ContentslistsavailableatScienceDirect
Digestive
and
Liver
Disease
j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d
Liver,
Pancreas
and
Biliary
Tract
Hepatitis
B
virus
related
cryoglobulinemic
vasculitis:
A
multicentre
open
label
study
from
the
Gruppo
Italiano
di
Studio
delle
Crioglobulinemie
–
GISC
Cesare
Mazzaro
a,∗,
Luigino
Dal
Maso
b,∗∗,
Teresa
Urraro
c,
Endri
Mauro
d,
Laura
Castelnovo
e,
Pietro
Casarin
d,
Giuseppe
Monti
e,
Valter
Gattei
a,
Anna
Linda
Zignego
c,
Gabriele
Pozzato
faClinicalandExperimentalOnco-HematologyUnit,CROAvianoNationalCancerInstitute,Aviano,Italy
bEpidemiologyandBiostatisticsUnit,CRO-AvianoNationalCancerInstitute,Aviano,Italy
cCentroManifestazioniSistemichedaVirusEpatitici,UniversityofFlorence,Firenze,Italy
dDepartmentofInternalMedicine,PordenoneGeneralHospital,Pordenone,Italy
eDepartmentofInternalMedicine,SaronnoGeneralHospital,Saronno(VA),Italy
fDepartmentofMedicalandSurgicalSciences,UniversityofTrieste,Trieste,Italy
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received10November2015
Accepted29March2016
Availableonline2April2016
Keywords: Cryoglobulinemia Entecavir HepatitisBvirus Vasculitis
a
b
s
t
r
a
c
t
Background:Cryoglobulinemicvasculitis(CV)relatedtoHepatitis-BVirus(HBV)israreanditstreatment isill-defined.
Aims:TodescribeclinicalandtreatmentcharacteristicsofHBV-relatedCVpatients.Inaddition,the effi-cacyoftreatmentwithantiviralagentnucleotide(NUC),includingEntecavir,Adefovir,andLamivudine, wasexplored.
Methods:InfourItaliancentres,17HBV-positiveCVpatients(medianage56years,range45–70)were enrolled.
Results:Theextrahepaticmanifestationswere:purpura(100%),arthralgias(71%),peripheralneuropathy (29%),chronichepatitis(47%),livercirrhosis(29%),andglomerulonephritis(18%).Mixed cryoglobuline-miasweretypeII(88%)andtypeIII(12%).Themediancryocritwas3%(range1–14),rheumatoidfactorwas 200U/L(range20–5850),C4was12mg/dl(range2–31),ALT71U/L(range36–114).Allpatientswere HBsAg-positiveand80%anti-HbeAg-positive.Atenrollment,theyweretreatedwithsteroids(eight), Entecavir(five),Alpha-IFN(two),AdefovirandLamivudine(oneeach).AfterNUCtreatment,nodisease progressionwasobservedand,inallpatients,HBV-DNAbecameundetectable.Moreover,aregression ofpurpuraandareductionofcryocritwereobserved.Fourpatientsdiedduringtherapy,twoofkidney failureandtwooflivercirrhosis.
Conclusion:NUCtherapyappearedtobesafeandeffectiveinCV-relatedHBV.
©2016EditriceGastroenterologicaItalianaS.r.l.PublishedbyElsevierLtd.Allrightsreserved.
1. Introduction
InfectionwithhepatitisB(HBV)isaseriousworldwidepublic healthproblem.Itisestimatedthatabout350millionpeopleare
∗ Correspondingauthorat:ClinicalandExperimentalOnco-HematologyUnit,CRO
AvianoNationalCancerInstituteIRCCS,ViaFrancoGallini2,Aviano,Pordenone
33081,Italy.
∗∗ Correspondingauthorat:EpidemiologyandBiostatisticsUnit,CROAviano
NationalCancerInstituteIRCCS,ViaFrancoGallini2,Aviano,Pordenone33081,Italy.
E-mailaddresses:cesare.mazzaro@gmail.com(C.Mazzaro),
epidemiology@cro.it(L.DalMaso).
chronicallyinfectedwithHBV.TheclinicalmanifestationsofHBV rangefromacuteorfulminanthepatitistovariousformsofchronic infection,includinganinactivecarrierstate,chronichepatitis, cir-rhosis,andhepatocellularcarcinoma[1,2].
