Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy.

0.21 MB·English

by  Mori, Shunsuke

Clinical and epidemiological research
CONCISE REPORT
Pneumococcal polysaccharide vaccination in
rheumatoid arthritis patients receiving tocilizumab
therapy
Shunsuke Mori,1 Yukitaka Ueki,2 Yukihiro Akeda,3 Naoyuki Hirakata,2 Motohiro Oribe,4
Yoshiki Shiohira,5 Toshihiko Hidaka,6 Kazunori Oishi7
HandlingeditorToreKKvien ABSTRACT Tocilizumab (TCZ), a humanised monoclonal
Objectives Weassessedtheimpactoftocilizumab antibodyagainsttheinterleukin-6(IL-6)receptor,is
▸Additionalmaterialis
(TCZ),ahumanisedmonoclonalanti-interleukin-6receptor effective and generally well tolerated when admi-
publishedonlineonly.Toview
pleasevisitthejournalonline antibody,onantibodyresponsefollowingadministration nistered either as monotherapy or in combination
(http://dx.doi.org/10.1136/ ofthe23-valentpneumococcalpolysaccharidevaccine withmethotrexate(MTX)inpatientswithmoder-
annrheumdis-2012-202658). (PPV23). ate to severeRA.IL-6 was originally identifiedas a
1DepartmentofRheumatology, Methods Atotalof190patientswithrheumatoid factor essential for B cell differentiation into
ClinicalResearchCenterfor arthritis(RA)receivedPPV23.Patientswereclassified antibody-producingplasmacells,2andIL-6-deficient
RheumaticDisease,NHO intoTCZ(n=50),TCZ+methotrexate(MTX)(n=54), mice had reduced antigen-specific IgG following
KumamotoSaishunsou
MTX(n=62)andRAcontrol(n=24)groups.We immunisation with a T-cell-dependent antigen.3
NationalHospital,Kohshi,
Kumamoto,Japan measuredserotype-specificIgGconcentrationsof PPV23 induces serotype-specific IgG in a
2RheumaticandCollagen pneumococcalserotypes6Band23FusingELISAand T-cell-independentpolysaccharideantigenpathway,
DiseaseCenter,SaseboChuo functionalantibodyactivityusingamultiplexed which can enhance pneumococcal opsonisation,
Hospital,Sasebo,Nagasaki, opsonophagocytickillingassay,reportedasthe phagocytosis and killing by phagocytic cells.4
J3RaepsaenarchInstitutefor opsonisationindices(OIs),beforeand4–6weeksafter PPV23immunogenicityisoftenimpairedincertain
MicrobialDiseases,Osaka vaccination.Positiveantibodyresponsewasdefinedasa groups of immunocompromised patients,1 but evi-
University,Suita,Osaka,Japan 2-foldormoreincreaseintheIgGconcentrationorasa denceofPPV23efficacyandsafetyislackinginRA
4OribeRheumachika-Naika ≥10-foldormoreincreaseintheOI. patientsreceivingTCZ.
C5Dlineipca,rOtmitae,ntOoitfa,InJtaeprnaanl Results IgGconcentrationsandOIsweresignificantly Theobjective of thepresent study wasto evalu-
Medicine,TomishiroCentral increasedinalltreatmentgroupsinresponseto ate the influence of TCZ therapy on antibody
Hospital,Tomigusuku, vaccination.TheTCZgroupantibodyresponserateswere response to PPV23 in RA patients. We determined
Okinawa,Japan comparablewiththoseoftheRAcontrolgroupforeach the serum concentrations of serotype-specific IgG
6InstituteofRheumatology, serotype.MTXhadanegativeimpactonvaccineefficacy. using ELISAs and the functional antibody activity
ZenjinkaiShimin-no-Mori MultivariatelogisticanalysisconfirmedthatTCZisnot using multiplexed opsonophagocytic killing assays
Hospital,Miyazaki,Miyazaki,
Japan associatedwithaninadequateantibodyresponseto (OPAs) in RA patients being treated with TCZ,
7InfectiousDisease eitherserotype.Nosevereadverseeffectwasobserved MTX or TCZ and MTX, and in control RA
SurveillanceCenter,National inanytreatmentgroup. patientswhoreceivedneitherdrug.
