SAPHO syndrome in pediatric patients with inflammatory bowel disease treated with infliximab

Pleasecitethisarticleinpressas:MarraniE,etal.SAPHOsyndromeinpediatricpatientswithinflammatoryboweldiseasetreatedwith infliximab.DigLiverDis(2018),https://doi.org/10.1016/j.dld.2018.09.001

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Contents lists available atScienceDirect

Digestive

and

Liver

Disease

Correspondence

SAPHOsyndromeinpediatricpatientswith inflammatoryboweldiseasetreatedwith infliximab

DearEditor,

SAPHOsyndromeisararediseasewithboneinvolvement (asep-ticosteitis)andskinmanifestations(palm-plantarpustulosis,acne orpustularpsoriasis).Duetoitssubtleclinicalpresentation,itis oftenmisdiagnosed andunrecognized.The associationbetween SAPHOandinflammatoryboweldisease(IBD)hasbeenreported since1992,withafewpediatriccasesdescribedsofar[1].Herewe describetwocasesofSAPHOsyndrome,whichoccurredintwo ado-lescentgirlswithCrohn’sdisease(CD)andUlcerativecolitis(UC), respectively.In contrasttopreviousreports ourpatients devel-opedtheclinicalfeaturesofthesyndromeduringtreatmentwith Infliximab(IFX),despiteremissionoftheunderlyingIBD.

ACaucasiangirlwasdiagnosedwithCDattheageof7years duetoacomplexperianalfistulizingdisease.AnMRIofthepelvis revealedan inter-sphincterfistulaand two peri-analabscesses. Endoscopic examination and histological findings were consis-tent with CD. According to current recommendations [2], IFX was started after drainage and fistulectomy, with obtainment of complete remission. After 2 years of maintenance regimen withinfusionsevery8weeks,endoscopyrevealedmucosal heal-ing.Infliximabwasthendiscontinuedand6-Mercaptopurinewas startedatadosageof1.5mg/kg/day.However,after15months,IFX wasresumedduetoCDluminalrelapse.WithscheduledIFX ther-apy,sheagainachievedclinicalremissionandsuchtreatmentwas continuedfor3yearswithoutneedofdoseadjustmentandwith normalgrowth.Attheageof14,endoscopicexaminationshowed deepremissionwithmucosalhealing. SerumlevelsofIFXwere inthetherapeuticrange(14.736mcg/ml)andanti-IFXantibodies wereabsent.Fecalcalprotectinlevelswerepersistentlylowatserial measurement.Threemonthslater,7weeksafterherlastIFX infu-sion,shedevelopedapalm-plantarvesiculopustularrash(Fig.1a) initiallydiagnosed as Coxsackieinfection. Aftera few days she developedlow-gradefeverandmarkedfatigue.Shewasadmitted toaperipheralhospitalwhereanti-TumorNecrosisFactor␣ (anti-TNF␣)inducingcutaneousreactionwassuspected.Despitelocal treatmentwithtazaroteneandIFXdiscontinuation,systemic symp-tomsdidnotsubside,andadditionalcutaneouslesionsappearedat thetrunkandlowerextremities.Moreover,thepatientstartedto complainofseverebonepaininmultiplesites(jaw,leftscapula, lumbarspine,rightknees).Thus,shewastransferredtoour hos-pital.Aninfectiousdiseasework-up,includingmycobacteria,was negative.Dermatologicfindings(Fig.1a–c)werecongruentwith anti-TNF␣inducedreaction,giventheconcomitanceof psoriasi-formeczemawithsecondaryalopeciaandpalm-plantarpustulosis. However,whole-body MRIshowed osteitis atclavicle,multiple costae,vertebralbodies,distalfemurandproximaltibiabilaterally

(Fig.2a–b).Bonebiopsyconfirmedthechronicaseptic inflamma-toryprocess,rulingoutmalignancyorinfectiousdisease.According to theproposedKahn criteria [3], a diagnosis of activeSAPHO syndromewasmade.Inconsiderationofthemarkedinvolvement ofvertebralbodies,treatmentwithPamidronate(1mg/kg/dayfor 3 days) was initiated. Pamidronate was discontinued after the firstinfusionbecauseofasharpriseofliverenzymescompatible withdrug-inducedliverinjury.SinceCrohn’sdiseasewasstillin remission(fecalcalprotectinlevel8mcg/g;normalintestinal ultra-sound)despiteactiveSAPHOsyndrome,aswitchtoAdalimumab (ADA)wasattemptedatadosageusedforrheumaticconditions (24mg/mq2_{everytwoweeks)incombinationwithmethotrexate}

(15mg/m2_{weeklysubcutaneously).Bothcutaneousand}

osteoar-ticularmanifestationsdramaticallyimprovedwiththistreatment andshemaintainsclinicalremission andnegativeinflammation markersat the12-months follow-up.TotalBodyMRIshoweda markeddecreaseofboneinflammatorylesions(Fig.2c).