About20% of HBV patients develop extrahepatic manifesta-tions;amongthem,polyarthritisnodosaandglomerulonephritis arethemostsevere.Othermanifestations(e.g.,dermatitis, poly-arthralgiasandarthritis,respiratorydisease,aplasticanemia)are rareandcryoglobulinemicvasculitis(CV)occursinapproximately 3%ofpatients[3,4].Noassociationhasbeenfoundbetweenthese manifestationsandviralgenotypes[3,4].Reportedcasesof HBV-relatedCVarerare,themosteffectivetreatmentisstillunknown,as nodefinitiveguidelineshavebeenissuedtodate.Theconventional
http://dx.doi.org/10.1016/j.dld.2016.03.018
immunosuppressive therapyused inrheumatologic disorders is not indicated in HBV-related CV, while antiviral therapy with nucleotide analogues seems to be the best treatment in these cases.Evidenceontheefficacyoftheantiviraltreatmentof HBV-relatedCVwithnucleosideanalogues islimited,sinceonlycase reports arepresently availablein theliterature[5–11]. Accord-ingtoBrouet etal.[12],thecryoglobulinemiasareclassifiedin threetypes.IntypeI,thecryoglobulinsareformedbymonoclonal immunoglobulinsonly, commonlyIgM. Thistype of cryoglobu-linsare associated with lymphoproliferative disorder (multiple myelomaorWaldenström’sdisease).IntypesIIandIII(socalled mixed cryoglobulinemias, MC), the cryoglobulins are immune-complexes composed by polyclonal IgGs, the antigen(s), and monoclonalorpoliclonalIgMs,respectively.TheIgMareendowed withrheumatoidfactoractivity,i.e.,againstpolyclonalIgG[12–14]. TypesIIandIIIareassociated withchronicviralinfections (i.e., HBVandHCV),connectivetissuediseases,andlymphoproliferative disorders.
The clinicalmanifestations of MC aredue tothe deposition of immune-complexes in several organs and tissues. MC may determinenot only purpura, arthralgias and asthenia, but also more serious lesions of the skin(large ulcers), and neurologic and renalinvolvement [15–19].The therapyof MCis based on immunosuppressiveagents(steroids,cyclophosphamide, azathio-prine,cyclosporine)forpatientswithmild-to-moderatedisease, whereas moreaggressivetreatments,suchas corticosteroidsor plasmapheresis or high-dose cyclophosphamide, are needed in patientswithseveredisease[20,21].More recently,dataonthe efficacyandsafetyofanti-CD20monoclonalantibodiesinMC vas-culitishaveemerged[22,23].
Thepurposeofthisretrospectivestudywastoassessthe treat-mentinagroupofpatientswithHBV-relatedCV.
2. Patientsandmethods
Seventeen consecutive patients (10 females and 7 males) affectedbyHBV-relatedCVwereincludedinthisstudy.Allcases wereenrolledbetween2006andDecember2014atthe Depart-mentofInternalMedicineofPordenoneGeneralHospital,atthe ‘CentroManifestazioniSistemichedaVirusEpatitici’,Universityof Florence,andattheDepartmentofInternalMedicineoftheSaronno GeneralHospital.
Theinclusioncriteriaofthisretrospectivestudywasthe pres-enceofchronicHBVassociatedwithclinicalsymptomsofCV.All patientswerepositiveforHBVsurfaceantigen(HBsAg)and mea-surablelevelsofserumHBV-DNAweredetectable.Thepatients showinganti-Hepatitis C and/oranti-human immunodeficiency virus(HIV) antibodies or with concomitant malignant diseases wereexcluded.
Clinical and biological data were recorded for each patient at onset, during follow-up, and at the end of follow-up. The visits were scheduled every 3 months and information col-lecteduntilJune2015.Liverfunctionaswellaskidneyfunction testing and haematological parameters, laboratory assessment, including determination of complement components, rheuma-toidfactorandcryoglobulinserumlevelswerecarriedoutusing standard methods. MC wasclassified as type IIin presence of monoclonalIgMcomplexedwithpolyclonal IgG,and typeIIIin presence of polyclonal immunoglobulins. Patients showing ele-vatedcreatininelevelsand24hproteinuriaunderwentbiopsyfor kidney involvement. Liver biopsieswere performed in patients showing only signs of chronic liver disease. The grading for liverfibrosiswasperformedbymeansoftransientelastography
[24].