InstituteofInfectious
Conclusions TCZdoesnotimpairPPV23
Diseases,Shinjyuku-ku,Tokyo,
immunogenicityinRApatients,whereasantibody
Japan METHODS
responsesmaybereducedwhenTCZisusedasa
Patients
Correspondenceto combinationtherapywithMTX.
ShunsukeMori,Department RA patients who were receiving TCZ therapy (at
ofRheumatology,Clinical least the first dose of an intravenous infusion of
ResearchCenterforRheumatic 8mg/kgevery4weeks)and/or MTX(4–18mgper
Disease,NHOKumamoto week) for ≥12weeks at our rheumatology out-
SaishunsouNationalHospital,
2659Suya,Kohshi,Kumamoto INTRODUCTION patient clinics were invited to participate in this
861-1196,Japan; Streptococcus pneumoniae (pneumococcus) infection open-labelstudy.RApatientswhohadbeentreated
[email protected] isresponsibleforsubstantialmortalityandmorbid- with bucillamine or salazosulfapyridine were also
ity among adults aged ≥65years or those with included as RA controls. All participants fulfilled
Received12September2012
underlying chronic or immunosuppressive condi- the 1987 American College of Rheumatology cri-
Revised21November2012
Accepted28December2012 tions. The CDC Advisory Committee on teria for RA diagnosis. Exclusion criteria were
PublishedOnlineFirst ImmunizationPracticehasrecommendedtheuseof currentprednisoloneuse(≥10mg/day),currentuse
23January2013 the23-valentpneumococcalpolysaccharidevaccine of immunosuppressive antirheumatic drugs other
(PPV23) for prevention of invasive pneumococcal than MTX (such as tacrolimus, cyclosporine, leflu-
disease in at-risk populations.1 Patients with nomide, cyclophosphamide and azathioprine), a
rheumatoidarthritis(RA)areatanincreasedriskof recent history (within 6months) of pneumococcal
contractinginfectiousdiseasesbecauseofimmuno- infection and a history of pneumococcal vaccin-
logical changes that are intrinsic to RA and that ation.Patientswhohadchangedtreatmentsduring
resultfromimmunosuppressiveagents,andthusit thefollow-upperiodorthosewhohadreceivedbio-
OpenAccess islikelythatpneumococcalvaccinationcanbenefit logical agents other than TCZ were also excluded
Scantoaccessmore
freecontent thispatientpopulation. fromthisstudy.
1362 AnnRheumDis2013;72:1362–1366.doi:10.1136/annrheumdis-2012-202658
Clinical and epidemiological research
Vaccine mean of log-transformed values. For details regarding statistical
We used commercially available PPV23 (Pneumovax NP, Merck analysis,seeonlinesupplementarytext.
Sharp & Dohme Corp., Tokyo, Japan) containing 25μg each of
23 capsular polysaccharide types.From October 2011 to March RESULTS
2012, each patient received a single dose of vaccine (0.5ml) Clinicalanddemographiccharacteristics
subcutaneously in the upper arm. For RA patients receiving A total of 190 RA patients were divided into four groups
TCZ, the vaccination was performed on the same day as the according to their ongoing anti-RA therapy. There was one
TCZinfusion. group of 50 patients treated with TCZ as monotherapy (TCZ
group), 62 patients treated with MTX alone (MTX group), 54
ELISAsforserotype-specificIgGandmultiplexedOPAs patients who received a combination therapy consisting of
Serawerecollectedimmediatelybeforeand4–6weeksaftervac- TCZ and MTX (TCZ+MTX group) and 24 patients who did
cinationandstoredat−30°Cuntiltested.Tomeasureserotype- not receive either drug (RA control group). Prior to participat-
specific IgG concentrations and functional antibody activity ingin thisstudy, nopatients hadreceived apneumococcalvac-
against pneumococcus serotypes 6B and 23F, we performed cination. Patients’ clinical and demographic characteristics are
ELISAs and multiplexed OPAs, respectively. For detailed proto- shownintable1.
cols,seeonlinesupplementarytext.