ThesecondcasewasaCaucasiangirl,diagnosedwithUCat8 years ofage.Pastmedical history wassignificantonlyfor mild psoriasis, treated withtopical medications. Becauseof pancoli-tisatdiseaseonset,inductiontreatmentwithcorticosteroidwas successfully adopted and then followed by maintenance treat-ment with 5-aminosalicylic acid (5-ASA). However, 5-ASA was discontinuedaftersixmonthsduetointoleranceandthegirl main-tainedspontaneousremissionwithouttherapyforthefollowing twoyears.Attheageof11,thegirlwasadmittedtohospitalfor anacutesevereattackofUC,unresponsivetocorticosteroid,and IFXwasstarted,accordingtocurrentguidelines[4].FollowingIFX therapy,sheachievedclinicalremissionwithlowfecalcalprotectin; thus,azathioprinewasaddedasmaintenancetreatment.Aftertwo monthsthiopurine-inducedleukopenialeadtotreatment discon-tinuationandIFXmonotherapywascontinued.SerumlevelsofIFX andanti-IFXantibodieswerenotavailable.Endoscopicevaluation aftereightmonthsofIFXreportedonlymildinflammationatcecum andfecalcalprotectinwas25mcg/g,sodoseadjustmentwasnot required.

Attheageof12years(after16monthsofIFXtreatment),the patientpresentedwithmicro-pustularrashatthetrunkwithonset 6 weeks afterher last IFX infusion: initially a diagnosis of fol-liculitis was made,and topical erythromycin was started, with onlypartialresponse.Duringthefollowingtwoweeks,thepatient experiencedseverebonepainatthespineandhipwithantalgic scoliosis.So,shewasadmittedtoourhospital,whereanew der-matologicexaminationdocumentedsterilepustulosisonsolesand erythematous-squamousplaquesonthescalpandonthetrunk.IFX treatmentwasdiscontinuedandtopicaltherapywithsteroidand emollientswasstarted.

Awhole-bodyMRIshowedosteitisatseveralvertebralbodies, sacro-iliacjoints,clavicleandsternum.Therefore,shewas diag-nosed withSAPHO syndromeand treatment withPamidronate (1mg/kg/dayfor3days)wasstarted.Duetopersistenceofbone

https://doi.org/10.1016/j.dld.2018.09.001

Pleasecitethisarticleinpressas:MarraniE,etal.SAPHOsyndromeinpediatricpatientswithinflammatoryboweldiseasetreatedwith infliximab.DigLiverDis(2018),https://doi.org/10.1016/j.dld.2018.09.001

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Fig.1.Cutaneousinvolvementinourpatient.(a)Markedxerosisanderythematous-squamousplaqueswithfewsterilepustulesonthenonweight-bearingareasofthe palmsandsoles;(b)chronicphaseofpalmo-plantarpustulosiswithresidualsquamousplaques;(c)crustedandscalingpatchaccompaniedbyalopeciaovertheoccipital scalp;(d)ill-defineditchyerythematoussquamouspatchesatthetrunkandlowerlimbs.

Fig.2.MRIfindingsofinflammatoryboneinvolvement(highlightedbyarrows)atthediagnosisofSAPHOsyndrome.(a)Involvementofdistalfemurandproximaltibia bilaterally.(b)Evidenceofosteitisatvertebralbody.

pain after treatment, she received ADA (24mg/mq2 _{every two}

weeks) with subsequent improvement of both cutaneous and skeletalsymptomsandnormalizationofinflammatorymarkersat a4-monthsfollow-up.

The acronym SAPHO stands for synovitis, acne, pustulosis, hyperostosisandosteitis,thusexplainingtheprominentfeatures ofthedisease.Nowadays,thisconditionisconsideredpartofthe spectrumofchronicnon-infectiousosteomyelitis(CNO),agroup ofraremultifactorialautoinflammatorydiseaseofthebone char-acterizedbyasepticchronicboneinflammation[3].Theassociation betweenSAPHOandIBDhavebeenreportedinliterature,withan estimatedprevalenceofaround0.2%inacohortofIBDpatients andashighas5%inpatientswithaprimarydiagnosisofSAPHO [1].AnunderestimationoftheexactprevalenceofSAPHOamong IBDpatientsmightbeduetoclinicalsimilaritieswithsome extra-intestinalmanifestationsofIBDanddrug-relatedsideeffects,such aspalmoplantarpustulosis.Palmoplantarpsoriasisisindeed fre-quentlyassociatedwithanti-TNF_␣useinIBDpatientsanditmight poseadiagnosticchallenge[5].