Table1
Baseline,clinical,biochemicalandhistologicalfeaturesof17patientswithHBV
positivecryoglobulinemicvasculitis.a
Median(range) N(%) Males 7(41%) TypeIIcryoglobulinemia 15(88%) Age 56(45–70) ALT(6–78U/L)b 71(36–114) Creatinine(0.50–1mg/dl)b 1.0(0.7–2.4) Cryocrit(%) 3.0(1.0–14.0)
Rheumatoidfactor(0–25IU/ml)b 200(20–5850)
C4(10–40mg/dl)b 12(2–31) Clinicalmanifestations Purpura 17(100%) Arthralgias 12(71%) Legulcer 1(6%) Peripheralneuropathy 5(29%) Raynaudphenomenon 3(18%) Glomerulonephritis 3(18%) Chronichepatitis 8(47%) Livercirrhosis 5(29%)
ALT,alanineaminotransferase.
aFollowedforamediantimeofobservationof5.2years(range0.5–19years).
bNormalvalues.
2.1. Treatment
Due to the retrospective nature of our study, the included patientshadreceiveddifferenttreatments.High-dose corticoste-roids(1–10m/kg)wereadministeredtotreatsystemicvasculitis andcriticalmanifestationsofMC(renal,neurologicaland hyper-viscosity syndromes) [21]. Low-medium corticosteroid doses (0.1–0.5mg/kg/day) were usedin mild or moderate cryoglobu-linemic vasculitis (purpura, arthralgias, peripheral neuropathy)
[21].Antiviraltherapywasalsonothomogeneous;indeed,some patients were treated with interferon-alpha-2b (5MU/die for 6 months), others with Entecavir 0.5mg/day, or with Adefovir 10mg/dieandevenwithLamivudine100mg/die.Biochemicaland clinicalparametersweremeasuredeverytwomonthsduring treat-ment,whileHBsAg,HBV-DNA,cryoglobulins,RFandcomplement fractionC4every6months.
2.2. Outcomemeasures
Aspreviouslyreported[25],fourtypesofresponsetotreatment wereinitiallydefined(virological,biochemical,immunological,and clinical)andhereinpresentedat48monthsofcontinuous treat-ment(afterenrollment).
2.3. Statisticalanalysis
Descriptivestatisticsofrelevantvariableswereperformedusing medianand range. Meanandstandard deviation(SD)werenot informativeandnotpresentedbecauseofthelimitednumberof patients.
3. Results
3.1. Patients’characteristics
The study enrolled 17 patients (seven males, 41%), median age56(range45–70years)withHBV-relatedCV.Table1shows patients’biochemical,clinical,andhistologicalcharacteristics.All of them presented purpura ontheleg and asthenia, and 12 of them(71%)alsoarthralgias.Peripheralneuropathywasfoundin five cases(29%), and one ofthem showeda largeulcer onthe left leg(6%). Fifteen cases(88%) had type IIMC andtwo cases
Table2
Biochemical,immunologicalandvirologicalparametersof5patientswithHBVpositivecryoglobulinemicvasculitistreatedwithEntecavirtherapyatbaseline,at12months
andat48monthsoftherapy.
Baseline At12months At48months
Purpurapositive 5 0 0
Median(range) Median(range) Median(range)
MeanALT(6–78U/L)a 71(39–82) 17(13–40) 26(13–33)
Creatinine(0.50–1mg/dl)a 1.0(0.7–1.2) 0.7(0.5–1.0) 0.8(0.6–1.2)
Cryocrit(%) 4(2–9) 1(0–3) 1(0–3)
Rheumatoidfactor(0–25IU/ml)a 119(88–5850) 80(31–5272) 82(20–5026)
C4(10–40mg/dl)a 8(4–31) 7(1–10) 10(2–24)
HBV-DNA(IU/ml) 2265(1540–4020) <20(–) <20(–)
UndetectableHBV 0 5(100%) 5(100%)
ALT,alanineaminotransferase.HBV,hepatitisBvirus.
aNormalvalues.
