Vaccinaties bij JIA

Beoordeeld: 17-02-2025

Uitgangsvraag

Wanneer en onder welke voorwaarden kunnen kinderen met JIA van 0 tot 18 jaar met gebruik van conventionele synthetische of biologische disease-modifying antirheumatic drugs (DMARDs) vaccinaties (rijksvaccinatieprogramma en vaccinatie tegen specifieke aandoeningen (zoals griep, covid, waterpokken)) toegediend krijgen?

Aanbeveling

Aanbeveling-1

Rijksvaccinatieprogramma (RVP)

Niet-levende vaccins in het RVP:

Niet-levende vaccins kunnen veilig worden toegediend aan alle JIA patiënten met en zonder immunosuppressieve behandeling en zijn meestal effectief.
Conform advies van de WHO en Joint Committee on Vaccination and Immunisation (JCVI) en de LCI richtlijn wordt uit voorzorg geadviseerd om immuun gecompromitteerde patiënten met JIA met een 3-dosesschema (0, 1 en 6 maanden) tegen HPV te vaccineren (zie de LCI richtlijn HPV-vaccinatie).
Adviseer adolescenten met JIA die anti-TNFα gebruiken ten tijde van de 14 jaar- meningokokkenconjugaat (MenACWY) vaccinatie zes maanden tot 1 jaar na deze vaccinatie een tweede MenACWY booster te laten geven. Dit geldt voor JIA patiënten die geboren zijn voor 2018.

Levend verzwakte vaccins in het RVP:

De primo BMR vaccinatie op 14 maanden wordt afgeraden bij kinderen met JIA behandeld met immunosuppressiva. Bij een mazelenuitbraak in de omgeving, kan de primo BMR vaccinatie wel worden overwogen.
De tweede BMR (booster) vaccinatie bij 9 jaar (vanaf 2025 bij 3 jaar) kan veilig gegeven worden aan patiënten met JIA zonder medicatie, aan diegenen die MTX gebruiken en kan overwogen worden bij patiënten met JIA die of lage dosis corticosteroïden, anti TNFα , anti IL-1 of anti IL-6 inhibitors gebruiken, zonder of in combinatie met methotrexaat
Overweeg serotiters te bepalen bij kinderen met JIA waarbij de booster BMR vaccinatie niet gegeven kan worden. De klinische implicatie is post-expositiebeleid (IVIG in geval van mazelenexposure bij de immuungecompromiteerde seronegatieve patiënt). Bij stoppen immunosuppressiva alsnog de booster geven.

NB Vaccinaties die in het ziekenhuis gegeven worden, kunnen geregistreerd worden bij het RIVM via het vaccinregistratieformulier.

Overige vaccinaties

Niet levende vaccins:

Adviseer ouders van kinderen met JIA met immunosuppressiva om hun kind jaarlijks te laten vaccineren tegen influenza.
Laat kinderen met JIA vaccineren met het pneumokokkenconjugaatvaccin PCV13 of PCV15, indien zij nog niet via het RVP zijn gevaccineerd.
Overweeg aanvullende vaccinatie met PPSV-23 bij ernstig immuungecompromitteerde JIA patiënten conform de LCI richtlijn.
Laat kinderen met JIA met een indicatie voor een tetanusbooster vaccineren volgens de richtlijn zoals dit ook bij gezonde kinderen wordt gedaan.
Geef passieve immunisatie in geval van postexpositie profylaxe bij JIA patiënten die B-cel depleterende therapie hebben ontvangen in de afgelopen 6 maanden.
Adviseer ouders van kinderen met JIA, ongeacht medicatie, om hun kind te laten vaccineren met Covid-19 vaccin(s) als er een oproep is vanuit de GGD of het RIVM.

Levend verzwakte vaccins:

Vermijd levend verzwakte vaccins buiten het RVP bij kinderen met JIA die immunosuppressiva gebruiken, met uitzondering van varicella zoster vaccinatie onder specifieke omstandigheden:
Screen kinderen met JIA op hun VZV status, eerst op basis van anamnese en waar nodig op basis van serologie.
Overweeg kinderen met JIA te laten vaccineren met een levend verzwakte VZV-vaccinatie, als zij varicella-naïef zijn. De vaccinatie kan dan het best gegeven worden wanneer kinderen nog geen systemische immunosuppressiva gebruiken (dus bespreken bij diagnose) of wanneer zij MTX monotherapie gebruiken maar de vaccinatie kan ook overwogen worden bij gebruik van lage dosis glucocorticoïden, anti-TNF, anti IL-1 en anti IL-6.

Reisvaccinaties:

Informeer ouders van kinderen met JIA ongeacht medicatiegebruik om hun kind te laten vaccineren met reisvaccinaties volgens de Landelijk Coördinatie centrum Reizigersadvisering (LCR) richtlijnen, met uitzondering van levend verzwakte vaccinaties.

Geef geen gele koorts vaccinatie aan kinderen met JIA die immunosuppressiva gebruiken.
Als deze toch gegeven moet worden, onderbreek dan indien mogelijk de behandeling voor de gestelde wash out periode (LCI richtlijn tabel 5b).

Timing

Laat bij voorkeur de vaccinatie geven wanneer de ziekteactiviteit laag is.
Wacht bij voorkeur met het starten van nieuwe immunosuppressieve therapie twee tot vier weken na vaccinatie, met name bij B-cel depleterende therapieën, maar stel nooit een noodzakelijke behandeling uit om een vaccinatie te kunnen geven.

Aanbeveling-2

Beoordeel en bespreek als behandelend specialist jaarlijks het volgende:

Vaccinatiestatus op basis van anamnese en eventueel vaccinatiepaspoort;
Indicaties voor vaccinaties in aanvulling op het Rijksvaccinatieprogramma (RVP) zoals de griepprik, varicella zoster-, meningokokkenbooster- en Covid-19 vaccinatie;
Indien van toepassing, indicaties voor het uitstellen van RVP-vaccinaties bij patiënten met JIA;
Indien mogelijk, vervang PCV10 in het RVP door PCV15. In Q4 2024 wordt PCV10 vervangen door PCV15 in het standaard RVP;
De varicella status middels anamnese en indien onduidelijk door serologie;
Communicatie vaccinatiebeleid met GGD.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Levend-verzwakte vaccins

In deze literatuursamenvatting worden de resultaten, gradering van bewijs en conclusies uitgesplitst in levend-verzwakte vaccins en dode vaccins. Wat betreft de levend-verzwakte vaccins (BMR-booster en VZV), suggereren de gevonden studies dat de veiligheid (bijwerkingen en ziekteactiviteit) en de werkzaamheid (effectiviteit, dat wil zeggen voorkomen van infecties, en immunogeniciteit) overeenkomstig zijn tussen kinderen met JIA en controles. Echter varieert de bewijskracht hiervan van laag tot zeer laag, door risico op bias en een kleine studiepopulatie.

Veiligheid

Voor de BMR booster is er low grade evidence dat het vaccin veilig is bij kinderen met JIA, inclusief patiënten op methotrexaat, lage dosis glucocorticoiden en anti-TNFα. Er zijn geen vaccin geïnduceerde infecties geobserveerd en de ziekteactiviteit neemt niet toe na het vaccin. Er zijn geen studies beschikbaar over de veiligheid en effeciviteit van de BMR primo vaccinatie. Voor de VZV primo vaccinatie is er geen data beschikbaar uit gecontroleerde studies over de veiligheid van het vaccin in vergelijking met gezonde controles. Wel zijn er in totaal 83 varicella naïeve kinderen met een reumatische ziekte in de literatuur beschreven die gevaccineerd zijn met het primo VZV, waarvan 66 met JIA. Bij deze patiënten zijn 3 milde vaccin geïnduceerde varicella infecties beschreven; zij ontwikkelden blaasjes zonder gedissemineerde ziekte die goed behandeld kon worden met (val)aciclovir. Er werd geen verschil gevonden in ziekteactiviteit tussen levend verzwakt gevaccineerde en ongevaccineerde patiënten met een biological DMARD.

Effectiviteit en immunogeniciteit en het effect van medicatie

Naast het bewijs uit de literatuur op basis van de zoekvraag, beschrijven de geïncludeerde studies ook het effect van medicatie op de uitkomstmaten. Qua effectiviteit vermelden studies vier patiënten, waarvan drie het VZV vaccin en één het BMR vaccin kregen, die ondanks vaccinatie de infectieziekte kregen waarvoor ze gevaccineerd werden. Van deze vier patiënten gebruikte één patiënt anti-TNFα, één abatacept, één methotrexaat en één patiënt een combinatie van corticosteroïden en methotrexaat. Qua immunogeniciteit lijkt er geen nadelig effect van het gebruik van DMARDs bij JIA patiënten, echter kleinere studies vonden bij enkele patiënten die methotrexaat, abatacept of andere biological DMARDs gebruiken een lagere immuunrespons vergeleken bij patiënten met JIA zonder immunosuppressieve medicatie. Over het algemeen lijkt de toegepaste immunosuppressieve medicatie bij JIA geen groot effect te hebben op de uitkomstmaten bij levend-verzwakte vaccins. Er zijn geen studies bekend naar de veiligheid en effectiviteit van vaccins tijdens het gebruik van targeted synthetic (ts)DMARDS.

Dode vaccins

Veiligheid, effectiviteit en immunogeniciteit dode vaccins bij JIA patiënten versus controles

Wat betreft de dode vaccins zijn er verschillen tussen de vaccins. Bij het DTP vaccin lijkt er geen verschil te zijn in het optreden van bijwerkingen tussen JIA patiënten en controles, maar is er mogelijk een lagere seroprotectie ratio in vergelijking met controles. Echter, de bewijskracht hiervan is zeer laag en kan dit dus niet met zekerheid worden geconcludeerd. De mogelijke klinische consequenties zijn onduidelijk.

De resultaten van de HPV-2 vaccinatie lijken qua veiligheid (bijwerkingen en ziekteactiviteit) en immunogeniciteit gelijk te zijn tussen JIA patiënten en controles, maar dit heeft een lage bewijskracht.

Er zijn meerdere studies gedaan naar influenzavaccinaties. De bewijskracht van de uitkomstmaten is desondanks zeer laag. De Influenzavaccins lijken qua bijwerkingen en ziekteactiviteit vergelijkbaar met respectievelijk gezonde controles en JIA controles die geen vaccinatie kregen. De vaccins lijken even effectief in het voorkomen van influenzainfecties en even immunogeen bij JIA patiënten als bij gezonde controles.

Wat betreft het HBV/HAV is er zeer lage bewijskracht dat bijwerkingen gelijk zijn bij JIA patiënten vergeleken met controles, maar mogelijk hebben JIA patiënten een lagere seroprotectie ratio dan controles. Ook hiervan is de bewijskracht echter zeer laag.

Voor meningokokkenconjugaat vaccinatie zijn geen verschillen in veiligheid met gezonde controles, wel zijn er aanwijzingen voor een verminderde immunogeniciteit van JIA patiënten vergeleken gezonde controles, met name diegene op specifieke immunosuppressiva (zie volgende paragraaf), maar ook hier is de bewijskracht zeer laag. Wat betreft de PCV/PPSV23 vaccinatie suggereert het bewijs met zeer lage bewijskracht dat de veiligheid (bijwerkingen en ziekteactiviteit), effectiviteit en waarschijnlijk ook de immunogeniciteit gelijk zijn tussen JIA patiënten en controles.

Bij de Covid-19 mRNA vaccinatie (BioNTech/Pfizer) lijkt de ziekteactiviteit na vaccinatie gelijk te blijven bij JIA patiënten met en zonder vaccinatie, maar dit heeft een zeer lage bewijskracht. Verder zijn de veiligheid, effectiviteit en immunogeniciteit van het vaccin bij JIA patiënten vergeleken met controles ook gelijk, met een lage bewijskracht.

Effect van medicatie op de uitkomstmaten bij dode vaccins

Immunosuppressieve medicatie heeft geen invloed op de veiligheid van de dode vaccins: bijwerkingen en veranderingen in ziekteactiviteit rondom vaccinatie waren gelijk bij JIA patiënten met en zonder medicatie. Geen enkele studie benoemt het effect van medicatie op de effectiviteit van de betreffende vaccins. De meeste studies, op twee na, beschrijven geen negatief effect van medicatie op de immunogeniciteit van vaccinaties bij JIA patiënten. Eén studie laat zien dat vier patiënten behandeld met anti-TNFα niet reageren op de hepatitis A vaccinatie en vijf patiënten (vier met anti-TNFα en één met sulfasalazine) niet op de hepatitis B vaccinatie. Een andere studie met het meningokokken ACWY vaccin laat een verminderde seroprotectie ratio zien voor meningokokken W bij JIA patiënten behandeld met TNFα. Er zijn geen studies bekend naar de veiligheid en effectiviteit van vaccins tijdens het gebruik van targeted synthetic (ts)DMARDS.

Overwegingen

In de overwegingen zullen we eerst ingaan op de verschillende vaccins. Hierna worden het patiëntperspectief, kosten en haalbaarheid besproken.

Rijksvaccinatieprogramma

Om kinderen met JIA zo optimaal mogelijk te beschermen tegen infecties wordt aangeraden het rijksvaccinatieprogramma volledig te doorlopen met uitzondering van de BMR primo vaccinatie bij patiënten op immunosuppressiva. Alle geïnactiveerde (dode) rijksvaccinaties zijn veilig voor JIA patiënten met of zonder immunosuppressieve behandeling en in de meeste gevallen effectief en immunogeen en kunnen dus volgens schema gegeven worden. Voor de levend verzwakte BMR booster vaccinatie bij de leeftijd van 9 jaar (vanaf 2025 bij 3 jaar) geldt dat deze veilig gegeven kan worden aan kinderen met JIA die ofwel geen immunosuppressiva gebruiken of methotrexaat gebruiken. De BMR booster kan overwogen worden bij patiënten die lage dosis (<0,5 mg/kg of <20 mg) glucocorticoïden of specifieke bDMARDs (anti-TNF, anti IL-1 of anti IL-6) gebruiken, eventueel in combinatie met methotrexaat. Er zijn geen data beschikbaar over de veiligheid van de primo BMR vaccinatie bij de leeftijd van 14 maanden bij JIA patiënten met immunosuppressiva. Daarom wordt de primo BMR vaccinatie afgeraden bij JIA patiënten die immunosuppressieve medicatie gebruiken. Dit advies kan eventueel worden heroverwogen ten tijde van een uitbraak van een van de ziekte of een situatie met een hoge kans op het oplopen van de ziekte.

Jaarlijks griepvaccin

Net als volwassen patiënten met een inflammatoire reumatische aandoening worden JIA patiënten die immunosuppressiva gebruiken als een risicogroep voor (ernstige) influenzainfecties beschouwd. Het influenzavaccin is bewezen veilig, effectief en even immunogeen als in gezonde controles. Daarom wordt sterk aangeraden, zoals ook benoemd in de EULAR richtlijn (Jansen, 2022; Jansen 2023), JIA patiënten behandeld met immunosuppressieve medicatie jaarlijks te laten vaccineren.

