of California, San Francisco
Disclosures
• None
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TeachingObjectives
• Beabletodistinguish septicarthritisfromcrystalinduced arthritis
• Befamiliarwithmanagementofacute&chronicgout
• Befamiliarwithdiagnosis andmanagementofcalciumpyrophosphate disease
Case1A75yearoldmanwithahistoryofdiabetes,CKD,andgoutisadmittedwith1dayofacuteswellingandpainintherightankle.Histempis101.4.Theankleiswarmandswollen.Theotherjointsseemunremarkable.ArthrocentesisintheEDdemonstratesnegativelybirefringentcrystals.Cellcount85,000WBC– 91%PMNs.Whatdoyoudonext:A. Holdallopurinol&waitforculturesB. InjectcorticosteroidsintothejointC. Prescribeaprednisone taperD. Prescribenaproxen500mgBIDE. PrescribeIVantibiotics&waitfor
theresultsofthegramstain&Cx
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75y.o.manwithDM,CKD with1dayacutelyswollen&warmanklewithfever.Synovialfluidshowsnegativelybirefringentcrystals&WBC85,000.
Whatdoyoudonext:
A. Holdallopurinol&waitforGS&Cx
B. InjectcorticosteroidC. Prednisone taperD. Naproxen500mgBIDE. IVantibioticsandwait
forGS&Cx
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Case1A75yearoldmanwithahistoryofdiabetes,CKD,andgoutisadmittedwith1dayofacuteswellingandpainintherightankle.Histempis101.4.Theankleiswarmandswollen.Theotherjointsseemunremarkable.ArthrocentesisintheEDdemonstratesnegativelybirefringentcrystals.Cellcount85,000WBC– 91%PMNs.Whatdoyoudonext:A. HoldallopurinolandwaitforculturesB. InjectcorticosteroidsintothejointC. Prescribeaprednisone taperD. Prescribenaproxen500mgBIDE. Prescribe IVantibioticsandwaitfor
theresultsofthegramstain&Cx
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DifferentialDiagnosisofmonoarticulararthritis
• SepticArthritis– GramPositivecocci– GramNegativeRods– Lymedisease– Tb/Fungal
• CrystalArthritis– Gout– Pseudogout
• Spondyloarthritis(e.g.Reactive Arthritis)
• Vasculitis• PalindromicRheumatism
• Trauma• Exacerbationof
Osteoarthritis
1-5%ofpatientswithcrystalarthritiswillalsohavesepticarthritisofthesamejoint(Papanicolas etal,JRheumatol 2012;ShahK,etal,JEmerg Med2007)
Whatcanhelpusdetermineifaninfectionispresentwithoutwaitingforthecultures?
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Riskfactorsforsepticarthritis
• Recentjointsurgery(Likelihood ratio6.9)Recentarthroplasty(LR3.1)
• Age>80(LR3.5)• Localwound/skininfection(LR2.8)• Diabetes(LR2.7)• Rheumatoidarthritis(LR2.5)
• Immunosuppression(esp.TNFinhibitors)• HIV• IVdruguse
Margaretten ME,etal, JAMA2007,PMID17405973
About50%ofpatientswillhaveafever>101°
SynovialFluidAnalysisisSomewhatHelpfultoIdentifySepticArthritis
• 49culture-positivesynovialfluidaspirates
• 39%hadWBC<50,000/mm3
• 55%hadanegativeGram’sstain– 56%ofthosepatientshadasynovialWBCof<50000/mm3.