Serotype-specificIgGconcentrations
After vaccination, serotype-specific IgG GMCs to pneumococ-
Antibodyresponse
cal serotypes 6B and 23F in all four groups were increased sig-
Fold increases relative to pre-vaccination values (post-
nificantly (p<0.0005; table 2). For serotype 6B, a significantly
vaccination value to pre-vaccination value ratios) were deter-
mined. Positive antibody response was defined as a 2-fold or higher post-GMC was obtained in the TCZ group compared
with that in the TCZ+MTX group (p=0.004). The TCZ
more increase in IgG concentrations or as a 10-fold or more
increaseinopsonisationindices(OIs).5 group also showed a significantly greater fold increase than did
the TCZ+MTX group (p=0.036). For serotype 23F, the TCZ
group also showed a significantly higher post-GMC than did
Monitoringadverseeffects
the MTX group (p=0.027). Increases were twofold or more in
Adverse events that occurred during a follow-up period of all treatment groups, and there were no statistically significant
4–6weeks after vaccination were recorded. Systemic adverse differences.
effects included fever, headache, myalgia, asthenia and fatigue.
Local adverse events included pain/tenderness, swelling/indur-
Opsonophagocytickillingassays
ationanderythemaattheinjectionsites.
After vaccination, GM-OIs for the 6B and the 23F serotypes
were increased significantly in all four groups (p<0.0005;
Statisticalanalysis table 2). For serotype 6B, the post-vaccination GM-OI was
To access the PPV23 immunogenicity in patients in each treat- significantly higher in the TCZ group compared with that in
ment group, IgG concentrations and OIs before and after the MTX group (p=0.001). The TCZ group also showed a
vaccination were transformed into logarithmic values. IgG geo- significantly higher post-vaccination GM-OI for serotype 23F
metric mean concentrations (GMCs) and geometric mean OIs compared with the MTX group (p=0.001) or with the TCZ
(GM-OIs) were calculated as the exponential of an arithmetic +MTX group (p=0.042). For either serotype, there were no
Table1 ClinicalanddemographiccharacteristicsofRApatientspriortopneumococcalvaccination
MTXgroup TCZ+MTXgroup TCZgroup RAcontrol pValuesbetween
(n=62) (n=54) (n=50) (n=24) treatmentgroups
Male/female 11/51 4/50 7/43 5/19 NS
Age,mean(95%CI)(years) 68.3(66.6to70.1) 65.1(63.1to67.0) 68.3(65.8to70.8) 69.2(65.3to73.1) NS
RAduration,mean(95%CI)(years) 10.0(7.8to12.1) 9.1(7.3to10.8) 12.5(9.6to15.3) 11.3(6.0to16.6) NS
MTXdose,median(IQR)(mg/week) 8(6to8) 8(6to8) – – NS
MTXduration,median(IQR)(months) 48(14.3to86.3) 48.5(26to81) – – NS
TCZduration,median(IQR)(weeks) – 56(16to95) 58(15to98) – NS
Useofprednisolone,numberofpatients(%) 17(27.4) 14(25.9) 12(24) 1(4.2) 0.018(MvsC)
0.029(T/MvsC)
0.049(TvsC)
Prednisolonedose,median(IQR)(mg/day) 0(0to2) 0(0to1) 0(0to1) 0(0to1) NS
PositiveRF,numberofpatients(%) 35(56.5) 39(72.2) 31(62) 8(33.3) 0.001(T/MvsC)
0.021(TvsC)
Positiveanti-CCPAbs,numberofpatients(%) 44(71.0) 46(85.2) 41(82) 11(45.8) 0.029(MvsC)
0.0003(T/MvsC)
0.001(TvsC)
Lymphocytes,mean(95%CI)(/μl) 1374(1230to1517) 1651(1420to1881) 1717(1545to1890) 1600(1358to1842) NS
SerumIgG,mean(95%CI)(mg/dl) 1286(1194to1377) 1172(1075to1269) 1196(1121to1271) 1394(1258to1530) NS
Datawereobtainedimmediatelybeforepneumococcalvaccination.pValuesbetweentreatmentgroupsweredeterminedusingtheMann–WhitneyUtest,ANOVA(analysisof
variance)withaTukey’sHSD(honestysignificantdifference)posthoctest,theKruskal–WallistestwithaScheffeposthoctest,theχ²testorFisher’sexactprobabilitytest.
anti-CCPAbs,anti-cycliccitrullinatedpeptideantibodies;M,MTXgroup;MTX,methotrexate;NS,notsignificant;RA,rheumatoidarthritis;RF,rheumatoidfactor;T,TCZgroup;
T/M,TCZ+MTXgroup;C,RAcontrol;TCZ,tocilizumab.