Pneumokokkenvaccin

De veiligheid en immunogeniciteit van pneumokokkenconjugaatvaccins (PCV's) is aangetoond bij patiënten met JIA, inclusief patiënten behandeld met MTX en glucocorticosteroïden. Daarnaast zijn er in de afgelopen 10 jaar gegevens over dit vaccin bij kinderen die bDMARDs gebruiken beschikbaar gekomen. Kinderen die anti- TNFα gebruiken, hebben gelijke seroprotectie ratio’s als controles in alle studies behalve één. Omdat het vaccin veilig, immunogeen en waarschijnlijk effectief is bij patiënten met JIA is het aanbevolen om alle kinderen met JIA indien mogelijk met een zo breed mogelijk pneumokokkenconjugaatvaccin (zoals PCV15, of PCV20 (indien beschikbaar) in plaats van PCV10) te vaccineren volgens het huidige RVP-schema. PCV15 komt eind 2024 in het RVP, maar is al wel geregistreerd. In de nabije toekomst wordt mogelijk PCV20 voor kinderen geregistreerd.

Helaas zijn er nog geen studies beschikbaar bij patiënten met JIA over de incidentie van invasieve pneumokokken ziekte (IPD). Daarnaast zijn er geen studies over de effectiviteit van de PPSV-23; namelijk of deze in staat is om in aanvulling op de PCV10/13 bij kinderen met JIA IPD te voorkomen. Studies met 27 JIA- en 30 jSLE-patiënten hebben aangetoond dat het PPSV-23-vaccin veilig is bij kinderen met een reumatische ziekte. Over de immunogeniciteit van PPSV-23 bij kinderen met JIA is weinig bekend: één studie rapporteerde slechts een adequate seroconversie voor alle serotypen bij respectievelijk 53% en 30% van de patiënten op MTX versus MTX in combinatie met anti-TNFα. Echter hanteerde deze studie een zeer hoge cut-off (1.3mcg/ml versus de gebruikelijke 0.35mcg/ml) en was er geen voorafgaande PCV gegeven, hetgeen in Nederland wel gebruikelijk is. Daarbij is het onduidelijk wat de protectieve titer is voor IPD. Vanwege het gebrek aan data bij kinderen met JIA zowel over de incidentie van IPD als over de potentie van het PPSV-23 vaccin om IPD te voorkomen heeft de werkgroep besloten dat het vaccineren met PPSV-23-vaccinatie naast de PCV13/15 niet standaard aan te bevelen is bij kinderen met JIA, zoals beschreven in de LCI richtlijn voor immuungecompromitteerde patiënten. Echter, PPSV-23 kan wel worden overwogen door de behandelaar bij sterk immuungecompromitteerde JIA patiënten, maar altijd voorafgegaan door zo breed mogelijk pneumokokkenconjugaatvaccin. Tussen PCV13/15 en de eventuele PPSV23 toediening dient een interval van minimaal 2 maanden te worden aangehouden. In geval wordt besloten PPSV23 te geven, houdt de beschermende werking maximaal 5 jaar aan. De werkgroep raadt daarom aan bij die subgroep van patiënten de PPSV-23 vervolgens elke 5 jaar te herhalen.

In het algemeen zijn conjugaatvaccins bij kinderen onder de 5 jaar meer immunogeen dan polysacharidevaccins en induceren conjugaatvaccins immunologisch geheugen in tegenstelling tot polysacharide vaccins. Onder de leeftijd van twee jaar is het geven van het polysacharidevaccin (PPV23) niet zinvol, een conjugaatvaccin is wel immunogeen < 2 jaar. In de nabije toekomst zullen de 23-valente polysacharide vaccins worden vervangen door 20 of meer- valente pneumokokken conjugaatvaccins.

Tetanusvaccin

De werkgroep beveelt aan om de tetanusvaccinatie volgens het RVP aan te houden, aangezien deze veilig en effectief is (Brunner, 2020). Conform de richtlijnen voor gezonde kinderen wordt ook bij JIA patiënten aanbevolen om een booster tetanus vaccinatie toe te dienen wanneer dit geïndiceerd is (bijvoorbeeld bij trauma, val of beet) (Embree, 2015), waarbij gezegd moet worden dat bij het normaal doorlopen van het RVP deze booster bij kinderen niet geïndiceerd is omdat het interval na vaccinatie altijd korter is dan 10 jaar. Daarnaast beveelt de werkgroep aan om bij JIA patiënten met B-cel depleterende therapie en een indicatie voor tetanus post expositie profylaxe, altijd passieve immunisatie toe te passen naast actieve vaccinatie. Studies in volwassenen uit de EULAR richtlijn wijzen namelijk uit dat de immunogeniciteit van het tetanusvaccin bij B-cel depleterende therapie gestoord is tot zes maanden na behandeling (Bingham, 2010; van der Kolk, 2002).

Meningokokkenconjugaatvaccin

In de literatuursamenvatting werd weinig bewijs gevonden over de immunogeniciteit van het meningokokken ACWY (MenACWY) conjugaatvaccin. Echter toont een recente Nederlandse studie in adolescenten met JIA en inflammatory bowel disease (IBD) aan dat bij 24% van de kinderen die anti TNFα gebruiken geen seroprotectie optreedt tegen MenW na een enkele MenACWY conjugaat vaccinatie (Ohm, 2023). Daarom valt te overwegen om alle JIA patiënten die anti TNFα gebruiken ten tijde van de MenACWY vaccinatie een tweede (booster) MenACWY vaccinatie te geven. Dit is voor een afgebakende periode want sinds 2020 is de meningokokkenconjugaat vaccinatie ACWY opgenomen in het RVP, waarbij kinderen op de leeftijd van 11 maanden de eerste MenACWY conjugaat vaccinatie ontvangen en daarna nogmaals op de leeftijd van 14 jaar hetgeen dus een als een booster vaccinatie beschouwd kan worden.

Kinderen worden in Nederland niet gevaccineerd tegen meningokokken B in het rijksvaccinatieprogramma. Het is niet bekend of immuungecompromitteerde kinderen met JIA extra risico lopen op een ernstig verloop van deze infectie. Als ouders deze vaccinatie wel zouden wensen dan is de werkgroep van mening dat deze op individuele basis veilig gegeven kan worden omdat het een doodvaccin is.

VZV vaccin

Immuungecompromitteerde patiënten, lopen een hoger risico op complicaties van een varicella zoster virus (VZV) infectie, namelijk bacteriële superinfectie van de huidlaesies, longontsteking, encefalitis, hepatitis of hemorragische complicaties (Edmunds & Brisson, 2002; Lin & Hadler, 2000; Rawson, 2001). Kinderen met JIA worden vaker gehospitaliseerd bij een varicella-infectie dan de gezonde populatie (Kearsley-Fleet 2022). In het afgelopen decennium zijn in totaal 83 varicella-naïeve kinderen met een autoimmuun inflammatoire reumatologische aandoening, waarvan 66 met JIA, beschreven die een primo VZV-vaccinatie kregen. Hierbij kregen patiënten lage doses glucocorticosteroïden (n=20), MTX (n=60) en/of bDMARD’s (TNFα inhibitor (n=20)) anti-IL6 (n=5) en anti-IL1 (n=5)). Aangezien de vaccinatie bij deze patiënten een primo immunisatie was, vormt dit een hoger risico op een door het vaccin geïnduceerde infectie met het verzwakte virus dan bij boostervaccins. Uit deze onderzoeken bleken er 3 kinderen een milde varicella infectie ontwikkeld te hebben van de huid en er werd geen verergering van ziekteactiviteit of opflakkeringen van JIA gezien. De immunogeniciteit van het levend verzwakte VZV vaccin is onderzocht bij kinderen met JIA, SLE en andere autoimmuun inflammatoire reumatologische aandoeningen. Bij 80% werd een humorale respons geïnduceerd en VZV-specifieke T-celreacties waren vergelijkbaar tussen patiënten en gezonde controles (Barbosa, 2012; Groot, 2017). Concluderend lijkt het vaccin veilig en meestal immunogeen. De werkgroep is van mening dat de eventuele risico’s van het vaccin niet op wegen tegen het risico van een ongecontroleerde varicellainfectie bij naïeve patiënten. Wel moeten zorgverleners waakzaam blijven voor een vaccin geïnduceerde VZV infectie en dan zo nodig (val)aciclovir starten.

Reizigersvaccins

Er is geen data beschikbaar over de veiligheid van het primo gelekoortsvaccin bij kinderen met een autoimmuun inflammatoire reumatologische aandoening, en daarom wordt gebruik van dit vaccin bij JIA patiënten met immunosuppressiva afgeraden. Er zijn casus beschreven waarbij volwassen patiënten forse ziekteverschijnselen ontwikkelden na gele koorts vaccinatie (Dos Reis, 2022). De werkgroep adviseert om serumantistoffen te meten bij patiënten die eerder een gelekoortsvaccinatie hebben ontvangen en willen afreizen naar endemische gebieden. In het geval van naïeve patiënten, kan overwogen worden, indien de ziekte dit toelaat, om immunosuppressiva voor de duur van de wash out-periode tot na vaccinatie te onderbreken (deze is per immunosuppressief medicament anders, zie LCI richtlijn tabel 5b.) In individuele gevallen kan de minimale duur van immunosuppressieve activiteit aangehouden worden, hetgeen iets meer ruimte geeft dan deze wash out periode. Deze staat samengevat in Tabel 2 in het artikel van Visser, 2012. Na een gele koorts vaccinatie dient minimaal 4 weken gewacht te worden alvorens de immunosuppressieve therapie herstart kan worden.

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

De beslissing om het kind wel of niet te laten vaccineren wordt niet genomen door de behandelaar, maar door de ouders/verzorgers en (bij oudere kinderen) het kind. Hun waarden en voorkeuren zijn hierin leidend: formeel heeft de behandelaar er geen zeggenschap over. Vaccinatie maakt immers geen deel uit van de behandeling. De behandelaar heeft bij deze keuze wel een belangrijke adviserende rol. Ouders en kinderen hechten veel waarde aan het advies van de behandelaar over vaccinaties (Makarova, 2023; Tabacchi, 2016; Wilson, 2022).

Deze richtlijn raadt behandelaars aan om vrijwel alle patiënten met jeugdreuma die medicatie gebruiken (en hun verzorgenden) te adviseren om (bijna) alle rijksvaccinaties te ondergaan. Er zijn slechts enkele uitzonderingen, die in de richtlijn expliciet worden benoemd.

In de praktijk blijken kinderen met jeugdreuma minder te worden gevaccineerd dan hun gezonde leeftijdsgenoten (David, 2022; Makarova, 2023; Morin, 2012). Verzorgenden en patiënten kunnen allerlei redenen hebben om zich niet te laten vaccineren (Tabachhi, 2016; Yaqub, 2014). Het is goed om die te bespreken.

De belangrijkste redenen hangen samen met twijfels over veiligheid en effectiviteit van het vaccin en de medicatie (Kostik, 2021; Tabacchi, 2016; Wilson, 2022). De aanbevelingen in deze richtlijn bieden antwoorden op dit terrein. Over het algemeen zijn vaccins effectief in kinderen met JIA en beschermen zij deze kinderen juist tegen ernstige infecties. Belangrijk is dat er geen verergering van hun ziekte wordt gezien na vaccinatie en dat vaccinaties veilig zijn.

Daarnaast kunnen ouders en kinderen ook andere zorgen en vragen hebben. We benoemen er hier twee: pijn en kosten.

Pijn en prikangst. Kinderen en jongeren met jeugdreuma worden veel geprikt. Er zijn aanwijzingen dat prikken voor deze groep extra pijnlijk zijn, en kunnen leiden tot prikangst (Jacobse, 2019; Sørensen, 2021). Vaccinatie betekent een extra prik erbovenop. Dat kan reden zijn om ervan af te zien. Echter zijn er verschillende mogelijkheden voor (non-farmacologische) pijnbestrijding bij vaccinatie, bijvoorbeeld zoals beschreven in de richtlijn Sedatie, Analgesie en niet-farmacologische interventies voor begeleiding van kinderen bij medische procedures.

Kosten. Vooral verzorgenden kunnen opzien tegen de eventuele kosten van vaccinaties, omdat sommige van de aanbevolen vaccinaties niet worden vergoed. Zie hieronder.

Het is belangrijk om de eventuele nadelen van vaccinatie niet zomaar weg te wuiven, maar de voordelen van vaccinatie te expliciteren en ertegenover te zetten (Wilson, 2022). De keuze is uiteindelijk aan de patiënt en de verzorgenden. De taak van de arts is om hierbij goede voorlichting te geven.

Kosten (middelenbeslag)

De vaccins in het Rijksvaccinatieprogramma (RVP), het griepvaccin en het Covid-19 vaccin worden vergoed. De VZV vaccinatie, meningokokken ACWY conjugaat booster en de meningokokken B vaccinatie worden niet vergoed, wat een barrière kan zijn voor ouders om hun kind en eventueel de directe omgeving van het kind om zich te laten vaccineren. De PCV13 en PCV15 en PPSV-23 vaccinatie worden wel vergoed (zie Zorginstituut Nl, (ZiN) website). Extra informatie over vergoeding van vaccinaties vind u hier.

Medicijnkosten.nl wel/niet opname vaccin in GVS en voorwaarden bijlages 1 & 2 (extramuraal)
Vaccins (farmacotherapeutischkompas.nl) (GVS, extramuraal)
Vergoeding vaccins – Immuno -start (immunostart.nl)

Aanvaardbaarheid, haalbaarheid en implementatie

De vaccinatiegraad bij kinderen met JIA is wereldwijd laag; in een retrospectieve cohortstudie in Canada bleek slechts ongeveer de helft van de kinderen met JIA op de leeftijd van 2,5 jaar en tweederde op de leeftijd van 10,5 jaar volledig gevaccineerd te zijn (Morin, 2012). Het is daarom belangrijk om hier als zorgverlener bewust van te zijn en hierover in gesprek te gaan met ouders. Uit de literatuur blijken de grootste barrières voor vaccinatie gebrek aan kennis en mispercepties over de onderliggende ziekte en over de bijwerkingen en effectiviteit van vaccinaties. Dit komt bij zowel de zorgverlener, patiënten en ouders voor. Voor het verhogen van de vaccinatiegraad in JIA patiënten, is het belangrijk om zorgverleners te onderwijzen over dat er voldoende bewijs is dat vaccins veilig en effectief zijn bij immuungecompromitteerde patiënten (Lloyd, 2023; Pittet & Psfay-Barbe, 2021). Hierdoor kan bezorgdheid bij zorgverleners over vaccinaties bij JIA patiënten worden weggenomen. Door middel van goede communicatie, een vertrouwensband en het geven van juiste informatie, kan aanvaardbaarheid van vaccins bij ouders en patiënten worden vergroot, waardoor de vaccinatiegraad zal verhogen (Pittet & Psfay-Barbe, 2021).

Vaccinaties die in het ziekenhuis gegeven worden kunnen geregistreerd worden bij het RIVM via het Vaccinregistratieformulier.