• WBC<10,000/mm3 hasaverystrongnegativepredictivevalueforsepticarthritis
• WBC>100,000/mm3 hasastrongpositivepredictivevalue
• Gramstainis40-60%sensitive
• Culturesare90%sensitive
McGillicuddy DC,etal,AmJEmerg Med,2007 Margaretten ME,etal, JAMA2007
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Anasideaboutsepticarthritis
Allofthefollowingtestsshouldbeconsideredina30yearoldwomanwithsubacutedevelopmentofawarmswollenkneewithsynovialfluid50,000WBCs/mm3 EXCEPT:a) Bloodculturesb) LymediseaseELISAonserumc) SynovialfluidLDHandglucosed) Vaginalswabforgonococcus&
chlamydia(bynucleicacidamplificationtesting)
e) PPD&synovialbiopsyforAFBstain&mycobacterialculture
Allofthefollowingtestsshouldbeconsideredina30y.o.womanwithsubacutekneeswelling&synovialfluidwith50,000WBCs/mm3 EXCEPT:
a) Bloodculturesb) LymediseaseELISAc) Synovial fluidLDHand
glucosed) VaginalswabforGC&
chlamydiae) PPD&synovial biopsy
forAFB
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Allofthefollowingtestsshouldbeconsideredina30yearoldwomanwithsubacutedevelopmentofawarmswollenkneewithsynovialfluid50,000WBCs/mm3 EXCEPT:a) Bloodculturesb) LymediseaseELISAonserumc) SynovialfluidLDHandglucosed) Vaginalswabforgonococcus&
chlamydia(bynucleicacidamplificationtesting)
e) PPD&synovialbiopsyforAFBstain&mycobacterialculture
García-AriasM,etal,BestPract ResClin Rheumatol,2011
Anasideaboutsepticarthritis
• Bloodculturesarereportedtobepositivein50–70%ofpts
• Routeofinfection:– Hematogenousseeding– infectedcontiguous fociorneighboringsoft-tissuesepsis
– directinoculationduetotrauma• Organisms
– Staphaureus(~50%)– Streptococcus species(~20%)– GramNegativeRods(20%)
• Septicjointsshould bedrained(repeatedaspirationorarthroscopically)
García-AriasM,etal,BestPract ResClin Rheumatol,2011
SepticArthritis
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Cantini Fetal,AnnRheumDis,2007,PMID17768172
SubacuteArthritisoftheKnee
ReactiveArthritisIBDassoc ArthritisAnkylosingSpondylitis
NoLymeDisease?…ItalianStudy
H
Backtoourquestion:Whatcanhelpusdetermineifaninfectionispresentwithoutwaitingforthecultures?
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AcuteGoutyArthritis
• Provocation: trauma,ethanol,exercise,newmedication
• FirstAttack:– fourth tosixthdecadeoflife– 90%Monoarticular– 50%Podagra
• Sites:– 1stMTP– Instep,mid-foot, ankle,knee– wrist, fingers,elbow
http://images.rheumatology.org/image_dir/album75676/md_99-14-0009.tif. jpg
SepticArthritismostcommonlyaffectslargejoints
TheValueofaCarefulJointExam
http://www.eorthopo d.co m/pu blic/pati en t_ed ucati on/65 88/gou t.h tml
Tip:Inapatientwithahistoryofmanyattacksofgout,attackstendtobeoligoarticular orpolyarticular.Thiscanbeappreciatedbydoingaverycarefuljointexamination.
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Case3
A53yearoldmanwithHTN&nephrolithiasiscomestoseeyou forrecurrentfootpain.Hisfirstattackofjointpaincameinhis1st toeabout2 yearsagowithasuddenonsetofintensepainthatgraduallyimprovedover2weeks.Sincethenhehashad2moreattacksaffectingjointsinboth feet.Themostrecentattackstarted3daysagoinhis1st toeandinstep.Onexaminationthereismarkedswelling,erythemaandtendernessover the1st MTPbursaaswellasthe1st metatarsal-tarsaljoint.
TestYourKnowledge…
AllofthefollowingarereasonabletreatmentsforacutegoutEXCEPT:
a) NSAIDS(naproxen500mgBID,indomethacin 50mgTID)
b) Prednisone: 40-60mg/d,taperedover6-18daysc) Intra-muscularcorticosteroidinjection.(Triamcinalone 60-
80mgIM;mayneedtorepeatinacoupleofdays)d) Intra-articular steroidinjection(Triamcinalone 20-40mg)e) Colchicine0.6mgevery30minutesuntilresolutionor GI
upset
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AllofthefollowingarereasonabletreatmentsforacutegoutEXCEPT:
A. NSAIDSB. Prednisone TaperC. IMTriamcinoloneD. Intra-Articular
TriamcinoloneE. Colchicine q30min
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TestYourKnowledge…
AllofthefollowingarereasonabletreatmentsforacutegoutEXCEPT:
a) NSAIDS(naproxen500mgBID,indomethacin 50mgTID)
b) Prednisone: 40-60mg/d,taperedover6-18daysc) Intra-muscularcorticosteroidinjection.(Triamcinalone 60-
80mgIM;mayneedtorepeatinacoupleofdays)d) Intra-articular steroidinjection(Triamcinalone 20-40mg)e) Colchicine0.6mgevery30minutes 1.2mgthen0.6mg1
hour later. Donotrepeatfor2weeksifPt hasCKD.