AnnRheumDis2013;72:1362–1366.doi:10.1136/annrheumdis-2012-202658 1363
Clinical and epidemiological research
Table2 Concentrationsofpneumococcalpolysaccharideantigenserotype-specificIgGantibodiesandopsonisationindicesintheRAtreatment
groupsbeforeandafter23-valentpneumococcalpolysaccharidevaccination
Serotype MTXgroup(n=62) TCZ+MTXgroup(n=54) TCZgroup(n=50) RAcontrolgroup(n=24) pValuesbetweentreatmentgroups
IgGGMCs(μg/ml)
6B
Before 1.2(1.0to1.5) 1.1(0.9to1.3) 1.3(1.0to1.7) 1.1(0.8to1.6) NS
After 2.2(1.7to2.7)* 1.7(1.3to2.3)* 6.1(2.6to4.9)* 2.5(1.5to4.4)* 0.004(T/MvsT)
Foldincrease 1.5(1.1to3.0) 1.6(1.2to1.9) 2.8(1.4to4.4) 1.8(1.3to3.7) 0.036(T/MvsT)
23F
Before 1.0(0.8to1.2) 0.9(0.7to1.2) 1.3(1.0to1.7) 1.0(0.6to1.5) NS
After 2.4(1.8to3.3)* 2.5(1.8to3.5)* 4.6(3.4to6.4)* 3.6(1.8to5.7)* 0.027(MvsT)
Foldincrease 2.6(1.4to4.1) 2.9(1.0to6.9) 3.4(1.5to6.8) 3.5(1.7to5.6) NS
GM-OIs
6B
Before 18.8(18.7to32.1) 24.5(14.7to42.1) 43.8(22.4to85.6) 20.70(7.0to61.0) NS
After 115.6(64.1to206.4)* 232.8(124.0to437.0)* 692.3(265.1to1366)* 262.4(74.4to916.0)* 0.001(MvsT)
Foldincrease 4.5(1to12.5) 6.8(1.7to35.5) 12(3.5to62.4) 8.5(2.2to52.0) NS
23F
Before 10.1(6.6to15.3) 15.5(10.3to23.6) 27.9(15.2to51.4) 17.6(7.5to42.1) 0.018(MvsT)
After 72.2(39.3to133.0)* 124.0(62.2to244.7)* 437.0(221.4to862.6)* 219.2(82.3to578.2)* 0.001(MvsT)
0.042(M/TvsT)
Foldincrease 7.0(2.7to15.8) 5.0(1to40) 18.8(2.7to75.1) 11.0(3.1to30.6) NS
IgGGMCsandGM-OIsareexpressedasthemean(95%CI).Foldincreasesareexpressedasthemedian(IQR).Differencesbetweenpre-andpost-vaccinationGMCsof
serotype-specificIgGandthosebetweenpre-andpost-vaccinationGM-OIswereassessedusingapaired-samplettest.Thefourtreatmentgroupswerecomparedusing
ANOVA(analysisofvariance)withaTukey’sHSD(honestlysignificantdifference)posthoctestortheKruskal–WallistestwithaScheffeposthoctest.
*p<0.0005comparedwithpre-vaccinationIgGGMCsorGM-OIs.
GMC,geometricmeanconcentration;GM-OI,geometricmeanopsonisationindex;M,MTXgroup;MTX,methotrexate;NS,notsignificant;RA,rheumatoidarthritis;T,TCZ
group;T/M,TCZ+MTXgroup;TCZ,tocilizumab.
significant differences in fold increases among the four treat- pneumococcalvaccinationforeitherIgGconcentrationsorOIs.
mentgroups. The negative association of current MTX use with antibody
There was a moderate correlation between IgG concentra- responsewas confirmed for IgG concentrations specific to sero-
tions and OIs for the 6B and the 23F serotypes (serotype 6B: types 6B and 23F (for serotype 6B: OR 0.45, 95% CI 0.25 to
r=0.623,p<0.0005;serotype23F:r=0.601,p<0.0005). 0.82, p=0.009; forserotype 23F: OR 0.56, 95% CI 0.31 to 1.04,
p=0.007) and OIs for serotype 23F (OR 0.54, 95% CI 0.29 to
0.99,p=0.046).