Rationale van aanbeveling-1

Niet-levende vaccins

Vaccins tegen HPV, hepatitis A en B, meningokokken conjugaat ACWY, pneumokokken (PPSV-23, PCV10 of PCV13), influenza, tetanus en difterie zijn onderzocht bij JIA-patiënten. Deze vaccins geven geen verergering of opvlamming van de ziekte en er zijn geen ernstige bijwerkingen gerapporteerd. De meeste studies toonden acceptabele immunogeniciteit. Dode vaccins kunnen daarom zonder bezwaar gegeven worden aan JIA patiënten met en zonder immunosuppressieve medicatie. Er zijn geen kosten verbonden aan vaccins die binnen het RVP gegeven worden. Als er buiten het RVP gevaccineerd wordt kunnen er wel kosten aan verbonden zitten omdat bepaalde vaccins door het ZiN niet vergoed worden (zie Kosten).

Levend verzwakte vaccins

Levend verzwakte vaccins moeten worden vermeden bij patiënten met JIA behandeld met immunosuppressiva vanwege het risico op infecties met de verzwakte ziekteverwekker. Uitzonderingen op dit principe zijn de levend verzwakte BMR booster en de varicellavaccinatie bij patiënten die met MTX, lage dosis glucocorticoiden en specifieke bDMARDs worden behandeld (zie aanbeveling Rijksvaccinatieprogramma).

Timing

Studies in volwassenen en kinderen laten wel zien dat de vaccinatierespons verminderd is bij specifieke therapieën zoals na B-cel depleterende therapieën en in mindere mate bij hoge dosis prednisolon (0,50 mg/kg/dag of >10-20 mg/dag) (Aikawa, 2012). Als er tijd is, kan overwogen worden de patiënt te vaccineren vóór start van deze therapie. Echter moet een noodzakelijke behandeling nooit worden uitgesteld om een vaccinatie te geven.

Rationale van sanbeveling-2: weging van argumenten voor en tegen de procedure

De beslissing om een kind wel of niet te laten vaccineren wordt niet genomen door de behandelaar, maar door de ouders/verzorgers en (bij oudere kinderen) het kind. Hun waarden en voorkeuren zijn hierin leidend: formeel heeft de behandelaar er geen zeggenschap over. In de praktijk blijken kinderen met jeugdreuma minder te worden gevaccineerd dan hun gezonde leeftijdsgenoten. Verzorgenden en patiënten kunnen allerlei redenen hebben om zich niet te laten vaccineren. Het is goed om die te bespreken.

Ouders en kinderen hechten veel waarde aan het advies van de behandelaar over vaccinaties. Het is belangrijk om de eventuele nadelen van vaccinatie niet zomaar weg te wuiven, maar de voordelen van vaccinatie te expliciteren en ertegenover te zetten. De keuze is uiteindelijk aan de patiënt en de verzorgenden. De taak van de arts is om hierbij goede voorlichting te geven.

Onderbouwing

Achtergrond

Patients with juvenile idiopathic arthritis (JIA) have an increased risk of infections caused by the disease itself and in particular by immunomodulatory or immunosuppressive treatment. Infection prevention is therefore vital in the management of patients with JIA. Vaccinations, mainly given through the National Immunization Programs (NIP), play an important role in infection prevention, even though there are specific considerations regarding vaccinations in immunosuppressed children. Unfortunately, vaccination coverage is surprisingly low in patients with JIA and other rheumatic diseases. One study in Canada showed that in 200 JIA patients complete vaccination according to schedule was present in only 52% of patients at the age of 2.5 years and 68% at 10.5 years (Morin, 2012). This was mainly caused by low MMR vaccine coverage at the age of 2.5 years (58%). Another study reported a coverage rate for children on biological disease-modifying antirheumatic drugs (bDMARDs) of only 46% compared with 65% for patients on conventional synthetic (cs)DMARDs and 84% for patients who never received immunosuppressive therapy (Bizjak, 2020).

In 2011, the European Alliance of Associations for Rheumatology (EULAR) established recommendations on vaccinations in children with autoimmune inflammatory rheumatic diseases. At that time, no data was available on human papillomavirus (HPV) vaccination, only one article was available on pneumococcal vaccination, COVID-19 vaccines did not yet exist, and little information existed on the safety and immunogenicity of live-attenuated vaccines. In addition, there were hardly any studies into the effect of bDMARDs on the safety and immunogenicity of vaccinations. Many recommendations were based on extrapolation of data from adult patients. Nowadays, the evidence in pediatric patients has at least doubled and an 2021 update of the EULAR/PRES recommendations was therefore published in 2022. The safety of the live-attenuated measles–mumps–rubella (MMR) and varicella zoster virus (VZV) vaccines has been studied in pediatric patients with autoimmune inflammatory rheumatic diseases (pedAIIRD) patients, including patients using methotrexate (MTX) and bDMARDs. Also, data on the safety and immunogenicity of HPV vaccinion in pedAIIRD patients has been published, as well as data on long-term immunogenicity of various vaccines. Data on immunogenicity in relation to biologicals (mainly tumor necrosis factor alpha inhibitors (TNFi)) have become available. After a systematic literature review, 6 overarching principles and 7 recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement.

In summary, it is recommended that the treating specialist should assess patients’ vaccination status annually. In general, the NIP should be followed for all patients with pedAIIRD, with few exceptions. If possible, vaccinations should be administered during quiescent disease and prior to immunosuppressive treatment, but immediately required treatment should never be postponed because of vaccinations. Protection as based on antibody levels (i.e., seroprotection) is often preserved in immunosuppressed patients following (re)vaccinations except for those on specific agents including high dose glucocorticoids, mycophenolate mofetil and B-cell depleting therapies (Barbati, 2022; Kohagura, 2021; Oesterreich, 2020; Stich, 2023). Regarding live-attenuated vaccines, the MMR booster can be administered safely to patients on MTX and can even be considered in patients on glucocorticoids and specified bDMARDS (TNFi, anti-IL1 and anti-IL6 therapy). The primo MMR vaccine cannot be administered to immunosuppressed patients, but this is less of a problem as most patients already had this vaccination before diagnosis. Finally, additional vaccinations not included in the NIP as standard may be considered: The yearly influenza vaccination should be strongly considered in all pedAIIRD patients and physicians should strongly consider the VZV vaccination in varicella naive patients, also whilst on MTX. They also should consider VZV vaccination in varicella naive patients on low dose glucocorticosteroids, TNFi, anti-IL1 and anti-IL6 therapy. The live-attenuated yellow fever (YF) vaccination should be avoided in all immunosuppressed pedAIIRD patients. These recommendations provide guidance to practitioners in daily practice to attain optimal infection prevention in immunocompromised patients with pedAIIRD.

In this national guideline, vaccinations recommendations are made for JIA patients in the Netherlands, mainly based on the 2021 EULAR/PRES recommendations, completed with new studies on covid-19 and Meningococcal ACWY conjugate vaccination. For recommendations about the use of biologicals in pregnancy, we refer to the guideline ‘Medicatiegebruik tijdens de zwangerschap’.

In this guideline, we use the definition of immunosuppressive therapy based on the EULAR guideline and the Landelijke Coördinatie Infectieziekten bestrijding (LCI) guideline. In these guidelines, a dose dependant immunosuppressive effect of prednisone is considered: prednisolone is considered as ‘immunosuppressive’ in children at a dose of ≥0.5 mg/kg/day or above the range of 10-20 mg/day for ≥2 weeks. csDMARDS are considered immunosuppressive at the following doses: cyclosporine >2.5 mg/kg/day, azathioprine ≥3 mg/kg/day, cyclophosphamide oral >2.0 mg/kg/day, leflunomide ≥0.5 mg/kg / day, mycophenolate mofetil ≥30 mg/kg/day or >1000 mg/day, MTX ≥15 mg/m2/week or ≥25 mg/week, tacrolimus >1.5 mg/day). All patients are considered immunocompromised when using bDMARDS or targeted synthetic (ts)DMARDS (e.g. JAK inhibitors). Finally, patients are considered immunocompromised when using a combination of the above drugs, regardless of dosage.

Conclusies / Summary of Findings

Live attenuated vaccines (VZV and MMR)

VZV

Efficacy

Very low GRADE

Live attenuated vaccines (VZV) may have similar efficacy in JIA patients when compared with controls, but the evidence is very uncertain.

Source: Groot, 2017

Immunogenicity

Very low GRADE

VZV vaccines may have similar immunogenicity in JIA patients when compared with controls, but the evidence is very uncertain.

Source: Groot, 2017.

Safety – adverse events

No GRADE

No evidence was found regarding the effect of VZV vaccines on– adverse events in JIA patients compared with controls.

Safety – disease activity

Very low GRADE

VZV vaccines may have similar effects on disease activity in JIA patients when compared with controls, but the evidence is very uncertain.

Source: Groot, 2017.

MMR

Efficacy

No GRADE

No evidence was found regarding the effect of MMR vaccines on efficacy in JIA patients compared with controls.

Immunogenicity

Very low GRADE

MMR vaccines may have similar immunogenicity in JIA patients when compared with controls, but the evidence is very uncertain.

Sources: Heijstek, 2013, Heijstek, 2012; Ingelman-Sundberg, 2016.

Safety – adverse events

Low GRADE

MMR vaccines may have similar effects on adverse events in JIA patients when compared with controls.

Source: Heijstek, 2013.

Safety – disease activity

Low GRADE

MMR vaccines may have similar effects on disease activity in JIA patients when compared with controls.

Source: Heijstek, 2013.

Inactivated vaccines

DTP

Efficacy

No GRADE

No evidence was found regarding the effect of DTP vaccines on efficacy in JIA patients compared with controls.

Immunogenicity

Very low GRADE

DTP vaccines may induce less immunogenicity in JIA patients compared with controls, but the evidence is very uncertain.

Sources: Brunner, 2020; Ingelman-Sundberg, 2016; Heijstek, 2012

Safety – adverse events

Very low GRADE

DTP vaccines may have similar effect on adverse events in JIA patients when compared with controls, but the evidence is very uncertain.

Source: Brunner, 2020

Safety – disease activity

No GRADE

No evidence was found regarding the effect of DTP vaccines on disease activity in JIA patients compared with controls.

Bi-valent HPV

Efficacy

No GRADE

No evidence was found regarding the effect of HPV2 vaccines on efficacy in JIA patients compared with controls.

Immunogenicity

Low GRADE

HPV2 vaccines may have similar immunogenicity in JIA patients when compared with healthy controls.

Sources: Heijstek, 2014; Esposito, 2014

Safety – adverse events

Low GRADE

HPV2 vaccines may have similar effect on adverse events in JIA patients when compared with controls.

Sources: Heijstek, 2014; Esposito, 2014

Safety – disease activity

Low GRADE

HPV2 vaccines may have similar effect on disease activity in JIA patients when compared with controls.

Sources: Heijstek, 2014; Esposito, 2014

HBV/HAV

Efficacy

No GRADE

No evidence was found regarding the effect of HBV/HAV vaccines on efficacy in JIA patients compared with controls.

Immunogenicity

Very low GRADE

HBV/HAV vaccines may induce less immunogenicity in JIA patients compared with control, but the evidence is very uncertain.

Sources: Çakmak, 2022; Erguven, 2010

Safety – adverse events

Very low GRADE

HBV/HAV vaccines may have similar effect on adverse events in JIA patients compared with controls, but the evidence is very uncertain.

Source: Erguven, 2010

Safety – disease activity

No GRADE

No evidence was found regarding the effect of HBV/HAV vaccines on efficacy in JIA patients compared with controls.

MenC conjugate

Efficacy

No GRADE

No evidence was found regarding the effect of MenC conjugate vaccines on efficacy in JIA patients compared with controls.

Immunogenicity

Very low GRADE

MenC conjugate vaccines may have similar immunogenicity in JIA patients compared with controls, but the evidence is very uncertain.

Source: Stoof, 2014

Safety – adverse events

No GRADE

No evidence was found regarding the effect of MenC conjugate vaccines on adverse events in JIA patients compared with controls.

Safety – disease activity

No GRADE

No evidence was found regarding the effect of MenC conjugate vaccines on disease activity in JIA patients compared with controls.

PCV/PPV23

Efficacy

Very low GRADE

PCV/PPV23 vaccines may have similar efficacy in JIA patients using etanercept compared with JIA patients using methotrexate, but the evidence is very uncertain.

Source: Aikawa, 2015

Immunogenicity

Very low GRADE

PCV/PPV23 vaccines may have similar immunogenicity in JIA patients using etanercept compared with JIA patients using methotrexate, but the evidence is very uncertain.

Source: Aikawa, 2015

Safety – adverse events

Very low GRADE

PCV/PPV23 vaccines may have similar effect on adverse events in JIA patients using etanercept compared with JIA patients using methotrexate, but the evidence is very uncertain.

Source: Aikawa, 2015

Safety – disease activity

Very low GRADE

PCV/PPV23 vaccines may have similar effect on disease activity in JIA patients using etanercept compared with JIA patients using methotrexate, but the evidence is very uncertain.

Source: Aikawa, 2015

Influenza

Efficacy

Very low GRADE

Influenza vaccines may have similar efficacy in JIA patients compared with controls, but the evidence is very uncertain.

Sources: Toplak, 2012; Carvalho, 2013

Immunogenicity

Very low GRADE

Influenza vaccines may have similar immunogenicity in JIA patients compared with controls, but the evidence is very uncertain.

Sources: Aikawa, 2012; Aikawa, 2013; Carvalho, 2013; Toplak, 2012; Woerner, 2011; Dell’Era, 2012; Camacho-Lovillo, 2017

Safety – adverse events

Very low GRADE

Influenza vaccines may have similar effect on adverse events in JIA patients compared with controls, but the evidence is very uncertain.

Sources: Dell’Era, 2012; Camacho-Lovillo, 2017; Toplak, 2012; Woerner, 2011

Safety – disease activity

Very low GRADE

Influenza vaccines may have similar effect on disease activity in JIA patients compared with controls, but the evidence is very uncertain.

Sources: Aikawa, 2013; Carvalho, 2013; Dell’Era, 2012; Camacho-Lovillo, 2017

Covid-19 mRNA vaccine of BioNTech/Pfizer

Efficacy

Low GRADE

Covid-19 mRNA vaccines may have similar efficacy in JIA patients compared with controls.

Source: Ziv, 2022

Immunogenicity

No GRADE

No evidence was found regarding the effect of Covid-19 vaccines on immunogenicity in JIA patients compared with controls.

Safety – adverse events

Low GRADE

Covid-19 mRNA vaccines may have similar effect on adverse events in JIA patients compared with controls.

Source: Ziv, 2022

Safety – disease activity

Very low GRADE

Covid-19 mRNA vaccines may have similar effect on disease activity in JIA patients compared with controls, but the evidence is very uncertain.