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EfficacyofOralColchicineforAcuteGout
Terkeltaub RA,etal,ArthritisRheum2010,PMID20131255
“high-dose”colchicine(1.2mgfollowedby0.6mgeveryhourfor6hours[4.8mgtotal])
“low-dose”colchicine(1.2mgfollowedby0.6mgin1hour[1.8mgtotal])
Diarrhea26%,0%77%,19%
% o
f pat
ient
s im
prov
ed
% improvement
any, severe
EfficacyofNSAIDs&Corticosteroids forAcuteGout
• NSAIDS(naproxen 500mgBID,indocin 50mgTID,diclofenac 50mgBID)
• Prednisone: 60mgqd, taperover6-18days
Janssens H, et al, Lancet 2008, PMID 18514729also see Rainer TH, et al, Ann Intern Med 2016, PMID 26903390
Prednisone
Naproxen
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TreatmentofAcuteGout
NSAIDsareproblematicinpatientswithCKD
Withdrawal of NSAIDs for 1 year (along with control of hyperuricemia) resulted in improved renal function in patients.
Perez-Ruiz F, et al, Nephron 2000, PMID 11096285
Henry D, et al, Br J Pharmacol 1997,
NSAIDsusewasassociatedwithincreased riskofCKDinpatientswithhyperuricemia orgout(matchedcase-control study)
[RiskofCKD]
MechanismofInflammation inGout
Neogi T, NEJM 2011, PMID 21288096
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IL-1antagonismingout
• Allpatientsreceivedanakinra (IL-1receptorantagonist)• Treatedwith100mgSQinjectiondailyfor3days ($50-100/injection)• All10patientswithacutegoutrespondedrapidlytoanakinra.• 9/10hadcompleteresolutionofgoutsymptomsin3days• Noadverse effectswereobserved.• SimilarResultsreportedbyChenKetal,Semin ArthritisRheum2010
Case3(continued)
Thesame53yearoldmanwithHTNandnephrolithiasisreturns9monthslatercomplainingofanotherflareofjointpaininhisfeet(now4totalin3years). HismedicationsincludeASA,HCTZ,lisinopril,andibuprofenforthejointpain. Heaskswhatcanbedonetoprevent futureattacks.Choose themostcorrectanswer:A. ModifyhisdiettoavoidallfoodswithhighpurinecontentB. StopthethiazideC. StoptheACEinhibitorD. TreatedwithprobenecidE. Treatwithcolchicine
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53y.o manwithHTNandnephrolithiasiswith4goutattacksover3yearsaskswhatcanbedonetoprevent
futureattacks.Choosemostcorrectanswer:
A. Avoidallhighpurinefoods
B. StopthiazideC. StopACEinhibitorD. TreatwithprobenecidE. Treatwithcolchicine
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Case3(continued)
Thesame53yearoldmanwithHTNandnephrolithiasisreturns9monthslatercomplainingofanotherflareofjointpaininhisfeet(now4totalin3years). HismedicationsincludeASA,HCTZ,lisinopril,andibuprofenforthejointpain. Heaskswhatcanbedonetoprevent futureattacks.Choose themostcorrectanswer:A. ModifyhisdiettoavoidallfoodswithhighpurinecontentB. Stopthe thiazideC. StoptheACEinhibitorD. TreatedwithprobenecidE. Treatwithcolchicine
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Non-PharmacologicTreatmentofGout
TreatmentApproaches:• ReduceIntake• ReduceProduction• (IncreaseMetabolism)• IncreaseExcretion
DietandRiskofGoutinMen
Adapted from Choi HK, et al, New Engl J Med 2004, PMID 15014182
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
TotalMeat Seafood Purine-richVegetables
TotalDairy
RelativeRiskofD
evelop
ingGou
t
Meninthetopquintileofintakecomparedwiththoseinthelowestquintile(multivariateanalysis)
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TreatingGout:Diet&Meds