Antibodyresponserates(percentagesofpatientswith
positiveantibodyresponse)
The TCZ group antibody response rates were comparable with Vaccinationsafety
thoseoftheRAcontrolgroupforserotypes6Band23F(figure1). Two patients in the TCZ+MTX group had a fever. Local
For the IgG concentration specific to serotype 6B, the anti- adverse events were observed in 12 patients (2 in the MTX
body response rate was significantly higher in the TCZ group group, 7 in the TCZ+MTX group and 3 in the TCZ group).
(56%) compared with that in the MTX group (37%) and the Alladverseeffectsweremild.
TCZ+MTX group (24%, p=0.046 and p=0.0009, respectively;
figure 1A). For serotype 23F, there was no significant difference
DISCUSSION
intheantibodyresponserateamongthefourtreatmentgroups
Following immunisation with PPV23, IgG concentrations and
(Control:67%;MTX:57%;TCZ+MTX:56%;TCZ:72%).The OIs for the 6B and the 23F serotypes were significantly
percentageofpatientswithpositiveantibodyresponseforboth
increased in all treatment groups. Antibody response rates in
strains were significantly greater in the TCZ group (46%) com-
the TCZ group were comparable with those of the RA control
pared with the TCZ+MTX group (20%, p=0.005) and the RA
group foreach serotype. Ongoing use of MTX is likely to have
controlgroup(21%,p=0.044).
affectedtheantibodyresponsetoPPV23.
ForOIsspecifictoserotype6B,theTCZgroupshowedasig-
Results of the present study indicate that TCZ does not
nificantly higher antibody response rate than did the MTX
diminish T-cell-independent antibody production after PPV23
group (56% vs 34%, p=0.019; figure 1B). For serotype 23F, the
immunisation. In addition, we recently reported that RA
antibody response rates were significantly higher in the TCZ
patients receiving TCZ can produce an adequate antibody
group (58%) compared with those in the MTX group (37%, response to influenza vaccine, which are T-cell-dependent
p=0.027)and the TCZ+MTX group (35%, p=0.020). For both protein antigens.6 These findings suggest that both
strains, a higher proportion of patients in the TCZ group
T-cell-dependent and T-cell-independent antibody response
responded to pneumococcal vaccination compared with the
pathways are conserved in RA patients who are treated with
patientsbeingtreatedwithMTXalone(34%vs16%,p=0.028).
TCZ. There is an increasing awareness of lethal synergism
betweeninfluenzavirusandpneumococcus;influenzaviruscon-
PredictivefactorsforantibodyresponsetoPPV23 tributestosecondarypneumococcal pneumoniaandcan subse-
In a multivariate logistic regression analysis, TCZ use was not quently increase mortality.7 8 In addition, a large-scale trial
identified as the predictive factor for antibody response to suggested that a significant proportion of viral pneumonia,
1364 AnnRheumDis2013;72:1362–1366.doi:10.1136/annrheumdis-2012-202658
Clinical and epidemiological research
Inthepresentstudy,nopatientswerereceivinghighdosesof
prednisolone or antirheumatic agents with immunosuppressive
effects other than MTX. In addition, there were no differences
intheprednisolonedoseamongthefourtreatmentgroups,and
the median dose of prednisolone was zero among all groups.
The number of prednisolone users was significantly lower in
theRAcontrolgroup;however,therewerenosignificantdiffer-
encesortrendsinantibodyresponsetoeachserotypecompared
with the other three groups. We can, therefore, say that the
influence of such agents on PPV23-induced antibody response
wasminimalinthepresentstudy.
Onelimitationofthisstudyistherelativelysmallnumberof
patients in each group and the RA control group in particular.