Source: Udaondo, 2022

Samenvatting literatuur

Description of studies

All but two studies were cohort studies, the study of Udaondo (2022) was an observational study and the study of Heijstek (2013) was a randomized trial. In total, 1681 JIA patients were included in the intervention groups and 6487 participants in the control groups. Most studies assessed the effect of influenza vaccine (n=7), followed by MMR (n=3) and DPT (n=3) vaccines. The majority of studies (n=16) included healthy controls in the control group. Most studies had a follow-up period of 12 months. Immunogenicity was assessed by all studies except Ziv (2022) and Udoando (2022), efficacy by five studies, adverse events (safety) by 11 studies, and disease activity (safety) by ten studies. Four studies assessed the outcomes for live-attenuated vaccines, i.e., VZV and MMR vaccines.

No studies researching rotavirus and tsDMARDs (JAK inhibitors) were found in the search.

Results

Results per outcome measure and vaccine are depicted in the tables below. Studies could not be pooled, due to heterogeneity in population, study design, and used vaccines.

Table 1. Study characteristics and outcomes for the outcome measure efficacy

First author, year	Vaccine	Patients	Medication used^a	Follow-up	Result	Effect of medication on results
PCV/PPV
Aikawa, 2015	PPV23	IG: n=17 JIA patients pre-etanercept CG: n=10 JIA patients using MTX	IG: MTX HD 2 weeks before ETA. CG: 10 LD MTX.	12 months	Invasive pneumococcal disease in 1 patient on TNFi: serotype NA	One patient using anti-TNF with IPD
Influenza
Toplak, 2012	Influenza (H1N1, H3N2, Influenza B)	IG: n=31 JIA patients CG: n=14 HC and n=31 not vaccinated JIA patients	18 NSAID, 2 DMARD, 7 DMARD + GC, 4 TNF	6 months	Equal influenza in JIA vs HC. Influenza infection in 1 vaccinated vs 4 unvaccinated patients.	Not reported
Carvalho, 2013	Influenza (H1N1, H3N2, B/Florida)	IG: n=44 JIA patients CG: n=10 healthy controls	IS in 34-44%	180 days	Positive influenza samples in 5/14 vs 1/7 patients. ILI increase in unvaccinated vs vaccinated.	Not reported
VZV (live-attenuated vaccine)
Groot, 2017	VZV (Oka strain, Varilrix as second dose)	IG: n=49 in total, 39 JIA patients CG: n=18 HC	49 MTX, 16 GCs, 3 biologicals	4-6 weeks after vaccination	N=3 patients with low antibody concentrations after vaccination had an episode of chickenpox at least 1 year after vaccination. The course of the episode was similar to health children.	When patients received the vaccination, one used abatacept, one MTX monotherapy, and one MTX and corticosteroids.
Covid-19
Ziv, 2022	Covid-19 (BNT162b2 mRNA vaccine)	IG: n=1639 patients with IRD, of which 380 with JIA CG: n=524.471 HC	Not reported	21.6 weeks [interquartile range (IQR) 14.7–39.1], 19.0 weeks (IQR 13.6–36.9) and 8.9 weeks (IQR 7.3–11.6) after one, two and three doses of vaccine, respectively.	COVID-19 infection after one dose of vaccination JIA: 0% Control: 12.6% P<0.01	Not reported

_{AB, antibody; ABT, abatacept; ADA, adalimumab; AE, adverse event; ANR, Anakinra; AZA, azathioprine; bDMARD, biological disease modifying anti-rheumatic drugs; CAM, canakinumab CG, control group; Cy, cyclophosphamide; CYC, cyclosporine; DTP, diphtheria tetanus pertussis; ETN, etanercept; GC, glucocorticosteroids; GMT, geometric mean titer; HC, healthy controls; HAV, hepatitis A virus; HBV, hepatitis B virus; HCQ, hydroxychloroquine; IBD, inflammatory bowel disease; IG, intervention group; IgG, immunoglobulinG; IFX, infliximab; ILI, influenza like illness; IRD, immune rheumatic diseases; IS, immunosuppression; IVIG, intravenous immunoglobulines; JIA, juvenile idiopathic arthritis; LEF, leflunomide; MMR(/V), measles mumps rubella (/varicella); MMF, mycophenolic acid; MV, measles vaccine; 6-MP, 6-mercaptopurine; MTX, methotrexate; NSAID, non-steroid anti-inflammatory drug; pts, patients; RAI, relative avidity index; RTX, rituximab; SAE, severe adverse event; SC, seroconversion; SP, seroprotection; SFU, spot forming units; TBE, tick-borne-encephalitis; TBEV, tick-borne-encephalitis virus; TCZ, tocilizumab; Thiopur, thiopurine; TNFi, tumor necrosis factor inhibitor; TT, tetanus toxoid; vacc, vaccine; VZV, varicella zoster virus;}

_{a Medication used in the intervention group, unless reported different. Numbers represent amount of patients using that medication}

Table 2. Study characteristics and outcomes for the outcome measure immunogenicity

First author, year	Vaccine	Patients	Medication used^a	Follow-up	Result	Effect of medication on results
DPT
Brunner, 2020	DT	IG: n=29 JIA patients CG: n=17 JIA patients not vaccinated	29 ABT, 22 MTX, 3 LD-GC	24 months	100% SP tetanus, 90% SP diphtheria 2 m post vaccine.	All patients had protective antibody levels to tetanus after ≥2 months of abatacept treatment and 26/29 (89.7%) patients had protective antibody levels to diphtheria.
Ingelman-Sundberg, 2016^b	DTP	IG: n=50 in total, 46 JIA patients CG: n=31 HC	10 NSAID, 8 MTX, 32 MTX+TNFi	Not applicable	IgG-TT reduced in MTX+TNFi group.	Patients treated with any DMARD had lower tetanus serum IgG compared to healthy controls and NSAID-treated patients.
Heijstek, 2012^b	DT	IG: n=400 JIA patients CG: n=2176 HC	93 MTX, 8 TNFi, 28 GC 10 mg/day	Not applicable	Reduced SP and GMT for tetanus.	Methotrexate use and glucocorticosteroid use did not have any effect on pathogen-specific GMT or seroprotection rates.
HPV
Heijstek, 2014	HPV-b(Cervarix vaccine)	IG: n=68 JIA patients CG: n=55 HC	24 MTX, 9 TNFi, 6 other DMARD	12 months	Equal SC and GMT in JIA and HC.	Methotrexate did not affect HPV16 or HPV18 antibodies. No difference in antibody concentrations in patient with anti-TNF, but the sample size was too small to draw definite conclusions.
Esposito, 2014	HPV-b (Cervarix vaccine)	IG: n=21 JIA patients CG: n=55 HC	10 NSAID, 5 MTX, 6 TNFi	7 months	100% SC. Reduced titers 1 month post 3th vaccine in JIA vs HC. No effect of medication.	No effect on immune response of NSAIDs, methotrexate, and etanercept.
HBV/HAV
Çakmak, 2022	Hepatitis B	IG: n=262 JIA patients CG: n=274 HC	Not reported	Not applicable	Anti-Hbs antibody: JIA patients: 59.1% Control: 72.9%, p=0.002. HbsAG positivity: N=0 in both groups Median anti-HBs titers JIA patients: 14 (range 0-1000) IU/L Control: 43.3 (range 0-1000) IU/L, p=0.01 Anti-nuclear antibody positivity JIA patients: 27.1%. Among these, anti-Hbs antibody seropositivity rate was 69.1% (n=49) while this rate was 56.2% (n=104) in the remaining ANA negative cases (n=185) (p=0.04).	Four patients were negative for anti-Hbs and were receiving DMARDs (methotrexate=1, sulfasalazine=1) and biological agents (etanercept=1, adalimumab=1)
Erguven, 2010	Hepatitis A	IG: n=47 JIA patients CG: n=67 HC	4 anti-TNF, 5 NSAIDs, 29 MTX, 12 prednisolone, 19 salazopyrine, 11 MTX-prednisolone	2 months after second dose	Positive anti-HAV IgG (n (%)): JIA: 43 (91.5%) Control: 67 (100%)	Four patients (3.5%) had negative titers, these were all male patients with active systemic JIA and using anti-TNF.
MenC
Stoof, 2014	MenC conjugate (NeisVac-C) vaccine	IG: n=127 JIA patients CG: n=1527 HC	42 MTX, 66 pre-MTX, 7 NA bDMARD, 53 pre-, 4 GC, 10 pre-GC	Not applicable	Equal SP 4 years post vaccine JIA vs HC. MenC-IgG decrease over time.	Starting methotrexate treatment did not affect the decline of MenC-specific IgG concentrations. However, starting biological treatment induced a trend towards accelerated decay in MenC-specific antibodies, with a faster predicted decay rate in 92.6% of patients.
PCV/PPV
Aikawa, 2015	PPV23	IG: n=17 JIA patients pre-etanercept CG: n=10 JIA patients using MTX	IG: MTX HD 2 weeks before ETA CG: 10 LD MTX	12 months	Equal SC at 2 (53 vs. 30%) and 12 months (36 vs. 40%) in JIA with and without TNFi.	Adequate vaccine response was similar between patients with anti-TNF and without anti-TNF.
Influenza
Aikawa, 2012	H1N1	IG: n=237 in total, 93 JIA patients CG: n=91 HC	90 GC, MTX 74, 43 AZA, 23 CYC, 13 MMF, 6 LEF, 3 Cy	21 days	Subgroup analysis: N=93 Before immunization, % (95%CI) 20.4 (12.2–28.6) After immunization, % (95%CI) 88.2 (81.6–94.8) Seroconversation rate, % (95%CI) 82.8 (75.1–90.5) (p<0.05)	Not reported
Aikawa, 2013	H1N1	IG: n=95 JIA patients CG: n=91 HC	16 TNFi, 63 DMARD(s)	3 weeks	Equal SP and GMT. Reduced SC in pts, irresp.of TNF/MTX	No difference in immunogenicity between patients with and without immunosuppressive drugs, and with and without MTX and with and without TNF blockers.
Carvalho, 2013	Influenza (H1N1, H3N2, B/Florida)	IG: n=44 JIA patients CG: n=10 healthy controls	IS, DMARDs, or anti-TNFα ranging from 55.7% to 70%	180 days	Equal SP & SC in JIA and HC. TNFi lower SP and SC for H1N1 but SP for h3N2 &B/Florida was normal (N = not reported).	Patients on anti-TNFα drugs presented lower seroconversion (p = 0.03) and seroprotection (60%) responses to H1N1 strain, but the seroprotection above the cut-off levels to the other strains: H3N2 (100%) and B/Florida (80%).
Toplak, 2012	Influenza (H1N1, H3N2, Influenza B)	IG: n=31 JIA patients CG: n=14 HC and n=31 not vaccinated JIA patients	18 NSAID, 2 DMARD, 7 DMARD + GC, 4 TNF	6 months	Equal SP pts and HC	GMTs for all vaccine viruses were significantly elevated 1 months after vaccination in patients using DMARDs. The group of 4 children with anti-TNF treatment did not respond significantly to any of the vaccine viruses. After 6 months, all 4 children with anti-TNF had protective titers but did not respond significantly as a group. Compared to the GMTs before vaccination, the values after 6 months were still significantly elevated for the Influenza B vaccine virus in both study groups including children treated with DMARDs, but not in a subgroup of 4 children also receiving anti-TNF-α therapy.
Woerner, 2011	Influenza (H1N1, H3N2, H1N1 MDCK cell adapted, H3N2 MDCK adapted, and influenza B MDCK adapted)	IG: n=34 in total, of which n=25 JIA patients CG: n=16 HC	18 MTX, 10 TNFi, 8 MTX+TNFi	4-8 weeks after single dose or after the second of two doses.	Equal SP pts vs. HC, reduced GMT.	Subgroup analysis for immunosuppressive medication (MTX vs. TNFα inhibitors vs. MTX and TNFα inihibitors) showed no significant differences between the treatment groups in seroprotection, seroconversion or post-vaccination GMTs. Treatment with TNFα inhibitors showed a trend toward a lower relative change between pre-vaccination and post-vaccination titers in comparison to treatment with MTX (p 0.06 resp. 0.66).
Dell’Era, 2012	Influenza (M59 adjuvanted, with H1N1, H3N2, and influenza B)	IG: n=60 JIA patients CG: n=30 HC	30 DMARD vs. 30 aTNF (Etanercept)	3 months	Equal SP & SC in JIA and HC. TNFi lower H1N1-GMT & more rapid decline in H3N2-GMT	All, except in one, 100% seroconversation and seroprotection in JIA patients treated with etanercept and DMARDs after follow-up. There was no difference in the B antigen immunogenicity endpoints between the DMARD-treated JIA patients and HC
Camacho-Lovillo, 2017	Influenza (H1N1, H3N2, B)	IG: n=25 JIA patients CG: n=6 healthy siblings	15 anti-TNFα (11 etanercept and 4 adalimumab), 4 anti-IL-1R (anakinra), 6 anti-IL-6R (tocilizumab)	1 year	SP after 4–8 weeks: 97.8% H1N1, 95.6% H3N2, 91.1% B.	No differences were observed in the short-time and long-time (after 1 year) antibody response and postvaccination seroprotection, GMT, and seroconversion rates to vaccination based on treatment. No difference in seroprotection or antibody titers in patients with biological treatment and concomitant systemic steroids (n=2), compared with patients with biological treatment with no steroids
MMR (live-attenuated vaccine)
Heijstek, 2013	MMR (MMR-NVI and M-M-RVAXPRO)	IG: n=68 vaccinated JIA patients CG: n=69 unvaccinated JIA patients	60 MTX, 15 biologicals, 3 GC	12 months	SP and GMT higher in vacc. vs. controls	Revaccinated patients taking biologics at the time of revaccination were seroprotected. One patient was taking methotrexate, 9.3 mg/m2 per week, at the time of vaccination and showed a small increase in mumps-specific antibodies at 3 months, but antibodies dropped below seroprotection levels at 12 months. Another patient using methotrexate was started just after vaccination, followed by etanercept at 9 months. This patient was seronegative for measles, mumps, and rubella at baseline and failed to produce a serologic response to mumps, whereas measles-specific antibodies increased 17-fold and rubella-specific antibodies 179-fold.
Heijstek, 2012^b	MMR	IG: n=400 JIA patients CG: n=2176 HC	93 MTX, 8 TNFi, 28 GC 10 mg/day	Not applicable	Reduced SP and GMT for mumps, rubella, but not measles.	Methotrexate use and glucocorticosteroid use did not have any effect on pathogen-specific GMT or seroprotection.
Ingelman-Sundberg, 2016^b	MMR	IG: n=50 in total, 46 JIA patients CG: n=31 HC	10 NSAID, 8 MTX, 32 MTX+TNFi	Not applicable	Equal IgG titers MV and RV, IgG-TT reduced in MTX+iTNF group. Vacc.-spec. mem. B cells preserved in patients with booster	No difference in measles and rubella titers rates between patients using DMARDs and patients using NSAIDs and HC.
VZV (live-attenuated vaccine)
Groot, 2017	VZV (Oka strain, Varilrix as second dose)	IG: n=49 in total, 39 JIA patients CG: n=18 HC	49 MTX, 16 GCs, 3 biologics	4-6 weeks after vaccination	Equal GMT in pts & HC, more VZV-spec. T cells.	Type of immunosuppressive drug did not have a significant effect on humoral response (p = 0.203) but patients who used biologics at time of vaccination of the first vaccination (n = 3) did not show an increase in antibody concentrations after vaccination. Of the two patients who used biologics and received two vaccines, one (using etanercept) responded to the second vaccine and one (using abatacept) did not.