FoodsModeratelytoVeryHighinPurines
• Hearts, sweetbreads,liver,Kidney,Herring, smelt,sardines, mussels,anchovies,Yeast
• Grouse, Turkey,Partridge,Goose, Pheasant,Mutton,Veal,Bacon
• Salmon,Trout, Haddock,Scallops
Medicationsthatinhibituricacidsecretion
• Thiazide diuretics• Loopdiuretics• Aspirin(<1gm/d)
JohnsHopkins:DietandGouthttp://www.johnshopkinshealthalerts.com/reports/arthritis/460-1.html
Beveragesassociatedwithhyperuricemia
• Beer• Highfructosedrinks
ReasonstoStartUricAcidLoweringTherapy(ULT):
AllofthefollowingareindicationsforstartingUricAcidLoweringTherapyinpatientswithanestablisheddiagnosis ofgoutyarthritisEXCEPT:
a. TophaceousGoutb. Recurrentattacksofgout(≥2attacks/year)c. Historyoferosions onx-rayscharacteristicofgoutd. Serumuricacid≥8.0e. PresenceofCKDclassIIorgreater
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AllofthefollowingareindicationsforstartingUricAcidLoweringTherapyinpatientswithanestablisheddiagnosisofgoutyarthritisEXCEPT:
a. Tophaceous goutb. ≥2goutattacks/yrc. Erosions onx-raysd. Uricacid≥8.0e. CKDclass≥II
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ReasonstoStartUricAcidLoweringTherapy(ULT):
AllofthefollowingareindicationsforstartingUricAcidLoweringTherapyinpatientswithanestablisheddiagnosis ofgoutyarthritisEXCEPT:
a. TophaceousGoutb. Recurrentattacksofgout(≥2attacks/year)c. Historyoferosions onx-rayscharacteristicofgoutd. Serumuricacid≥8.0e. PresenceofCKDclassIIorgreater
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IncidenceofGoutamongMen
SerumUrateLevel: <6 6-6.9 7-7.9 8-8.9 9-9.9 >105-yearcumulative 0.5% 0.6% 2.0% 4.1% 9.8% 30%Incidence
Campion E,etal,Asymptomatichyperuricemia.Am.J.Med.82:421,1987.
Recurrenceofacutegoutarthritisfollowing initialattack:<1year62%1-2 years 16%2-5years 11%Never 7%Gutman AB,Gout,Beeson&McDermott(ed):Textbook ofMedicine,12thEd.,1958
ChronicManagementinpatientswithrecurrentattacksofgout
UricAcidLoweringTherapytoPrevent&TreatTophi!
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ImprovedOutcomesinGoutPatientswhoachieveUricAcidReductionstoLevels≤6.0mg/dl
Reducedfrequencyofattacks(Li-YuJetal.JRheumatol 28:577-580,2001;ShojiAetal.ArthritisRheum51:321-325,2004;BeckerMAetal.NEngl JMed353:2540-2461,2005)
Reducedtophussize(Perez-RuizFetal.JClin Rheumatol 5:49-55,1999;BeckerMAetalNEngl JMed353:2540-2461,2005)
Depletecrystalstoresinsynovial fluid(Li-YuJetal.JRheumatol 28:577-580,2001)
ImprovedrenalfunctionwithreductionofNSAIDuse(Perez-RuizFetal.Nephron856:287-291,2000)
Slowsprogressionofexistingrenaldisease(Siu Y-Petal.AmJKidneyDis47:51-59,2006)
Perez-RuizFandLiote F.Loweringserumuricacidlevels:whatistheoptimaltargetforimprovingclinicaloutcomesingout?ArthritisRheum57:1324-1328,2007
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PharmacologicUricAcidLoweringTherapy
TreatmentApproaches:• ReduceIntake• ReduceProduction• (IncreaseMetabolism)• IncreaseExcretion
PharmacologicUricAcidLoweringTherapy
• Uricosurics (probenecid) arerecommendedforpatientswithnormalkidneyfunction&withouturatenephrolithiasis whoare“underexcretors”(24hr urinecollection:<700mg/d ofuricacid)
• Themajorityofpatientswithrecurrentgoutwillhavechronickidney diseaseandshould betreatedwithxanthineoxidase inhibitors(allopurinol, febuxostat).
