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r e v b r a s r e u m a t o l . 2017;57(5):483–486

w w w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Case

report

Whipple’s

disease

manifested

as

difficult-to-diagnose

polyarthralgia:

a

case

report

and

literature

review

Doenc¸a

de

Whipple

manifestada

como

poliartralgia

de

difícil

diagnóstico:

relato

de

caso

e

revisão

da

literatura

Guilherme

Almeida

Rosa

da

Silva

,

José

Soares

Pires

Neto

UniversidadeFederaldoEstadodoRiodeJaneiro(UNIRIO),RiodeJaneiro,RJ,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received30January2014 Accepted7December2014 Availableonline20July2015

Introduction

Whipple’sdiseaseisararesystemicdisease,describedin1907 byGeorgeWhippleatJohnsHopkinsHospital.1Yearslater,in

1961,wasshowntobecausedbythebacteriumTropheryma whipplei.2Thisisamandatoryintracellularorganism,which

inhabitsmainlythegastrointestinaltractand,duetothelack ofdataprovingitsbenefittothehost,canbeconsidered a parasite.3

InfectionbyTropherymawhippleimaybeasymptomaticor presentwithseveralclinicalmanifestationssuchasfever, pol-yarthralgia,diarrhea,weightloss,fatigue,lymphadenopathy, pulmonary, heart, and skin involvement, and neurolog-ical disorders, such as oculomasticatory myorhythmia, oculo-facio-skeletalmyorhythmia,dementiaandintracranial hypertension.4 Itisarare disease andthe clinicalfeatures

are extensive and varied,with absolutely variable order of appearanceofsymptoms,determininganextremelydifficult

Correspondingauthor.

E-mail:drguialmeida@gmail.com(G.A.Silva).

diagnosis.Without properantibiotictreatment, the disease invariably culminates in dissemination and is potentially fatal.5

Whipple’sdiseasehasanincidencethatismuchlowerthan 1:1,000,000people,withandoccurrenceof12newcasesper yearworldwidebeingestimated.Ithasacorrelationwith cel-lularimmunitydeficienciesandHLADRB1*13,DQB1*06and HLAB27.6,7 Itaffectsmainlymiddle-agedmen,aroundfifty

years,witharatioof6:1comparedtowomen.8Complaints

ofmigratorypolyarthralgiausuallyprecedediarrheainmany years.9

Thisarticleaimstoreportacasemarkedbypolyarthralgia thathaddifficultetiologicaldefinitionanddelayeddiagnosis, the conclusionofwhichwasWhipple’s disease andreview therelatedliterature.Thepatientwhosecasewasreportedin thisstudyagreedwiththepublicationandtheResearchEthics CommitteeofHospitalGaffréeandGuinleapprovedthestudy undernumber631,797.

http://dx.doi.org/10.1016/j.rbre.2015.05.003

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rev bras reumatol.2017;57(5):483–486

Case

report

Male, brown, 45-year-old patient, who has been married for 26 years, Brazilian from the city of Simonésia, in the stateofMinasGerais,businessman,evangelicalChristian.He presentedin2006with severe episodicright hip arthralgia thatremittedwithanalgesics.In2007hepresentedadditive, episodicandsometimesmigratoryarthralgiathataffectedthe rightkneejoint,rightsacroiliacjoint,rightelbowarthritisand, somemonthslater,rightanklearthritis.Duringthisperiod, the patientwas seenbyseveral physicians,who could not establish adiagnosis and prescribed painkillers,parenteral andoralanti-inflammatorydrugs.

He started tohave nocturnal flares of generalized non-specific pain, with dysesthesia, requiring several visits to emergency rooms with use ofweak opioids between 2008 and2009.Duringthisperiod,theclinicalfeaturesofadditive, migratory,episodicpolyarthralgiaevolvedtogeneralized pol-yarthritis,alsoaffectingthesternoclavicularjoint.Thepatient mainpaincomplaints referredtohip and sacroiliac joints. He has taken analgesics, nonsteroidal anti-inflammatory drugs, oral corticosteroids and weak opioids with partial response.

Therheumatologistassistantchosetostarttherapywith abiologicalagentinfliximab.Aftertheseconddose,he pre-sentedafeverandmaculopapularrashinthedorsalregion and upperlimbs. Duetodissatisfaction withthe resultsof treatment,in2010hesoughtphysiciansofotherspecialties andalternativetherapiesforpainreliefwithoutsuccess.