_{AB, antibody; ABT, abatacept; ADA, adalimumab; AE, ad verse event;ANR, Anakinra; AZA, azathioprine; bDMARD, biological disease modifying anti-rheumatic drugs;CAM, canakinumab; CG, control group; Cy, cyclophosphamide; CYC, cyclosporine; DTP, diphtheria tetanus pertussis; ETN, etanercept; GC, glucocorticosteroids; GMT, geometric mean titer; HAV, hepatitis A virus; HBV, hepatitis B virus; HC, healthy controls; IBD, inflammatory bowel disease; IFX, infliximab; IG, intervention group; IgG, immunoglobulin G; HCQ, hydroxychloroquine; IRD, immune rheumatic diseases; IS, immunosuppression; IVIG, intravenous immunoglobulines; JIA, juvenile idiopathic arthritis; LEF, leflunomide; MMF, mycophenolic acid; MMR(/V), measles mumps rubella (/varicella); 6-MP, 6-mercaptopurine; MTX, methotrexate; MV, measles vaccine; NSAID, non-steroid anti-inflammatory drug; pts, patients; RAI, relative avidity index; RD, rheumatic diseases; RTX, rituxim; SAE, severe adverse event; SC, seroconversion; SFU, spot forming units; SP, seroprotection; TBE, tick-borne-encephalitis; TBEV, tick-borne-encephalitis virus; TCZ, tocilizumab; Thiopur, thiopurine; TNFi, tumor necrosis factor inhibitor; TT, tetanus toxoid; vacc, vaccine; VZV, varicella zoster virus}

_{aMedication used in the intervention group, unless reported different. Numbers represent amount of patients using that medication.}

_{b Studies are reported twice due to use of two different vaccines}

Table 3. Study characteristics and outcomes for the outcome measure safety – adverse events

First author, year	Vaccine	Patients	Medication used^a	Follow-up	Result	Effect of medication on results
DPT
Brunner, 2020	DT	IG: n=29 JIA patients using abatacept CG: n=17 JIA patients not vaccinated using abatacept	All ABT, 22 MTX, 3 LD-GC	24 months	SAE 4, AE 29 (all ABT – no vaccine related)	Not reported
HPV
Heijstek, 2014	HPV-b(Cervarix vaccine)	IG: n=68 JIA patients CG: n=55 HC	24 MTX, 9 TNFi, 6 other DMARD	12 months	AE similar in JIA and HC, no SAE	Not reported
Esposito, 2014	HPV-b (Cervarix vaccine)	IG: n=21 JIA patients CG: n=55 HC	10 NSAID, 5 MTX, 6 TNFi	7 months	Similar AE as HC	Not reported
HBV/HAV
Erguven, 2010	Hepatitis A	IG: n=47 JIA patients CG: n=67 HC	4 anti-TNF, 5 NSAIDs, 29 MTX, 12 prednisolone, 19 salazopyrine, 11 MTX-prednisolone	2 months after second dose	No side effects were encountered in any of the patients. No reactivation was seen and there was no increment in CHAQ scores.	Not reported
PCV/PPV
Aikawa, 2015	PPV23	IG: n=17 JIA patients pre-etanercept CG: n=10 JIA patients using MTX	IG: MTX HD 2 weeks before ETA CG: 10 LD MTX	12 months	No increased AE.	1 patient without anti-TNF had redness and swelling in the injection site. No difference in upper respiratory tract infections between patients with and without anti-TNF (n=11, 60% vs n=3 (30%) respectively, p=0.12)
Influenza
Dell’Era, 2012	Influenza (M59 adjuvanted, with H1N1, H3N2, and influenza B)	IG: n=60 JIA patients CG: n=30 HC	30 DMARD vs. 30 aTNF (Etanercept)	3 months	AE similar in JIA and HC	No AEs directly related to medication
Camacho-Lovillo, 2017	Influenza (H1N1, H3N2, B)	IG: n=25 JIA patients CG: n=6 healthy siblings	15 anti-TNFα (11 etanercept and 4 adalimumab), 4 anti-IL-1R (anakinra), 6 anti-IL-6R (tocilizumab)	1 year	No severe AE were observed. 7/41 local reactions, 2/41 systemic AE: drug reactions	Two (4.9%) had systemic adverse drug reactions (one in control and one in biological treatment group). 11 patients had febrile episodes, not related to vaccination (four in the non-biological and seven in the biological therapy group)
Toplak, 2012	Influenza (H1N1, H3N2, Influenza B)	IG: n=31 JIA patients CG: n=14 HC	18 NSAID, 2 DMARD, 7 DMARD + GC, 4 TNF	6 months	Similar AE	Not reported
Woerner, 2011	Influenza (H1N1, H3N2, H1N1 MDCK cell adapted, H3N2 MDCK adapted, and influenza B MDCK adapted)	IG: n=34 in total, of which n=25 JIA patients CG: n=16 HC	18 MTX, 10 TNFi, 8 MTX+TNFi, 16 no medication	4-8 weeks after single dose or after the second of two doses.	Similar AE	No difference in AE between immunosuppressed and immunocompetent group.
MMR (live-attenuated vaccine)
Heijstek, 2013	MMR (MMR-NVI and M-M-RVAXPRO)	IG: n=68 vaccinated JIA patients CG: n=69 unvaccinated JIA patients	60 MTX, 15 biologicals, 3 GC	12 months	No MMR infections induced by vaccination	Not reported
Covid-19
Ziv, 2022	Covid-19 (BNT162b2 mRNA vaccine)	IG: n=1639 patients with IRD, of which 380 with JIA CG: n=524.471 HC	Not reported	21.6 weeks [interquartile range (IQR) 14.7–39.1], 19.0 weeks (IQR 13.6–36.9) and 8.9 weeks (IQR 7.3–11.6) after one, two and three doses of vaccine, respectively.	One patient with JIA (0.12%) was hospitalized due to COVID-19 infection, compared with 0.08% in the control group.	Not reported

_{AB, antibody; ABT, abatacept; ADA, adalimumab; AE, adverse event; ANR, Anakinra; AZA, azathioprine; bDMARD, biological disease modifying anti-rheumatic drugs; CAM, canakinumab; CG, control group; CYC, cyclosporine; Cy, cyclophosphamide; DTP, diphtheria tetanus pertussis; ETN, etanercept; GC, glucocorticosteroids; GMT, geometric mean; HAV, hepatitis A virus; HBV, hepatitis B virus; HC, healthy controls; pts, patients; HCQ, hydroxychloroquine; IBD, inflammatory bowel disease; IFX, infliximab; IG, intervention group; IgG, immunoglobulin G; IRD, immune rheumatic diseases; IS, immunosuppression; IVIG, intravenous immunoglobulines; JIA, juvenile idiopathic arthritis; LEF, leflunomide; MMF, mycophenolic acid; MMR(/V), measles mumps rubella (/varicella); 6-MP, 6-mercaptopurine; MTX, methotrexate; MV, measles vaccine; NSAID, non-steroid anti-inflammatory drug; RAI, relative avidity index; RD, rheumatic diseases; RTX, rituxim; SAE, severe adverse event; SC, seroconversion titer; SFU, spot forming units; SP, seroprotection; TBE, tick-borne-encephalitis; TBEV, tick-borne-encephalitis virus; TCZ, tocilizumab; Thiopur, thiopurine; TNFi, tumor necrosis factor inhibitor; TT, tetanus toxoid; vacc, vaccine; VZV, varicella zoster virus;}

_{^a Medication used in the intervention group, unless reported different. Numbers represent amount of patients using that medication}

Table 4. Study characteristics and outcomes for the outcome measure safety – disease activity

First author, year	Vaccine	Patients	Medication used^a	Follow-up	Result	Effect of medication on results
HPV
Heijstek, 2014	HPV-b (Cervarix vaccine)	IG: n=68 JIA patients CG: n=55 HC	24 MTX, 9 TNFi, 6 other DMARD	12 months	Stable DA 1 year post vaccine	Not reported
Esposito, 2014	HPV-b (Cervarix vaccine)	IG: n=21 JIA patients CG: n=55 HC	10 NSAID, 5 MTX, 6 TNFi	7 months	No increase in JADAS-27	Not reported
PCV/PPV
Aikawa, 2015	PPV23	IG: n=17 JIA patients pre-etanercept CG: n=10 JIA patients using MTX	IG: MTX HD 2 weeks before ETA. CG: 10 LD MTX.	12 months	Stable DA in JIA patients	Significant decrease in DA parameters over time in patients with anti-TNF compared with patients without anti-TNF.
Influenza
Aikawa, 2013	H1N1	IG: n=95 JIA patients CG: n=91 HC	16 TNFi, 63 DMARD(s)	3 weeks	DAS stable	Not reported
Carvalho, 2013	Influenza (H1N1, H3N2, B/Florida)	IG: n=44 JIA patients CG: n=10 HC	IS in 34-44%	180 days	Equal ACRped30 pre and post vaccination	Not reported
Dell’Era, 2012	Influenza (M59 adjuvanted, with H1N1, H3N2, and influenza B)	IG: n=60 JIA patients CG: n=30 HC	30 DMARD vs. 30 aTNF (Etanercept)	3 months	Stable DA during follow-up	Not reported
Camacho-Lovillo, 2017	Influenza (H1N1, H3N2, B)	IG: n=25 JIA patients CG: n=6 healthy siblings	15 anti-TNFα (11 etanercept and 4 adalimumab), 4 anti-IL-1R (anakinra), 6 anti-IL-6R (tocilizumab)	1 year	No flares, increased JADAS in 6pt	Not reported
MMR (live-attenuated vaccine)
Heijstek, 2013	MMR (MMR-NVI and M-M-RVAXPRO)	IG: n=68 vaccinated JIA patients CG: n=69 unvaccinated JIA patients	60 MTX, 15 biologicals, 3 GC	12 months	Stable DA, incl. pts on biologicals	No difference in JADAS-27 score between patients with MMR booster and control group in patients taking methotrexate (JADAS-27 difference over time, 0.02; 95% CI, -1.1 to 1.2) or biologics (JADAS-27 difference over time, 0.6; 95% CI, -1.2 to 2.4) No difference in relative risk of a flare between revaccinated patients and controls in patients using methotrexate or biologics (although small patient number precluded definite conclusions).
VZV (live-attenuated vaccine)
Groot, 2017	VZV (Oka strain, Varilrix as second dose)	IG: n=49 in total, 39 JIA patients CG: n=18 HC	49 MTX, 16 GCs, 3 biologicals	4-6 weeks after vaccination	3 patients had a slight increase in JADAS-71 score after vaccination (median JADAS increase: 1)	Three patients (one using MTX, corticosteroids and ciclosporine; one using MTX and corticosteroids and one using MTX per day and corticosteroids) reported having mild temperature elevation and a mild vesicular rash within the first two weeks after vaccination, compared with one HC having fever after vaccination.
Covid-19
Udaondo, 2022	Covid-19 (BNT162b2 mRNA vaccine)	IG: n=40 in total, 26 JIA patients CG: n=24 HC	35 immunosuppressive treatment, 11 adalimumab, 9 etanercept, 3 infliximab, 5 mycophenolate mofetil, 5 baricitinib, 1 cyclosporine, 14 methotrexate between 10 and 15 mg/m2/weekly combined with other treatment.	3 weeks after complete vaccination regime	No inflammatory arthritis flares in JIA patients were reported, in the context of either vaccination time points.	Not reported

_{AB, antibody; ABT, abatacept; ADA, adalimumab; AE, adverse event; ANR, Anakinra; AZA, azathioprine; bDMARD, biological disease modifying anti-rheumatic drugs; CAM, canakinumab; CG, control group; Cy, cyclophosphamide; CYC, cyclosporine; DTP, diphtheria tetanus pertussis; ETN, etanercept; GC, glucocorticosteroids; GMT, geometric mean titer; HAV, hepatitis A virus; HBV, hepatitis B virus; HC, healthy controls; pts, patients; IBD, inflammatory bowel disease; IFX, infliximab; IG, intervention group; IgG, immunoglobulin G; IRD, immune rheumatic diseases; IS, immunosuppression; IVIG, intravenous immunoglobulines; HCQ, hydroxychloroquine; JIA, juvenile idiopathic arthritis; LEF, leflunomide; MMF, mycophenolic acid; MMR(/V), measles mumps rubella (/varicella); 6-MP, 6-mercaptopurine; MTX, methotrexate; MV, measles vaccine; NSAID, non-steroid anti-inflammatory drug; RAI, relative avidity index; SAE, severe adverse event; RD, rheumatic diseases; RTX, rituxim; SC, seroconversion; SP, seroprotection; SFU, spot forming units; TBE, tick-borne-encephalitis; TBEV, tick-borne-encephalitis virus; TCZ, tocilizumab; Thiopur, thiopurine; TNFi, tumor necrosis factor inhibitor; TT, tetanus toxoid; vacc, vaccine; VZV, varicella zoster virus;}

_{^a Medication used in the intervention group, unless reported different. Numbers represent amount of patients using that medication}

Table 5 describes the effect of medication on the results. However, as this was not part of the search question, this table is presented in an informative and narrative manner and no assessment of the level of evidence is performed.