2012AmericanCollegeofRheumatologyguidelinesformanagementofgoutKhanna D,etal,ArthritisRheum2012,PMID23024028
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PharmacologicUricAcidLoweringTherapy
ManypatientsarestartedonAllopurinol300mg/danddonotachieveUricAcid<6.0
Roddy E,etal,AnnRhueum Dis2007AmericanCollegeofRheumatologyGuidelines
Khanna D,etal,ArthritisCare&Res2012
SowhatistheconcernaboutallopurinolinpatientswithCKD?
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Allopurinol warnings
• 2%develop arash– MuchhigherinpatientswithHLA–B*5801.HighfrequenciesseeninHanChinese&Thaipopulations
• 0.1%develophypersensitivity reaction(DRESS)
• CutaneousRash92%• Fever87%• RenalDysfunction85%• Eosinophilia73%• Hepatitis68%• Leukocytosis39%• Death21%
Hande etal,AmJMed76:47,1984
RecommendedmaintenancedoseofallopurinolbasedontheGFR
GFR(ml/min) Dose(mg/d)100 30080 25060 20040 15020 10010 50
AdaptedfromKelley,TextbookofRheumatology, 1997
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DoseAdjustment ofAllopurinolAccordingtoCreatinineClearanceDoesNotProvideAdequateControlofHyperuricemiainPatientswithGout
Dalbeth Netal.JRheumatol 2006
Renally-DosedAllopurinol :SafetyandEfficacy
Adherence topublishedallopurinoldosingguidelinesledtosuboptimalcontrolofhyperuricemiaanddidnotpreventhypersensitivityreactions.Dalbeth Netal.JRheumatol, 2006
Severehypersensitivityreactionsarenotdosedependent.Puig JGetal.J.Rheumatol,1989
Noincreaseinadversereactionstoallopurinolinpatientsreceivinghigherthanrecommendedcreatinine clearance-adjusteddoses.Vazquez-Mellado Jetal.AnnRheumDis,2001
Starting allopurinolatadoseof1.5mgperunitofestimatedGFRisassociatedwithareducedriskofallopurinolhypersensitivity. StampLK,etal,Arthritis Rheum2012
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Whynotjustprescribefebuxostat?
19230
59
706
162
1944
0
500
1000
1500
2000
1-month 12-month
USDollars
AllopurinolProbenecidFebuxostat
CourtesyofGabriela
SchmajukUCSF
Costs ofurate-loweringtherapies
Useoffebuxostat as2nd linetherapyafterallopurinoliscosteffectiveBeardSM,etal,Eur JHealthEcon2014
TreatwithColchicinewheninitiatinguricacidreducingagent
• >60%ofpatientswillhaveagoutflareafterstartingtreatment withfebuxostatorallopurinol.(BeckerMA,etal,NEJM2005)
• Colchicine0.6mg/dprophylactictherapyhelpspreventattacks
• Avoidcontinuingcolchicine formorethan6months
• Colchicinetoxicity: (especiallyinrenalinsufficiency)– Myopathy– Neuropathy– Bonemarrowsuppression– GIupset
2012AmericanCollegeofRheumatologyguidelinesformanagementofgoutKhanna D,etal,ArthritisRheum2012,PMID23024028
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“TreatmentFailureGout”
• Inthemajorityofpatientswithgout,thereisinadequatecontrolofhyperuricemiaorgoutsymptoms
• Usuallythisisdueto:– Inadequatemanagementbythephysician– Poorcompliance bythepatientwith medicaltherapy
Case4
An82yearoldmanwithahistoryofdiabetes,CKD,andosteoarthritisisbrought toseeyou foragitation.Onexamhistempis101.1°Fandheissomewhatdisoriented.Theexamisonlynotableforwarmth&swellingoftherightknee.Inadditiontoobtainingbloodandurine tests&cultures,youaspiratethekneetoevaluatefor:A. SepticArthritisB. GoutC. Pseudogout(acuteCPPD)D. Alloftheabove