(12%)typeIIIMC.Cryocritrangedfrom1%to14%(median3%), serumcomplementC4levelswerelow inallcases(median12; range:2–31mg/dl),and serumlevels ofrheumatoid factor (RF) werehigherthan recommendedin14 cases(82%), median200 (range:20–5850IU/L).ALT waselevatedin14 cases(82%)with median=71 (range: 36–114U/L), serum creatinine levels were abnormal(>1mg/dl)inthreecases(18%),proteinuriainthe24h waselevatedinthreecases(18%),rangingfrom3to5g/24h.Renal biopsyshowedthepresenceofmembraneproliferative glomeru-lonephritistype I in all three cases (18%). All patientsshowed positivetestresultsforHBsAgandantiHbeAg,whereastestresults for anti-HBsAg, HBeAg were negative. HBV-DNA wastested in five cases treated with Entecavir. The median value was 2265 (1540–4020IU/ml).
3.2. Effectoftherapeuticregimenonresponsetotreatmentand outcome
Allpatients were suitable for therapeutic regimens; in par-ticular,therapeuticschedules wereasfollows:corticosteroid, in eight cases; Entecavir, in five cases; Interferon-alpha, in two cases; and Adefovir and Lamivudine, in one case each. Two patients with HBV-related CV and glomerulonephritis treated with Interferon-alpha 5MU/day for 6 months, did not obtain clinical response of the purpura and arthralgias. Since their levels of cryocrit, RF, complement fraction C4, ALT, creatinine, proteinuria/24hremained unchanged, theywereconsidered as non-responders.Aftersubsequenttreatmentwithlow-dose cor-ticosteroid, both patients obtained clinical and immunological response but, as expected, no virological response. Five addi-tionalpatientsweretreatedwithlow-dosecorticosteroid for48 months:purpuraandarthralgiasregressedinthreepatients;while clinicalsymptomspersisted intwocasesaftertheendof treat-ment.
Corticosteroidtherapyinduced animprovementofvasculitis (i.e., purpura: eight positive at enrolment; two at 12 months; andfourat48 months)and areduction ofcryocrit levelsinall patients(median=3%atenrolment,1.5%after48months),butno patientshowedundetectablelevelsofcryoglobulinsattheendof treatment(datanotshown).TheRFlevelremainedelevatedafter treatmentinall patients. C4serumlevels remainedunchanged (median=12mg/dl) at theend of treatmentin allpatients. No virologicalresponsewasobservedinfivepatientstreatedwith cor-ticosteroidswhohad not receivedantiviral therapy.Attheend oftreatmentwithcorticosteroids,ahighmedianlevelofALTwas observed(62U/L),unchangedincomparisonwiththatatenrolment (median=66).
3.3. VirologicalresponsewithNUC(Entecavir,Adefovirand Lamivudine)
DuringtreatmentwithEntecavirinfivepatients(Table2), Ade-fovirin one patient and Lamivudine in another, HBV-DNA had undetectableviremiainallofthem(100%),after12monthsof ther-apy.Attheendoftherapy,allpatientsmaintainedundetectable viremia,whileHBsAgremainedpositiveinallofthem.
3.4. ClinicalresponsewithNUC
Purpuraregressedattheendoftherapyinallpatientstreated with Entecavir (Table 2). An improvement of arthralgias was observedinthreepatientsattheendoftreatment.Theulceron thelegregressedinonepatient,attheendtherapy.Purpuraand arthralgiasregressedinonepatienttreatedwithAdefovirandin anotherpatienttreatedwithLamivudine.
3.5. ImmunologicalresponsewithNUC
Entecavirinducedareductionofcryocritlevelsinallcases,but onlytwocasesshowedundetectablelevelsofcryoglobulinsatthe endoftreatment(Table2).TheRFlevelsdecreasedinallpatients, butanormalRFwasobservedinonlyonecaseattheendoftherapy andatfollow-up(Table2).C4serumlevelsremainedlowduring treatmentandattheendoftherapy.AnormalC4serumlevelwas notobservedinallpatients,attheendoftherapy.
Inonepatient,treatedwithAdefovir,cryocritdisappearedfrom serum,from5%to0%,RFlevelsdecreasedfrom200to140and 120U/Lduringtreatmentandattheendoftherapy.C4serumlevel remainedlowfrom8to6and8mg/dlduringtreatmentandatthe endoftherapy.
InthepatienttreatedwithLamivudine, cryocritregressedin serum,from14%to12%and12%,RFregressedfrom2900to2490 and 2900U/L, C4serum levelremainedlow from12 to11 and 11mg/dlduringtreatmentandtheendoftherapy.