Table 5. The effect of different medication on the outcomes efficacy, immunogenicity, and safety

N reported in the table is the amount of patients in the intervention group using that medication

Medication	Effect of medication on efficacy	Effect of medication on safety – adverse events	Effect of medication on safety – disease activity	Effect of medication on immunogenicity
Anti-TNFα
Anti-TNFα (not further specified)	n=1 Invasive pneumococcal disease in 1 patient.	n = 24 No difference in AE and respiratory tract infections between patients with and without anti-TNFα.	n= 17 Decrease in DA parameters in patients using anti-TNFα compared with patients using MTX.	N=60^a No difference in seroprotection, seroconversion or post-vaccination GMTs in patients using anti-TNFα compared with control. 4 patients were non respondent to Hepatitis A vaccine and 4 to Hepatitis B vaccine.
Adalimumab				n=5 No difference in seroprotection, seroconversion or post-vaccination GMTs in patients using adalimumab compared with control.
Etanercept		n=31 No AEs related to etanercept.		n=49 No difference in seroprotection, seroconversion or post-vaccination GMTs in patients using etanercept compared with control. One patient had an vaccine response after the second dose.^b
Immunosuppressives
Abatacept	n=1 Chickenpox infection with normal disease course in 1 JIA patient. ^b			n=30 No effect of abatacept on protective antibody levels. No response to the second dose in 1 patient.^b
Interleukin inhibiters
Tocilizumab				n=6 No difference in seroprotection, seroconversion or post-vaccination GMTs in patients using tocilizumab compared with control.
Anakinra				n=4 No difference in seroprotection, seroconversion or post-vaccination GMTs in patients using anakinra compared with control.
Amino salicylates
Sulfasalazine				n=1 Patient using sulfasalazine was negative for anti-hepatitis B.
DMARDs
DMARDs (not further specified)		n=30 No AE related to DMARDs.		n=79 No differences in seroprotection, seroconversion, or GMTs in patients using DMARDs compared with control. n=40 No effect on titers rates.^c
Methotrexate	n=1 Chickenpox infection in 1 JIA patient with normal disease course.^b	n=18 No difference in AEs between patients with and without MTX.	n=60 No difference in JADAS score and flares between vaccinated and unvaccinated patients using MTX.^c	n=228 No difference in seroprotection, seroconversion or post-vaccination GMTs in patients using MTX compared with control. n=95 1 patients had no seroprotection for mumps.^c 1 patient had no seroprotection for mumps, no effect on measles and rubella.^c No effect of MTX on GMT and seroprotection.^c
NSAIDs
NSAIDs				n=10 Usage of NSAIDs had no effect on the immune response.
Biologics
Biologics (not further specified)		n=15 No AEs related to biologics.	n=15 No difference in JADAS score and flares between vaccinated and unvaccinated patients using biologics.^c	n=15 Revaccinated patients taking biologics at the time of revaccination were seroprotected.^c n=3 No increase in antibody concentrations (n=3) when using biologics at time of first vaccination.^b
Corticosteroids
Glucocorticosteroid				n=28 Usage of glucocorticosteroids had no effect on GMT or seroprotection. n=28 Usage of glucocorticosteroids had no effect on GMT and seroprotection.^c
Combinations
Corticosteroids and MTX	n=1 Chickenpox infection in 1 JIA patient with normal disease course.^b		n=2 Temperature elevation and mild rash after vaccination.^b
TNF and MTX		n=8 No difference in AEs between patients with and without MTX.		n=8 No differences in seroprotection, seroconversion or post-vaccination GMTs in patients using anti-TNFα combined with MTX compared with control.
MTX, corticosteroids and ciclosporine			n=1 Temperature elevation and mild rash after vaccination^b

_{AE, adverse event; DA, disease activity; GMT, geometric mean titer; JIA, juvenile idiopathic arthritis; DMARDs, disease-modifying antirheumatic drugs; JADAS, Juvenile Arthritis Disease Activity Score; MTX, methotrexate; NSAIDs, non-steroidal anti-inflammatory drugs; TNF, tumor necrosis factor.}

_{^aExact patient number is unknown, because one study did not report the exact amount of patients using anti-TNFα}

_{^bStudy results in patients receiving VZV vaccination}

_{^cStudy results in patients receiving MMR vaccination}

Level of evidence of the literature

The level of evidence and conclusions were divided into live-attenuated vaccines and inactivated vaccines. Live-attenuated vaccines used in this literature review were VZV and MMR vaccines. All the other vaccines were inactivated. Adverse events for MMR started on high level of evidence, since this was assessed by the RCT of Heijstek (2013). All the other outcomes started at low level of evidence, because these were only or also assessed by observational studies.

Live attenuated vaccines

VZV

Efficacy

The level of evidence regarding the outcome measure efficacy was downgraded by one level because of number of included patients (imprecision).

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of number of included patients (imprecision).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was not assessed due to the lack of studies.

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was downgraded by two levels because of study limitations (risk of bias) and number of included patients (imprecision).

MMR

Efficacy

The level of evidence regarding the outcome measure efficacy was not assessed due to the lack of studies.

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of study limitations (risk of bias).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by two levels because study limitations (risk of bias) and number of included patients (imprecision).

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was downgraded by two levels because of study limitations (risk of bias) and number of included patients (imprecision).

Inactivated vaccines

DTP

Efficacy

The level of evidence regarding the outcome measure efficacy was not assessed due to the lack of studies.

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of study limitations (risk of bias).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by one level because of study limitations (risk of bias).

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was not assessed due to the lack of studies.

HPV

Efficacy

The level of evidence regarding the outcome measure efficacy was not assessed due to lack of studies.

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by zero levels.

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by zero levels.

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was downgraded by zero levels.

HBV/HAV

Efficacy

The level of evidence regarding the outcome measure efficacy was not assessed due to lack of studies.

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of study limitations (risk of bias).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by one level because of study limitations (risk of bias).

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was not assessed due to lack of studies.

MenACWY conjugate vaccine

Efficacy

The level of evidence regarding the outcome measure efficacy was not assessed due to lack of studies.

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of study limitations (risk of bias).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was not assessed due to lack of studies.

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was not assessed due to lack of studies.

PCV/PPV

Efficacy

The level of evidence regarding the outcome measure efficacy was downgraded by one level because of number of included patients (imprecision).

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of number of included patients (imprecision).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by one level because of number of included patients (imprecision).

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was downgraded by one level because of number of included patients (imprecision).

Influenza

Efficacy

The level of evidence regarding the outcome measure efficacy was downgraded by one level because of study limitations (risk of bias).

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was downgraded by one level because of study limitations (risk of bias).

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by one level because of study limitations (risk of bias).

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was downgraded by one level because of study limitations (risk of bias).

Covid-19 mRNA vaccine of BioNTech/Pfizer

Efficacy

The level of evidence regarding the outcome measure efficacy was downgraded by zero levels.

Immunogenicity

The level of evidence regarding the outcome measure immunogenicity was not assessed due to the lack of studies.

Safety – adverse events

The level of evidence regarding the outcome measure safety – adverse events was downgraded by zero levels.

Safety – disease activity

The level of evidence regarding the outcome measure safety – disease activity was downgraded by one level because of study limitations (risk of bias).

Zoeken en selecteren

A systematic review of the literature was performed to answer the following question: What is the efficacy, immunogenicity and safety of vaccines available for paediatric patients with juvenile idiopathic arthritis?

P:	juvenile idiopathic arthritis
I:	immunization/vaccination
C:	Healthy controls, non-vaccinated with JIA, vaccinated JIA without medication, no controls
O:	Efficacy, safety, and immunogenicity

Relevant outcome measures

The guideline development group considered efficacy and safety as critical outcome measures for decision making; and immunogenicity as an important outcome measure for decision making.

The guideline development group defined the outcomes measure efficacy as prevention of the infectious disease. Safety is defined as effect on the underlying autoimmune disease or adverse effects upon vaccination. Immunogenicity is based on antibody measurements and defined as seroprotection in case of a correlate of protection or seroconversion or fold-increase of antibody levels.

Search and select (Methods)

The guideline development group suggested using an international systematic review and guideline about the efficacy, immunogenicity, and safety of vaccination in pediatric patients with autoimmune inflammatory rheumatic diseases (Jansen, 2022). The patient population in this review was defined broader compared with our PICO. Therefore, only studies concerning JIA patients were included in this literature review, which resulted in 16 unique studies included in the review of Jansen (2022).

Additionally, the search of Jansen (2022) was updated and the search terms COVID, rotavirus, and RS virus were added. For this update, the databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from July 2020 on 10-02-2023. The detailed search strategy is depicted in the appendix. The systematic literature search resulted in 80 hits. Systematic reviews, RCTs and cohort studies were selected based on the following criteria; juvenile idiopathic arthritis and vaccinations. 19 studies were initially selected based on title and abstract screening. After reading the full text, 15 studies were excluded (see the table with reasons for exclusion in the appendix), and 4 studies were included.

In total, the literature review resulted in 20 unique studies about the safety, efficacy and/or immunogenicity of vaccinations in JIA patients, of which 16 from Jansen (2020) and 4 found in the updated search.