Giventheuncertaintyofthecase,helookedforthe Inter-nal Medicine Unit of the University Hospital Gaffrée and Guinle – UNIRIO. After history and physical examination, newcomplementarytestswererequested(Table1).Thefact that the patient had joint complaints, consulted multiple specialists,hadnegativecomplementarytestsforrheumatic diseases and presentedanon-reactive PPD,althoughliving in an endemic area of tuberculosis, was noted. This was interpretedasapossibledefectofcellimmunity.Withthis information,thediagnosishypothesiswasanarticular man-ifestationofasystemicdisease.SinceHLAB27wasnegative, the classic seronegative spondyloarthropathies(ankylosing spondylitis, inflammatory bowel disease, Reactive Arthri-tis, Psoriatic Arthritis) was less likely, but not impossible. Behc¸et’sdisease andWhipple’sdisease werecontemplated. Thepatientreceivedawrittensummaryoftheclinical fea-tures and an immediate request of upper gastrointestinal endoscopywithduodenalbiopsytospecificallyruleout Whip-ple’s disease. Despite this evaluation, the patient did not followtheindicationsandhedidnotreturn.

In 2011, together withthe articular features, he started a refractory very severe headache. Associated with the headache bursts, he developed a right hemiparesis and a leftfacialparalysisthatremittedspontaneously.Inaddition, hehadepisodesofdiarrheawithhematochezia,nauseaand vomiting,resultinginsignificantweightlossandmuscle atro-phy.

In2012,thediseaseprogressedandthepatientrequired hospitalization in the Intensive CareUnit (ICU) inthe city of Juiz de Fora, state ofMinas Gerais. He had intracranial

Table1–TestresultsperformedatconsultationtoInternalMedicineUnitonJanuary8,2010.

TestsofJanuary8,2010

Erythrocytes(106mm3) 4.61 ALT(U/L) 32

Hgb(g/dL) 12.2 AST(U/L) 38

MCV(fL) 82 AF(U/L) 91.6

MCH(pg) 26 GGT(U/L) 78

MCHC(%) 31.5 Albumin(g/dL) 3.22

RDW(%) 15.6 Globulin(g/dL) 3.9

Leucocytes(cell/mm3) 6900 Proteinelectrophoresis Normal

Platelets(cell/mm3) 329,000 TB(mg/dL) 0.24

ESR(mm/h) 93 IB(mg/dL) 0.15

CRP(mg/L) 100 DB(mg/dL) 0.9

PT(INR) 1.21 CK(U/L) 71.2

APTT(Rel) 1.0 HepatitisB Neg

BloodGlucose(mg/dL) 81 HepatitisC Neg

BUN(mg/dL) 42 HIV Neg

Creatinine(mg/dL) 1.2 ANA Neg

UricAcid(mg/dL) 5.0 RF Neg

Sodium(mEq/L) 134 C3(mg/dL) 168

Potassium(mEq/L) 4.3 C4(mg/dL) 27.4

Chloride(mEq/L) 102 HLAB27 Neg

Freecalcium(mg/dL) 5.2 ANCA Neg

Phosphorus(mg/dL) 3.9 TSH(mcUi/mL) 2.54

PPD Nonreactive FreeT4 1.1

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rev bras reumatol.2017;57(5):483–486

485

Fig.1–Specimencollectedbyduodenalbiopsy.Periodic Acid–Schiff(PAS)staining.Markedaccumulationof

PAS-positivemacrophages(whitearrow)onsubmucosa

andpresenceoffibrosis(blackarrow)suggestingachronic process.

hypertension due to cerebral edema, confirmed by mag-neticresonance imaging(MRI) associatedwith dyspneaon minimalexertion, paroxysmal nocturnal dyspnea, prerenal failure, pleural effusion and generalized edemaconsistent withcongestiveheartfailure.Theechocardiographyshowed amitralvalvevegetationandinsufficiency.Themedicalteam who conductedthe case requested an upper gastrointesti-nalendoscopywithduodenal biopsy forWhipple’s disease investigation after reviewing information collected in the consultationattheInternalMedicineUnitin2011. Histopatho-logicalspecimenexaminationandpolymerasechainreaction (PCR)wereperformedatthePasteurInstituteinFrance(Fig.1), whichconfirmedTropherymawhipplei.Theprimer oligonu-cleotidesequenceusedwaspW3FE(5′-GGAATTCCAGAGATA

CCCGCCGCCCAA-3′)andpW2RB(5-CGGGATCCCATTCGC

TCCACCTTGCGA-3′).10

In view of the diagnosis, therapy was initiated with trimethoprim-sulfamethoxazole, soon interrupted due to severe gastrointestinal intolerance. Therapy was replaced with doxycycline100mg orally 2 tablets bid and hydroxy-chloroquine600mgorally once a day. Thepatient showed dramaticclinicalimprovementandwasdischargedfor out-patientmonitoring.