3.6. BiochemicalresponsewithNUC
EntecavirinducedanALTnormalizationinfourpatientsafter 12monthsoftreatment(Table2).Noexacerbationswereobserved. AdefovirinducedanALTnormalizationfrom85to30and34and U/Lattheendoftherapyandatfollow-up.Lamivudineinducedan ALTnormalizationfrom78to20and21andU/Lafter12months oftreatment.
Atthelastfollow-upvisit,inDecember2014,allpatients con-tinued thetreatment withEntecavir,Adefovir and Lamivudine. Duringtherapy,adverseeventswerenotobserved.Inthisgroup,
fivepatientsdied(29%);thecausesofdeathwerecirrhosis com-plications,ascites,andencephalopathy(twocases),hepatocellular carcinoma in cirrhosis, sepsis in kidney failure (one case), and kidneyandheartfailure(onecase).
4. Discussion
HBV-relatedCVis rareas compared toHCV-related CV,and thetreatmentisstillpoorlyunderstood.Antiviraltherapy,mostly basedonmono-therapywithNUCsuchasLamivudine[5,6,9], Ade-fovirDipivoxil[26],Entecavir[8],Telbivudine[10],orTenofovir
[40]hasgivenencouragingresultsintermsofviralclearanceand clinicalremissioninHBV-relatedCV.Manystudieshavesuggested apossibleroleof HBVreplicationin theCVpathogenesisand a relationshipbetweenundetectableHBV-DNAandregressionofCV afterantiviraltherapy[5–11].Ourstudyisinagreementwith pre-viousresults,showingmultipleorganinvolvement(skin,liver,and kidney),andwiththebeneficialeffectoftherapywithEntecavir, Adefovir,andLamivudineonclinical,immunologicaland virologi-calparameters.Thus,aroleofHBVinfectionincryoglobulinemia emerged.
The severity of hepatic and extrahepatic manifestations promptedustostartantiviraltherapy,leadingtoaregressionof purpura,adecreaseofcryocrit,andHBV-DNAbecameundetectable in all patients. In this study, Interferon-alfawas ineffective for clinicalsymptomsofvasculitisandsuppressionofHBV.While cor-ticosteroidtherapywaseffectiveforclinicalsymptomsofvasculitis, itwasineffectivefor suppressionofHBVviremiaand immuno-logicalfeatures.ThepatientswithHBVrelatednephropathywere non-responderstoInterferon-alfaandcorticosteroidstherapy.In thisstudy,nopatienttreatedwithNUCwasaffectedbyHBVrelated nephropathy.
RenalinvolvementinMCshowedapoorprognosis,as previ-ouslyreported[27,28].NUChavealsobeenadministeredwithsome benefittotreatHBV-relatednephropathy[29,30].Recently,new findingsontheefficacyandsafetyofanti-CD20monoclonal anti-bodiesandInterferoninMCwithglomerulonephritishaveemerged
[31,32].Inthisstudy,twopatientsdiedofkidneyfailure,proving thispoorprognosis.TheobservationthattherapywithNUCin HBV-relatedCVwaswithoutsideeffectsindicatedthatcomplianceis promisingforthesepatients.
ConcerningthetreatmentofHBVrelatedCV,severalquestions remainunansweredaboutthepropertimetoinitiateantiviral ther-apyandthesuitableduration.ThegoalofHBVtherapyshouldbe viralsuppression,althoughthismayrequirealong-termtherapyin chronichepatitis.InpatientswithHBVrelatedCV,antiviraltherapy maybediscontinuedafterpersistentHBsAgseroconversionin anti-HBsandundetectableHBV-DNA,asrecommendedbyinternational guidelines[33].RatesofHBs-Aglossfollowing12monthsof treat-mentwere0%withLamivudine,Adefovir,andEntecavir[34,35]. Hbs-Aglossrateincreasedto9%atthreeyearsand12%atfiveyears followingPeginterferonalpha-2atherapy[36,37].Incontrast, HBs-Aglosswasrarelyobservedduringthefirstfour-to-fiveyearsof NUCtherapyinHBe-negativepatients[38,39].
In conclusion,ourstudy demonstratedtheeffectiveness and safetyof therapywithNUCforHBV-relatedCV.Since the sam-plesizeofthisstudywassmall,large-scalecooperativestudiesare neededtoassessthisissue.
Conflictofinterest
Nonedeclared.
Acknowledgment
The authors wish to thank Mrs. Luigina Mei for editorial assistance.
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