Results

Twenty (20) studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

Referenties

1 - Aikawa NE, Campos LM, Goldenstein-Schainberg C, Saad CG, Ribeiro AC, Bueno C, Precioso AR, Timenetsky Mdo C, Silva CA, Bonfá E. Effective seroconversion and safety following the pandemic influenza vaccination (anti-H1N1) in patients with juvenile idiopathic arthritis. Scand J Rheumatol. 2013;42(1):34-40. doi: 10.3109/03009742.2012.709272. Epub 2012 Sep 20. PMID: 22992045.
2 - Aikawa NE, Campos LM, Silva CA, Carvalho JF, Saad CG, Trudes G, Duarte A, Miraglia JL, Timenetsky Mdo C, Viana VS, França IL, Bonfa E, Pereira RM. Glucocorticoid: major factor for reduced immunogenicity of 2009 influenza A (H1N1) vaccine in patients with juvenile autoimmune rheumatic disease. J Rheumatol. 2012 Jan;39(1):167-73. doi: 10.3899/jrheum.110721. Epub 2011 Nov 15. PMID: 22089462.
3 - Aikawa NE, França IL, Ribeiro AC, Sallum AM, Bonfa E, Silva CA. Short and long-term immunogenicity and safety following the 23-valent polysaccharide pneumococcal vaccine in juvenile idiopathic arthritis patients under conventional DMARDs with or without anti-TNF therapy. Vaccine. 2015 Jan 29;33(5):604-9. doi: 10.1016/j.vaccine.2014.12.030. Epub 2014 Dec 29. PMID: 25554240.
4 - Barbati F, Marrani E, Volpi B, Ferrara G, Lodi L, Mastrolia MV, Canessa C, Maccora I, Simonini G, Azzari C, Ricci S. Mycophenolate mofetil-induced hypogammaglobulinemia and infectious disease susceptibility in pediatric patients with chronic rheumatic disorders: a monocentric retrospective study. Eur J Pediatr. 2022 Sep;181(9):3439-3448. doi: 10.1007/s00431-022-04560-2. Epub 2022 Jul 14. PMID: 35834043.
5 - Barbosa CM, Terreri MT, Rosário PO, de Moraes-Pinto MI, Silva CA, Hilário MO. Immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus. Clin Exp Rheumatol. 2012 Sep-Oct;30(5):791-8. Epub 2012 Oct 17. PMID: 22935227.
6 - Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C, Trzaskoma B, Martin F, Agarwal S, Kelman A. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 2010 Jan;62(1):64-74. doi: 10.1002/art.25034. PMID: 20039397.
7 - Bizjak M, Blazina Š, Zajc Avramovi? M, Markelj G, Av?in T, Toplak N. Vaccination coverage in children with rheumatic diseases. Clin Exp Rheumatol. 2020 Jan-Feb;38(1):164-170. Epub 2019 Oct 2. PMID: 31577215.
8 - Brunner HI, Tzaribachev N, Cornejo GV, Joos R, Gervais E, Cimaz R, Calvo Penadés I, Cuttica R, Lutz T, Quartier P, Gandhi Y, Nys M, Wong R, Martini A, Lovell DJ, Ruperto N; Pediatric Rheumatology Collaborative Study Group and the Paediatric Rheumatology International Trials Organisation. Maintenance of antibody response to diphtheria/tetanus vaccine in patients aged 2-5?years with polyarticular-course juvenile idiopathic arthritis receiving subcutaneous abatacept. Pediatr Rheumatol Online J. 2020 Feb 22;18(1):19. doi: 10.1186/s12969-020-0410-x. PMID: 32087715; PMCID: PMC7036185.
9 - Camacho-Lovillo MS, Bulnes-Ramos A, Goycochea-Valdivia W, Fernández-Silveira L, Núñez-Cuadros E, Neth O, Pérez-Romero P. Immunogenicity and safety of influenza vaccination in patients with juvenile idiopathic arthritis on biological therapy using the microneutralization assay. Pediatr Rheumatol Online J. 2017 Aug 7;15(1):62. doi: 10.1186/s12969-017-0190-0. PMID: 28784185; PMCID: PMC5547451.
10 - Carvalho LM, de Paula FE, Silvestre RV, Roberti LR, Arruda E, Mello WA, Ferriani VP. Prospective surveillance study of acute respiratory infections, influenza-like illness and seasonal influenza vaccine in a cohort of juvenile idiopathic arthritis patients. Pediatr Rheumatol Online J. 2013 Mar 7;11:10. doi: 10.1186/1546-0096-11-10. PMID: 23510667; PMCID: PMC3602114.
11 - David E, Roy P, Belot A, Quartier P, Bader Meunier B, Aeschlimann FA, Human Papilloma Virus Vaccination in Patients with Rheumatic Diseases in France: A Study of Vaccination Coverage and Drivers of Vaccination. J Clin Med. 2022;11(14).
12 - Dell'Era L, Corona F, Daleno C, Scala A, Principi N, Esposito S. Immunogenicity, safety and tolerability of MF59-adjuvanted seasonal influenza vaccine in children with juvenile idiopathic arthritis. Vaccine. 2012 Jan 20;30(5):936-40. doi: 10.1016/j.vaccine.2011.11.083. Epub 2011 Dec 3. PMID: 22138210.
13 - Dos Reis BS, Staub FC, Koishi A, Zanluca C, Dos Santos CND, Skare TL, Kahlow BS. Seroconversion of rheumatoid arthritis patients after yellow fever vaccination. Clin Rheumatol. 2022 Mar;41(3):705-708. doi: 10.1007/s10067-021-05962-7. Epub 2021 Oct 21. PMID: 34674083.
14 - Edmunds WJ, Brisson M. The effect of vaccination on the epidemiology of varicella zoster virus. J Infect. 2002 May;44(4):211-9. doi: 10.1053/jinf.2002.0988. PMID: 12099726.
15 - Embree J, Law B, Voloshen T, Tomovici A. Immunogenicity, safety, and antibody persistence at 3, 5, and 10 years postvaccination in adolescents randomized to booster immunization with a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliomyelitis vaccine administered with a hepatitis B virus vaccine concurrently or 1 month apart. Clin Vaccine Immunol. 2015 Mar;22(3):282-90. doi: 10.1128/CVI.00682-14. Epub 2014 Dec 24. PMID: 25540274; PMCID: PMC4340898.
16 - Esposito S, Corona F, Barzon L, Cuoco F, Squarzon L, Marcati G, Torcoletti M, Gambino M, Palù G, Principi N. Immunogenicity, safety and tolerability of a bivalent human papillomavirus vaccine in adolescents with juvenile idiopathic arthritis. Expert Rev Vaccines. 2014 Nov;13(11):1387-93. doi: 10.1586/14760584.2014.943195. Epub 2014 Jul 28. PMID: 25066387.
17 - Groot N, Pileggi G, Sandoval CB, Grein I, Berbers G, Ferriani VPL, Wulffraat N, de Roock S. Varicella vaccination elicits a humoral and cellular response in children with rheumatic diseases using immune suppressive treatment. Vaccine. 2017 May 15;35(21):2818-2822. doi: 10.1016/j.vaccine.2017.04.015. Epub 2017 Apr 12. PMID: 28412076.
18 - Heijstek MW, Kamphuis S, Armbrust W, Swart J, Gorter S, de Vries LD, Smits GP, van Gageldonk PG, Berbers GA, Wulffraat NM. Effects of the live attenuated measles-mumps-rubella booster vaccination on disease activity in patients with juvenile idiopathic arthritis: a randomized trial. JAMA. 2013 Jun 19;309(23):2449-56. doi: 10.1001/jama.2013.6768. PMID: 23780457.
19 - Heijstek MW, Scherpenisse M, Groot N, Tacke C, Schepp RM, Buisman AM, Berbers GA, van der Klis FR, Wulffraat NM. Immunogenicity and safety of the bivalent HPV vaccine in female patients with juvenile idiopathic arthritis: a prospective controlled observational cohort study. Ann Rheum Dis. 2014 Aug;73(8):1500-7. doi: 10.1136/annrheumdis-2013-203429. Epub 2013 May 30. PMID: 23723319.
20 - Heijstek MW, van Gageldonk PG, Berbers GA, Wulffraat NM. Differences in persistence of measles, mumps, rubella, diphtheria and tetanus antibodies between children with rheumatic disease and healthy controls: a retrospective cross-sectional study. Ann Rheum Dis. 2012 Jun;71(6):948-54. doi: 10.1136/annrheumdis-2011-200637. Epub 2011 Dec 15. PMID: 22172491.
21 - Ingelman-Sundberg HM, Laestadius Å, Chrapkowska C, Mördrup K, Magnusson B, Sundberg E, Nilsson A. Diverse effects on vaccine-specific serum IgG titres and memory B cells upon methotrexate and anti-TNF-? therapy in children with rheumatic diseases: A cross-sectional study. Vaccine. 2016 Mar 4;34(10):1304-11. doi: 10.1016/j.vaccine.2016.01.027. Epub 2016 Jan 29. PMID: 26827664.
22 - Jacobse J, Ten Voorde W, Rissmann R, Burggraaf J, Ten Cate R, Schrier L. The effect of repeated methotrexate injections on the quality of life of children with rheumatic diseases. Eur J Pediatr. 2019;178(1):17-20.
23 - Jansen MH, Rondaan C, Legger G, Minden K, Uziel Y, Toplak N, Maritsi D, van den Berg M, Berbers G, Bruijning P, Egert Y, Normand C, Bijl M, Foster H, Kone-Paut I, Wouters C, Ravelli A, Elkayam O, Wulffraat NM, Heijstek MW. Efficacy, Immunogenicity and Safety of Vaccination in Pediatric Patients With Autoimmune Inflammatory Rheumatic Diseases (pedAIIRD): A Systematic Literature Review for the 2021 Update of the EULAR/PRES Recommendations. Front Pediatr. 2022 Jul 6;10:910026. doi: 10.3389/fped.2022.910026. PMID: 35874582; PMCID: PMC9298835.
24 - Jansen MHA, Rondaan C, Legger GE, Minden K, Uziel Y, Toplak N, Maritsi D, van den Berg L, Berbers GAM, Bruijning P, Egert Y, Normand C, Bijl M, Foster HE, Koné-Paut I, Wouters C, Ravelli A, Elkayam O, Wulffraat NM, Heijstek MW. EULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: update 2021. Ann Rheum Dis. 2023 Jan;82(1):35-47. doi: 10.1136/annrheumdis-2022-222574. Epub 2022 Jun 20. PMID: 35725297.
25 - Kohagura T, Kawabe S, Abe N, Nakaseko H, Iwata N. Efficacy of hepatitis B vaccination in children with rheumatic diseases. Pediatr Int. 2021 Jul;63(7):752-756. doi: 10.1111/ped.14533. Epub 2021 Jun 24. PMID: 33145843.
26 - Kostik MM, Lubimova NA, Fridman IV, Goleva OV, Kharit SM. The vaccine coverage and vaccine immunity status and risk factors of non-protective levels of antibodies against vaccines in children with juvenile idiopathic arthritis: cross-sectional Russian tertiary Centre study. Pediatric Rheumatology. 2021;19(1):108.
27 - Lin F, Hadler JL. Epidemiology of primary varicella and herpes zoster hospitalizations: the pre-varicella vaccine era. J Infect Dis. 2000 Jun;181(6):1897-905. doi: 10.1086/315492. Epub 2000 Jun 5. Erratum in: J Infect Dis. 2013 May 15;207(10):1625. PMID: 10837168.
28 - Lloyd AR, Ardura MI, Wise K, Chavarin DJ, Boyle B, Sivaraman V. Barriers to vaccination in immunocompromised children: A needs assessment in children with childhood-onset SLE and inflammatory bowel disease. Front Pediatr. 2023 Mar 1;11:1103096. doi: 10.3389/fped.2023.1103096. PMID: 36937959; PMCID: PMC10014617.
29 - Makarova E, Khabirova A, Volkova N, Gabrusskaya T, Ulanova N, Sakhno L, Vaccination coverage in children with juvenile idiopathic arthritis, inflammatory bowel diseases, and healthy peers: Cross-sectional electronic survey data. World J Clin Pediatr. 2023;12(2):45-56.
30 - Morin MP, Quach C, Fortin E, Chédeville G. Vaccination coverage in children with juvenile idiopathic arthritis followed at a paediatric tertiary care centre. Rheumatology (Oxford). 2012 Nov;51(11):2046-50. doi: 10.1093/rheumatology/kes175. Epub 2012 Aug 3. PMID: 22864995.
31 - Morin MP, Quach C, Fortin E, Chédeville G. Vaccination coverage in children with juvenile idiopathic arthritis followed at a paediatric tertiary care centre. Rheumatology (Oxford, England). 2012;51(11):2046-50.
32 - Oesterreich S, Lindemann M, Goldblatt D, Horn PA, Wilde B, Witzke O. Humoral response to a 13-valent pneumococcal conjugate vaccine in kidney transplant recipients. Vaccine. 2020 Apr 9;38(17):3339-3350. doi: 10.1016/j.vaccine.2020.02.088. Epub 2020 Mar 13. PMID: 32178906.
33 - Ohm M, van Straalen JW, Zijlstra M, de Joode-Smink G, Jasmijn Sellies A, Swart JF, Vastert SJ, van Montfrans JM, Bartels M, van Royen-Kerkhof A, Wildenbeest JG, Lindemans CA, Wolters VM, Wennink RAW, de Boer JH, Knol MJ, Heijstek MW, Sanders EAM, Verduyn-Lunel FM, Berbers GAM, Wulffraat NM, Jansen MHA. Meningococcal ACWY conjugate vaccine immunogenicity and safety in adolescents with juvenile idiopathic arthritis and inflammatory bowel disease: A prospective observational cohort study. Vaccine. 2023 Jun 7;41(25):3782-3789. doi: 10.1016/j.vaccine.2023.04.056. Epub 2023 May 15. PMID: 37198018.
34 - Pittet LF, Posfay-Barbe KM. Vaccination of immune compromised children-an overview for physicians. Eur J Pediatr. 2021 Jul;180(7):2035-2047. doi: 10.1007/s00431-021-03997-1. Epub 2021 Mar 5. PMID: 33665677; PMCID: PMC8195953.
35 - Rawson H, Crampin A, Noah N. Deaths from chickenpox in England and Wales 1995-7: analysis of routine mortality data. BMJ. 2001 Nov 10;323(7321):1091-3. doi: 10.1136/bmj.323.7321.1091. PMID: 11701571; PMCID: PMC59681.
36 - Sørensen K, Skirbekk H, Kvarstein G, Wøien H. I don't want to think about it: a qualitative study of children (6-18?years) with rheumatic diseases and parents' experiences with regular needle injections at home. Pediatric rheumatology online journal. 2021;19(1):8.
37 - Stich M, Di Cristanziano V, Tönshoff B, Weber LT, Dötsch J, Rammer MT, Rieger S, Heger E, Garbade SF, Burgmaier K, Benning L, Speer C, Habbig S, Haumann S. Humoral immune response and live-virus neutralization of the SARS-CoV-2 omicron (BA.1) variant after COVID-19 mRNA vaccination in children and young adults with chronic kidney disease. Pediatr Nephrol. 2023 Jun;38(6):1935-1948. doi: 10.1007/s00467-022-05806-9. Epub 2022 Nov 21. PMID: 36409368; PMCID: PMC9684918.
38 - Stoof SP, Heijstek MW, Sijssens KM, van der Klis F, Sanders EA, Teunis PF, Wulffraat NM, Berbers GA. Kinetics of the long-term antibody response after meningococcal C vaccination in patients with juvenile idiopathic arthritis: a retrospective cohort study. Ann Rheum Dis. 2014 Apr;73(4):728-34. doi: 10.1136/annrheumdis-2012-202561. Epub 2013 Mar 16. PMID: 23505231.
39 - Tabacchi G, Costantino C, Napoli G, Marchese V, Cracchiolo M, Casuccio A, Determinants of European parents' decision on the vaccination of their children against measles, mumps and rubella: A systematic review and meta-analysis. Hum Vaccin Immunother. 2016;12(7):1909-23.
40 - Toplak N, Subelj V, Kveder T, Cucnik S, Prosenc K, Trampus-Bakija A, Todorovski L, Avcin T. Safety and efficacy of influenza vaccination in a prospective longitudinal study of 31 children with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2012 May-Jun;30(3):436-44. Epub 2012 Jun 26. PMID: 22513085.
41 - van der Kolk LE, Baars JW, Prins MH, van Oers MH. Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood. 2002 Sep 15;100(6):2257-9. PMID: 12200395.
42 - Visser LG. The immunosuppressed traveler. Infect Dis Clin North Am. 2012 Sep;26(3):609-24. doi: 10.1016/j.idc.2012.06.003. PMID: 22963773.
43 - Wilson J, Costello W, Angevare S, Beesley R. P63?Parents report that healthcare professionals play an influential role in deciding whether to vaccinate against COVID-19: Results of a patient-led survey in Canada. Rheumatol Adv Pract. 2022;6(Suppl 1).
44 - Woerner A, Sauvain MJ, Aebi C, Otth M, Bolt IB. Immune response to influenza vaccination in children treated with methotrexate or/and tumor necrosis factor-alpha inhibitors. Hum Vaccin. 2011 Dec;7(12):1293-8. doi: 10.4161/hv.7.12.17981. Epub 2011 Dec 1. PMID: 22185812.
45 - Yaqub O, Castle-Clarke S, Sevdalis N, Chataway J. Attitudes to vaccination: a critical review. Social science & medicine (1982). 2014;112:1-11.

Evidence tabellen

Evidence table for systematic review of RCTs and observational studies (intervention studies)

Research question: What is the efficacy, immunogenicity and safety of vaccines available for paediatric patients with juvenile idiopathic arthritis?

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Jansen, 2022

Study characteristics are extracted from Jansen, 2022, unless stated otherwise.

Systematic literature review of all original studies (including cohort, cross-sectional, and RCT)

Literature search between November 2010 and July 2020.

A: Brunnner, 2020

B: Heijstek, 2012

C: Heijstek, 2014

D: Esposito, 2014

E: Stoof, 2014

F: Aikawa, 2015

G: Aikawa, 2012

H: Aikawa, 2013

I: Carvalho, 2013

J: Toplak, 2012

K: Woerner, 2011

L: Camacho-Lovillo, 2017

M: Heijstek, 2013

N: Heijstek, 2012^a

O: Ingelman-Sundberg, 2016

P: Groot, 2017

Q: Dell’Era, 2012

R: Ingelman-Sundberg, 2016^a

Source of funding and conflicts of interest:

Funded by the European League against Rheumatism (EULAR). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Inclusion criteria SR:

Children with paediatric autoimmune/inflammatory rheumatic diseases.
Terminology for medication is according to the new nomenclature of DMARDs, including conventional synthetic (cs)DMARDs, targeted synthetic (ts)DMARDs and biological (b)DMARDs
All available vaccines were included in the search, except for the COVID vaccine.

Exclusion criteria SR:

Exclusion criteria were studies that focussed exclusively on

non-rheumatic autoimmune diseases [except for inflammatory

bowel disease (IBD)] or vaccine development. Phase I trials,

in vitro studies, non-English papers and abstracts presented on scientific meetings were also excluded. Papers concerning

the potential role of vaccinations in inducing pedAIIRD were excluded, because these recommendations focus on the effect of vaccination on established disease.

In total, 55 studies were included. However, only the studies that comply with our search are presented here.

Important patient characteristics at baseline:

Not reported.

Groups comparable at baseline?

Not reported.

A: (n=29) DT vaccine.

Medication: 29 ABT, 22 MTX, 3 LD-GC

B: (n=400) DT vaccine.

Medication 93 MTX, 8 TNFi, 28 GC 10 mg/day

C: (n=68) HPV vaccine.

Medication 24 MTX, 9 TNFi, 6 other DMARD

D: (n=21) HPV-b vaccine.

Medication 10 NSAID, 5 MTX, 6 TNFi

E: (n=127) MenC.

Medication 42 MTX, 66 pre-MTX, 7 NA bDMARD, 53 pre-, 4 GC, 10 pre-GC

F: (n=17 JIA pre-eternercept) PPV23 vaccine.

Medication Group 1: MTX HD 2 weeks before ETA. Medication Group 2: 10 LD MTX.

G: (n=237 in total, 93 JIA) H1N1 (influenza)

Medication 90 GC, MTX 74, 43 AZA, 23 CYC, 13 MMF, 6 LEF, 3 Cy

H: (n=95) H1N1 (influenza).

Medication 16 TNFi, 63 DMARD(s)

I: (n=44) Influenza

IS in 34-44%

J: (n=31) Influenza

Medication 18 NSAID, 2 DMARD, 7 DMARD + GC, 4 TNF

K: (n=34 in total, 25 JIA) Influenza

Medication 18 MTX, 10 TNFi, 8 MTX+TNFi, 16 no

medication

L: (n=25) Influenza (H1N1, H3N2, B) vaccine.

Medication anti TNF, anti IL-1, anti IL-6

M: (n=68) JIA with MMR vaccine.

Medication 60 MTX, 15 biologicals, 3 GC

N: (n=400) MMR vaccine.

Medication 93 MTX, 8 TNFi, 28 GC 10 mg/day

O: (n=50 in total, 46 JIA) MMR vaccine.

Medication 10 NSAID, 8 MTX, 32 MTX+TNFi

P: (n=49 in total, 39 JIA) VZV vaccine

Medication 49 MTX, 16 GCs, 3 biologicals

Q: (n=60) Influenza vaccine (M59 adjuvanted)

Medication 30 DMARD vs. 30 aTNF (Etanercept)

R: (n=50 in total, 46 JIA) TT vaccine.

Medication 10 NSAID, 8 MTX, 32 MTX+TNFi

A: (n=17) JIA patients not vaccinated, all using abatacept

B: (n=2176) Healthy controls

C: (n=55) Healthy controls

D: (n=21) Healthy controls

E: (n=1527) Healthy controls

F: (n=10) JIA MTX

G: (n=91) Healthy controls

H: (n=91) Healthy controls

I: (n=10) Healthy controls

J: (n=14) Healthy controls and (n=31) children with JIA not vaccinated against influenza.

K: (n=16) Healthy controls

L: (n=6) Healthy siblings

M: (n=69) JIA patients not vaccinated

N: (n=2176) Healthy controls

O: (n=31) Age-matched healthy controls

P: (n=18) Healthy controls

Q: (n=30) Healthy controls

R: (n=31) Age-matched controls

End-point of follow-up:

A: 24 months

B: NA

C: 12 months

D: 7 months

E: NA

F: 12 months

G: 21 days

H: 3 weeks

I: 180 days

J: 6 months

K: 4-8 weeks after single dose or after the second of two doses.