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82y.o.manwithfever,delerium andkneeswelling.Youaspiratethekneetoevaluatefor:
A. SepticArthritisB. GoutC. PseudogoutD. Alloftheabove
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Case4
An82yearoldmanwithahistoryofdiabetes,CKD,andosteoarthritisisbrought toseeyou foragitation.Onexamhistempis101.1°Fandheissomewhatdisoriented.Theexamisonlynotableforwarmth&swellingoftherightknee.Inadditiontoobtainingbloodandurine tests&cultures,youaspiratethekneetoevaluatefor:A. SepticArthritisB. GoutC. Pseudogout(acuteCPPD)D. Alloftheabove
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TipsforKneeAspirationwatchNEJMvideo:DOI10.1056/NEJMvcm051914
• Ifsendingcultures,– Acheive sterileenvironmentwithbetadine orhibiclens.
– Usesterilegloves• Anesthetizewith1%lidocaine(butcandissolve crystals)
• Usea20-22Gneedleand10ccsyringe
Don’t:• Aspiratethroughcellulitis
• Aspirateafteracuteinjury andfractureisaconcern
• Aspirateaprostheticjoint
• (patientisanti-coagulated)
AcuteCPPDisanexcellentmimickerofsepticarthritis
• SystemicSymptoms arecommon, especially intheelderly– 25%ofpatientspresentwithfever38-39°C– 10%ofpatientshavementalstatuschanges
• Preferentiallyaffectslargerjoints(wrists, elbows,shoulders, hips, knees, ankles)
• CPPDcancoexistswithsepticarthritis(just likegout)
MasudaI&KIshikawa,Clin Orthop Relat Res,1988,PMID3349673Papanicolas LE,etal, JRheumatol 2012
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http://courses .washington.e du/hu bio5 53/ im ages/crystal. jpg
http:/ /aaaamom.blogspo t.co m/2008/0 3/crystal -qu een. html
http:/ /www.rad.washingto n.ed u/static pix/mskb ook/CP P DAPW ris t. jpg
Chondrocalcinosis
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Calciumpyrophosphate(CPP)crystalmediateddisease(CPPD)
RosenthalAK&RyanLM,NatRevRheumatol 2011
Calciumpyrophosphate(CPP)crystalmediateddisease(CPPD)
Abhishek A&DohertyM,NatRevRheumatol 2011
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SecondarycausesofCPPD
• Hyperparathyroidism• Hypophosphatasia• Hypomagnesemia
– Barttersyndrome(hypomagnesemia,hypokalemia,metabolicalkalosis)
– Gitelman syndrome(hypomagnesemia,tubularhypokalemia,hypocalciuria)
• Hemochromatosis
TreatmentofPseudogout
• JointAspiration• CorticosteroidInjection
• NSAIDS(naproxen500mgBID,indocin 50mgTID,voltaren)
• Prednisone: 30-60mgqd,taperover6-18days• Colchicine 0.6mgqD - BID
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Summary
• In patients presenting with monoarticular arthritis, infection is the primary concern
• Recognize signs of acute gout • Gout can cause severe arthritis but can easily be
managed (although often it is not).• Acute calcium pyrophosphate disease (CPPD) is
a strong mimicker of septic arthritis in the elderly.
Thanks!
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AdditionalReading
• 2012AmericanCollegeofRheumatologyguidelinesformanagement ofgout.Part1&2,ArthritisCare&Res2012,PMID23024028&23024029
• Doesthisadultpatienthaveseptic arthritis?MargarettenME,etal,JAMA2007,PMID17405973
• EULARrecommendationsforcalciumpyrophosphatedeposition.PartI&II;AnnRheumDis,2011