Discussion

Whipple’s disease has a variable presentation of pol-yarthralgia, including symmetric and asymmetric formsof intermittentnature,sometimesbeingmigratoryoradditive. Joint involvementispresent in over 90% ofcasesand can precedetheexuberantmanifestationofthediseaseinabout adecade.11

Thepatientpresentedthepolyarticulararthritisfeatures aboutfiveyearsbeforethesevereillness.During theinitial period, he had consultations with multiple internists and

rheumatologistswithoutaspecificdiagnosis,alsoundergoing immunosuppressivetherapies(infliximab)thatworsenedthe disease.Thesearchforpainreliefwasaddedtothefrustration ofnotreceivinganaccuratediagnosis,includingseeking alter-nativetherapies.Whenhewasseenatourclinic,somedetails calledourattention.Thefirstwasthefactthatexperts,even orderinganextensivelistoftests,couldnotprovideaclear diagnosticdefinition,whatreinforcedthehypothesisthatthis wasajointdiseaseprobablyrelatedtoararesystemicdisease, possiblyindirectlyrelatedtorheumatology.

Other relevant information was the absence of symp-tomssuchaschronicdiarrhea(inflammatoryboweldisease), lesionssuggestiveofpsoriasisoranyotherskininvolvement (psoriasis, SAPHO or Behcet’s disease), no history of sexu-allytransmitteddiseases(ReactiveArthritis),featuresthatare non-excludingwhenconsideringthatthearticular manifes-tationmayprecedeothersymptoms.ThenegativeHLAB27 wasvaluedbecauseofitsknowncorrelationwithseronegative spondyloarthropathies.12

Finally, wehighlight the fact ofPPD not being reactive, something possible, but unusual in a resident of a highly endemictuberculosisregion.Thenon-reactivePPDleadusto thinkofcellularimmunitychanges,notlinkedtoAIDS,given thatHIVtestwasnegative.ThehypothesisofWhipple’s dis-easewassuggested,13–15butthepatientdidnotreturntothe

outpatient’sclinicwiththeuppergastrointestinalendoscopy andduodenalbiopsythathadbeenrequested.Abandonment wasattributedtothepatient’s lackoftrustintheabilityof medicinetosolvetheproblemofchronicpain.Thecasehas evolvedinto atypicalformofacomplex clinicalsyndrome relatedtoWhipple’sdisease.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1.WhippleGH.Ahithertoundescribeddiseasecharacterized anatomicallybydepositsoffatandfattyacidsinthe intestinalandmesentericlymphatictissues.BullJohns HopkinsHosp.1907;18:382–91.

2.ChearsWC,AshworthCT.Electronmicroscopicstudyofthe intestinalmucosainWhipple’sdisease:demonstrationof encapsulatedbacilliformbodiesinthelesion.

Gastroenterology.1961;41:129–38.

3.WilsonKH.Whipplediseaseresearchaccelerates.JInfectDis. 2011;204:4–5.

4.DobbinsWOIII.Whipple’sdisease.MayoClinProc. 1988;63:623–4.

5.GuthikondaB,RouahE,KrishnanB,PowellSZ,GoodmanJC, GopinathSP,etal.Whipplediseaseofthecentralnervous system:anunusualoccurrenceinassociationwithacquired immunedeficiencysyndrome.JNeurosurg.2010;112:983–9.

6.MartinettiM,BiagiF,BadulliC,FeurleGE,MullerC,MoosV, etal.TheHLAallelesDRB1*13andDQB1*06areassociatedto Whipple’sdisease.Gastroenterology.2009;136:2289–94.

7.FeurleGE.AssociationofWhipple’sdiseasewithHLA-B27. Lancet.1985;325:1336.

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assessmentoftreatmentin29patients.MayoClinProc. 1988;63:539–51.

9. TanTQ,VogelH,TharpBR,CarrolCL,KaplanSL.Presumed centralnervoussystemWhipple’sdiseaseinachild:case report.ClinInfectDis.1995;20:883–9.

10.FenollarF,FournierP,RaoultD.Quantitativedetectionof TropherymawhippleiDNAbyreal-timePCR.JClinMicrobiol. 2002;40:1119–20.

11.DurandD,LecomteC,CathedrasP,RoussetH,GodeauP. Whipple’sdisease.ClinicalReviewof52cases.TheSNFMI ResearchGrouponWhipple’sdisease.SocieteNationale FrancaisedeMedecineInterne.MedTropherymaWhipplei. 1997;76:170–84.

12.McHughNJ.Otherseronegativespondyloarthropathies. Medicine.2010;78:190–3.

13.DobbinsWOIII.IsthereanimmunedeficitinWhipple disease?DigDisSci.1981;26:247–52.

14.KentSP,KirkpatrickPM.Whippledisease.Immunologicaland histochemicalstudiesofeightcases.ArchPatholLabMed. 1980;104:544–7.

15.GrollA,ValbergLS,SimonJB,EidingerD,WilsonB,Forsdyke DR.ImmunologicaldefectinWhipple’sdisease.

Imagem

Table 1 – Test results performed at consultation to Internal Medicine Unit on January 8, 2010.
Fig. 1 – Specimen collected by duodenal biopsy. Periodic Acid–Schiff (PAS) staining. Marked accumulation of PAS-positive macrophages (white arrow) on submucosa and presence of fibrosis (black arrow) suggesting a chronic process.

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