Since most RA patients had already received one or more
immunosuppressive antirheumatic drugs, as recommended by
the current therapeutic guidelines, it was difficult to recruit a
sufficient number of patients who had never received such
drugs. Another limitation is that we determined antibody
response to only two pneumococcal serotypes. We chose sero-
types 6B and 23F because these are the main causative sero-
types of pneumococcal pneumonia in Japan and these are
representative penicillin-resistant pneumococci.20 However, the
immune response to PPV23 may not be consistent among the
23 serotypes. Lastly, unlike influenza vaccines, antibody levels
that are protective against invasive pneumococcal disease in
adults have not been clearly defined. We used a 2-fold increase
in the IgG concentration or a 10-fold increase in the OI as a
measure of positive antibody response to PPV23 in this study,
which was also used in previous studies;5 however, how this
threshold may best correlate with protection against invasive
Figure1 (A)Percentagesofpatientswithtwofoldormoreincreases
pneumococcaldiseaseremainstobedetermined.
inserotype-specificIgGconcentrationsforserotypes6Band23Finthe
In conclusion, ongoing TCZ therapy does not preclude
rheumatoidarthritis(RA)treatmentgroups.*p=0.046(TCZvsMTX)
pneumococcal polysaccharide vaccination in RA patients;
andp=0.0009(TCZvsTCZ+MTX).**p=0.005(TCZvsTCZ+MTX)
andp=0.044(TCZvsCont).(B)Percentagesofpatientswith10-foldor however, antibody responses may be reduced when TCZ is
moreincreasesinOIsforserotypes6Band23FintheRAtreatment administeredincombinationwithMTX.
groups.*p=0.019(TCZvsMTX).**p=0.027(TCZvsMTX)and
Acknowledgements TheauthorsaregratefultoMichiyoHayakawaandYumiHattori
p=0.020(TCZvsTCZ+MTX).***p=0.028(TCZvsMTX).Datawere
comparedusingtheχ2testorFisher’sexactprobabilitytest.OIs, fortechnicalassistanceinmeasuringserotype-specificIgGconcentrationsandOIs.
opsonisationindices;Cont,RAcontrolgroup;MTX,methotrexategroup; Contributors Allauthorscontributedtostudyconceptionanddesign,acquisitionof
TCZ,tocilizumabgroup;TCZ+MTX,combinationtherapygroup. data,analysisandinterpretationofdata,anddraftingofthemanuscriptwithregard
toimportantintellectualcontent.
including influenza, is attributable to bacterial co-infection and Funding ThestudywassupportedbyresearchgrantsfromtheMinistryofHealth,
LabourandWelfareofJapanandresearchfundsfromtheNationalHospital
that this co-infection may be preventable by bacterial vaccin- Organization(NHO),Japan.
ation.9 Immunisation with both influenza and pneumococcal
Competinginterests THhasreceivedlecturefeesfromMitsubishi-Tanabe
vaccinesmay,therefore,provideadditivebenefitsforRApatients PharmaceuticalCo.,EisaiCo.Ltd.andAbbottJapanCo.Ltd.Theotherauthorshave
compared with a single vaccination, even if they are receiving nofinancialrelationshipsthatcouldleadtoaconflictofinterest.
TCZtherapy. Patientconsent Obtained.
Previous studies have shown that MTX therapy reduced the
Ethicsapproval Theethicscommitteesofparticipatinghospitalsapprovedthe
antibodyresponsetoPPV23,10–13whichisinagreementwiththe protocolforthisstudy.
data obtained in the present study. Although T-cell-dependent
Provenanceandpeerreview Notcommissioned;externallypeerreviewed.
proteinantigensmaybemoreimmunogenicthanpolysaccharide
OpenAccess ThisisanOpenAccessarticledistributedinaccordancewiththe
antigens in immunocompromised patients,14 MTX was also
CreativeCommonsAttributionNonCommercial(CCBY-NC3.0)license,which
reportedtobeastrongpredictivefactorforanimpairedantibody permitsotherstodistribute,remix,adapt,builduponthisworknon-commercially,and
response to protein-conjugate pneumococcal vaccine.15 Offering licensetheirderivativeworksondifferentterms,providedtheoriginalworkis
PPV23 vaccination before introduction of MTX therapy may be properlycitedandtheuseisnon-commercial.See:http://creativecommons.org/
considered in RA patients.11 16 In contrast, a study by Elkayam licenses/by-nc/3.0/
et al17 did not demonstrate a detrimental effect of immunosup-
pressive drugs such as MTX on PPV23 immunogenicity in RA
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