InSAPHOsyndromeanti-TNF␣haveproventobeeffective[6], thussuggestingacrucialroleforTNF-␣asamediatorinSAPHO pathogenesis.However,ourpatientsdevelopedSAPHOsyndrome whileunderantiTNF␣treatment.Inaddition,inbothpatientsthe underlyingIBDwasinremissionandthusthiswasincontrastswith thereportedassociationbetweenactivebowelinflammationand clinicalmanifestationofSAPHOsyndrome[1].Sofar,onlytwocases ofSAPHOhavebeenreportedduringtreatmentwithanti-TNF␣: twoadultpatientswithIBDreceivedadiagnosisofSAPHOshortly afterstartingtreatmentwithIFXandADA,respectively[7,8].Inthe lattercase,theauthorssuggestedacausalrelationshipbetween adalimumabtreatmentandSAPHOmanifestation.Inouropinion, thepotentialtriggeringroleofIFXinthesecasesiscontroversial. Ononehand,alongwithpalm-plantarpustulosisorpustular pso-riasis,twoprominentfeaturesofSAPHO,thepatientspresented withxerosisandpsoriasiformeczema,whichhavebeenrecordedas commoncutaneousadverseeventsinpatientstreatedwithIFX[9]. Ontheotherhand,theclinicalfeaturesofSAPHOinitiallyworsened despiteIFXdiscontinuation,whileimprovingwhentheyhadbeen givenasecondanti-TNF␣treatment(adalimumab).Moreover,the

Pleasecitethisarticleinpressas:MarraniE,etal.SAPHOsyndromeinpediatricpatientswithinflammatoryboweldiseasetreatedwith infliximab.DigLiverDis(2018),https://doi.org/10.1016/j.dld.2018.09.001

ARTICLE IN PRESS

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YDLD-3858; No.ofPages3

Correspondence/DigestiveandLiverDiseasexxx(2018)xxx–xxx 3 clinicalevolutionofourpatientisincontrastwiththehigh

per-centageofrecurrenceorpersistenceoftherashinpatientswith anti-TNF␣inducedpsoriasisandtreatedwithasecondanti-TNF␣ [5].Indeed,cutaneousadverseeventsunderanti-TNF␣areknown tobeclass-specific,sincetheyarerelatedtotheinhibitionofthe physiologicalfunctionofTNF␣intheskin[10].Therefore,these cluesleadustoconsiderthepossibilityofSAPHOsyndromeonset asadenovoeventnotrelatedtotheconcomitanttreatmentwith IFX.

Becauseoftherarityoftheassociation,treatmentofpatients withSAPHOandIBDisnotstandardized.Duetovertebralspine involvement,wepreferredbisphosphonateasfirstlinetherapyfor ourpatients,inlinewithcurrentevidencefromSAPHOandCNO [3].Adalimumabwasthenadministeredbecauseofreportedgood responseofSAPHOtothisagent[3].However,alowrheumatologic dosagewaschosen,consideringthatIBDwasinremissioninboth patients;inaddition,otherimmunomodulatoryagentsweregiven incombinationwithADA.Methotrexatewasaddedinthefirstcase inwhichpamidronatewasdiscontinuedduetoanadverseeffect;in thesecondpatientacourseofpamidronatewascompletedbefore treatmentwithADA.

Hence,SAPHOsyndromeshouldbeexcludedinIBD patients complainingofskinandosteo-articularsymptoms,irrespectiveof theresolutionofintestinalinflammationandsimultaneousbiologic treatment.Furthercases arenecessary toelucidate the mecha-nismsunderlyingSAPHOduringTNF-inhibitionandtodetermine whetheracausallinkmightexist.

Conflictofinterest

Nonedeclared.

Acknowledgment

WethanksRobertoMaglie,MD,tohavecontribuitedtoclinical datacollectionandreviewofparadoxicalskinreactionsofanti-TNF.

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EdoardoMarrani∗ GildaBelli GabrieleSimonini UniversityofStudiesofFlorence,Departmentof Neurofarba SandraTrapani UniversityofStudiesofFlorence,Departmentof HealthSciences MarziaCaproni UniversityofStudiesofFlorence,Skin ImmunopathologyandRareDermatologicalDiseases Unit,1stDermatologicalClinicP.O.PieroPalagi,USL ToscanaCentro,Firenze,Toscana,Italy PaoloLionetti UniversityofStudiesofFlorence,Departmentof Neurofarba

∗_{Correspondingauthorat:UniversitàdegliStudidi}

Firenze,DipartimentoNEUROFARBA,Ospedale PediatricoAnnaMeyer,vialeGaetanoPieraccini, 24,50139Firenze,Italy. E-mailaddress:edoardo.marrani@unifi.it (E.Marrani)