L: 1 year

M: 12 months

N: NA

O: NA

P: 4-6 weeks after vaccination.

Q: 3 months

R: NA

Lost to follow-up

A: IG: 0

CG: 1, due to adverse events.

IG: 7

CG: 1

D: not reported.

F: n=3 in group with anti-TNF, n=0 in group without anti-TNF

G: no lost to follow-up.

H: not reported

I: no lost to follow-up.

J: not reported.

K: not reported.

L: IG n=23

CG not reported

M: IG: n=5; 3 withdrew consent and 2 started other treatment.

CG: n=1

Reason unknown.

P: not reported.

Q: n=0

Efficacy

Defined as prevention of infectious disease.

A: NA

B: NA

C: NA

D: NA

E: NA

F: Pneumoc. Invasive dis. in patients on TNFi: serotype NA

G: NA

H: NA

I: Pos. Influenza samples 5/14 vs. 1/7 & ILI increase in unvacc vs. vacc.

J: Equal influenza JIA vs HC. Infections in 1 vacc. vs 4 unvacc. pts

K: NA

L: NA

M: NA

N: NA

O: NA

P: NA

Q: NA

R: NA

Safety

Defined as effect on the underlying autoimmune disease or adverse events.

Adverse events:

A: SAE 4, AE 29 (all ABT- no vaccine related)

B: NA

C: AE smilar in JIA and HC, no SAE

D: Similar AE as HC

E: NA

F: No increased AE. 1 SAE: pneumococcal invasive dis.

G: NA

H: Mild AE, similar in pts and HC. More arthralgia in JIA

I: NA

J: Similar AE

K: Similar AE

L: No severe AE. 7/41 local reactions, 2/41 systemic AE: drug reactions

M: No MMR infections induced by vaccination

N: NA

O: NA

P: NA

Q: AE similar in JIA

and HC

R: NA

Disease activity:

A: NA

B: NA

C: SD 1 year post vaccine

D: No increase in JADAS-27

E: NA

F: SD in JIA pts

G: NA

H: DAS stable

I: Equal ACRped30 pre&post vacc

J: Flare rate at 6 mths: 36% vs. 23% vacc vs. control JIA (but lower basel. DA)O:

K: NA

L: No flares, increased JADAS in 6pt

M: Stable DA, incl. pts on biologicals

N: NA

O: NA

P: 3 patients had a slight increase in JADAS-71 score after vaccination (median JADAS increase: 1)

Q: Stable DA during follow-up

R: NA

Immunogenicity

Defined as seroprotection and/or seroconversion.

A: 100% SP tetanus, 90% SP diphtheria 2 m post vaccine.

B: Reduced SP and GMT for tetanus. No effect MTX or GC.

C: Equal SC and GMT in JIA and HC.

D: 100% SC. Reduced titers 1 month post 3th vaccine in JIA vs HC. No effect of medication.

E: Equal SP 4 years post vaccine JIA vs HC.MenC-IgG decrease over time, upward trend bDMARDs (n=7).

F: Equal SC at 2 (53 vs. 30%) and 12 months (36 vs. 40%) in JIA with and without TNFi.

G: Subgroup analysis: N=93

Before immunization, % (95%CI) 20.4 (12.2–28.6)

After immunization, % (95%CI) 88.2 (81.6–94.8)

Seroconversation rate, % (95%CI) 82.8 (75.1–90.5) (p<0.05)

H: Equal SP and GMT.

Reduced SC in pts, irresp.of TNF/MTX

I: Equal SP & SC in JIA and HC. TNFi lower SP and SC for H1N1 but SP for h3N2 &B/Florida was normal (N = not reported).

J: Equal SP pts and HC

K: Equal SP pts vs. HC, reduced GMT. In multiv.

anal. no effect MTX/TNFi

L: SP after 4–8 wks: 97.8%

H1N1, 95.6% H3N2, 91.1%

B. No effect medication

M: SP and GMT higher in vacc. vs. controls, no effect medication

N: Reduced SP and GMT for mumps, rubella, but not measles. No effect of MTX or GC.

O: Equal IgG titres MV and RV,

IgG-TT reduced in MTX+iTNF group. Vacc.-spec. mem. B cells preserved in pts with

booster

P: Equal GMT in pts & HC, more VZV-spec. T cells.

Q: Equal SP & SC in JIA and HC. TNFi lower H1N1-GMT & more rapid decline in H3N2-GMT

R: IgG-TT reduced in

MTX+TNFi group.

Level of evidence

Based on the standards of the Oxford Centre for Evidence-Based Medicine, adopted from Jansen, 2022.

A: Eff NA, Imm 4, Saf 4

B: Eff NA, Imm 2b, Saf NA

C: Eff NA, Imm 2b, Saf 4

D: Eff NA, Imm 2a, Saf 4

E: Eff NA, Imm 2c, Saf NA

F: Eff 4. Imm 2b, Saf 4

G: Eff NA, Imm 2b, Saf 4

H: Eff NA, Imm 2b, Saf 4

I: Eff 4, Imm 2b, Saf 4

J: Eff 4, Imm 2b, Saf 2b

K: Eff NA, Imm 2b, Saf 4

L: Eff NA, Imm 2b, Saf 4

M: Eff NA, Imm 1b, Saf 1b

N: Eff NA, Imm 2b, Saf NA

O: Eff NA, Imm 2b, Saf NA

P: Eff 3, Imm 2b, Saf 4

Q: Eff NA, Imm 2b, Saf 2b

R: Eff NA, Imm 2b, Saf NA

^aStudies use multiple vaccins, so are described separately per vaccine.

Jansen, 2022

Study characteristics are extracted from Jansen, 2022, unless stated otherwise.

Systematic literature review of all original studies (including cohort, cross-sectional, and RCT)

Literature search between November 2010 and July 2020.

A: Brunnner, 2020

B: Heijstek, 2012

C: Heijstek, 2014

D: Esposito, 2014

E: Stoof, 2014

F: Aikawa, 2015

G: Aikawa, 2012

H: Aikawa, 2013

I: Carvalho, 2013

J: Toplak, 2012

K: Woerner, 2011

L: Camacho-Lovillo, 2017

M: Heijstek, 2013

N: Heijstek, 2012^a

O: Ingelman-Sundberg, 2016

P: Groot, 2017

Q: Dell’Era, 2012

R: Ingelman-Sundberg, 2016^a

Source of funding and conflicts of interest:

Inclusion criteria SR:

Children with paediatric autoimmune/inflammatory rheumatic diseases.
Terminology for medication is according to the new nomenclature of DMARDs, including conventional synthetic (cs)DMARDs, targeted synthetic (ts)DMARDs and biological (b)DMARDs
All available vaccines were included in the search, except for the COVID vaccine.

Exclusion criteria SR:

Exclusion criteria were studies that focussed exclusively on

non-rheumatic autoimmune diseases [except for inflammatory

bowel disease (IBD)] or vaccine development. Phase I trials,

in vitro studies, non-English papers and abstracts presented on scientific meetings were also excluded. Papers concerning

the potential role of vaccinations in inducing pedAIIRD were excluded, because these recommendations focus on the effect of vaccination on established disease.

In total, 55 studies were included. However, only the studies that comply with our search are presented here.

Important patient characteristics at baseline:

Not reported.

Groups comparable at baseline?

Not reported.

A: (n=29) DT vaccine.

Medication: 29 ABT, 22 MTX, 3 LD-GC

B: (n=400) DT vaccine.

Medication 93 MTX, 8 TNFi, 28 GC 10 mg/day

C: (n=68) HPV vaccine.

Medication 24 MTX, 9 TNFi, 6 other DMARD

D: (n=21) HPV-b vaccine.

Medication 10 NSAID, 5 MTX, 6 TNFi

E: (n=127) MenC.

Medication 42 MTX, 66 pre-MTX, 7 NA bDMARD, 53 pre-, 4 GC, 10 pre-GC

F: (n=17 JIA pre-eternercept) PPV23 vaccine.

Medication Group 1: MTX HD 2 weeks before ETA. Medication Group 2: 10 LD MTX.

G: (n=237 in total, 93 JIA) H1N1 (influenza)

Medication 90 GC, MTX 74, 43 AZA, 23 CYC, 13 MMF, 6 LEF, 3 Cy

H: (n=95) H1N1 (influenza).

Medication 16 TNFi, 63 DMARD(s)

I: (n=44) Influenza

IS in 34-44%

J: (n=31) Influenza

Medication 18 NSAID, 2 DMARD, 7 DMARD + GC, 4 TNF

K: (n=34 in total, 25 JIA) Influenza

Medication 18 MTX, 10 TNFi, 8 MTX+TNFi, 16 no

medication

L: (n=25) Influenza (H1N1, H3N2, B) vaccine.

Medication anti TNF, anti IL-1, anti IL-6

M: (n=68) JIA with MMR vaccine.

Medication 60 MTX, 15 biologicals, 3 GC

N: (n=400) MMR vaccine.

Medication 93 MTX, 8 TNFi, 28 GC 10 mg/day

O: (n=50 in total, 46 JIA) MMR vaccine.

Medication 10 NSAID, 8 MTX, 32 MTX+TNFi

P: (n=49 in total, 39 JIA) VZV vaccine

Medication 49 MTX, 16 GCs, 3 biologicals

Q: (n=60) Influenza vaccine (M59 adjuvanted)

Medication 30 DMARD vs. 30 aTNF (Etanercept)

R: (n=50 in total, 46 JIA) TT vaccine.

Medication 10 NSAID, 8 MTX, 32 MTX+TNFi

A: (n=17) JIA patients not vaccinated, all using abatacept

B: (n=2176) Healthy controls

C: (n=55) Healthy controls

D: (n=21) Healthy controls

E: (n=1527) Healthy controls

F: (n=10) JIA MTX

G: (n=91) Healthy controls

H: (n=91) Healthy controls

I: (n=10) Healthy controls

J: (n=14) Healthy controls and (n=31) children with JIA not vaccinated against influenza.

K: (n=16) Healthy controls

L: (n=6) Healthy siblings

M: (n=69) JIA patients not vaccinated

N: (n=2176) Healthy controls

O: (n=31) Age-matched healthy controls

P: (n=18) Healthy controls

Q: (n=30) Healthy controls

R: (n=31) Age-matched controls

End-point of follow-up:

A: 24 months

B: NA

C: 12 months

D: 7 months

E: NA

F: 12 months

G: 21 days

H: 3 weeks

I: 180 days

J: 6 months

K: 4-8 weeks after single dose or after the second of two doses.

L: 1 year

M: 12 months

N: NA

O: NA

P: 4-6 weeks after vaccination.

Q: 3 months

R: NA

Lost to follow-up

A: IG: 0

CG: 1, due to adverse events.

IG: 7

CG: 1

D: not reported.

F: n=3 in group with anti-TNF, n=0 in group without anti-TNF

G: no lost to follow-up.

H: not reported

I: no lost to follow-up.

J: not reported.

K: not reported.

L: IG n=23

CG not reported

M: IG: n=5; 3 withdrew consent and 2 started other treatment.

CG: n=1

Reason unknown.

P: not reported.

Q: n=0

Efficacy

Defined as prevention of infectious disease.

A: NA

B: NA

C: NA

D: NA

E: NA

F: Pneumoc. Invasive dis. in patients on TNFi: serotype NA

G: NA

H: NA

I: Pos. Influenza samples 5/14 vs. 1/7 & ILI increase in unvacc vs. vacc.

J: Equal influenza JIA vs HC. Infections in 1 vacc. vs 4 unvacc. pts

K: NA

L: NA

M: NA

N: NA

O: NA

P: NA

Q: NA

R: NA

Safety

Defined as effect on the underlying autoimmune disease or adverse events.

Adverse events:

A: SAE 4, AE 29 (all ABT- no vaccine related)

B: NA

C: AE smilar in JIA and HC, no SAE

D: Similar AE as HC

E: NA

F: No increased AE. 1 SAE: pneumococcal invasive dis.

G: NA

H: Mild AE, similar in pts and HC. More arthralgia in JIA

I: NA

J: Similar AE

K: Similar AE

L: No severe AE. 7/41 local reactions, 2/41 systemic AE: drug reactions

M: No MMR infections induced by vaccination

N: NA

O: NA

P: NA

Q: AE similar in JIA

and HC

R: NA

Disease activity:

A: NA

B: NA

C: SD 1 year post vaccine

D: No increase in JADAS-27

E: NA

F: SD in JIA pts

G: NA

H: DAS stable

I: Equal ACRped30 pre&post vacc

J: Flare rate at 6 mths: 36% vs. 23% vacc vs. control JIA (but lower basel. DA)O:

K: NA

L: No flares, increased JADAS in 6pt

M: Stable DA, incl. pts on biologicals

N: NA

O: NA

P: 3 patients had a slight increase in JADAS-71 score after vaccination (median JADAS increase: 1)

Q: Stable DA during follow-up

R: NA

Immunogenicity

Defined as seroprotection and/or seroconversion.

A: 100% SP tetanus, 90% SP diphtheria 2 m post vaccine.

B: Reduced SP and GMT for tetanus. No effect MTX or GC.

C: Equal SC and GMT in JIA and HC.

D: 100% SC. Reduced titers 1 month post 3th vaccine in JIA vs HC. No effect of medication.

E: Equal SP 4 years post vaccine JIA vs HC.MenC-IgG decrease over time, upward trend bDMARDs (n=7).

F: Equal SC at 2 (53 vs. 30%) and 12 months (36 vs. 40%) in JIA with and without TNFi.

G: Subgroup analysis: N=93

Before immunization, % (95%CI) 20.4 (12.2–28.6)

After immunization, % (95%CI) 88.2 (81.6–94.8)

Seroconversation rate, % (95%CI) 82.8 (75.1–90.5) (p<0.05)

H: Equal SP and GMT.

Reduced SC in pts, irresp.of TNF/MTX

I: Equal SP & SC in JIA and HC. TNFi lower SP and SC for H1N1 but SP for h3N2 &B/Florida was normal (N = not reported).

J: Equal SP pts and HC

K: Equal SP pts vs. HC, reduced GMT. In multiv.

anal. no effect MTX/TNFi

L: SP after 4–8 wks: 97.8%

H1N1, 95.6% H3N2, 91.1%

B. No effect medication

M: SP and GMT higher in vacc. vs. controls, no effect medication

N: Reduced SP and GMT for mumps, rubella, but not measles. No effect of MTX or GC.

O: Equal IgG titres MV and RV,

IgG-TT reduced in MTX+iTNF group. Vacc.-spec. mem. B cells preserved in pts with

booster

P: Equal GMT in pts & HC, more VZV-spec. T cells.

Q: Equal SP & SC in JIA and HC. TNFi lower H1N1-GMT & more rapid decline in H3N2-GMT

R: IgG-TT reduced in

MTX+TNFi group.

Level of evidence

Based on the standards of the Oxford Centre for Evidence-Based Medicine, adopted from Jansen, 2022.

A: Eff NA, Imm 4, Saf 4

B: Eff NA, Imm 2b, Saf NA

C: Eff NA, Imm 2b, Saf 4

D: Eff NA, Imm 2a, Saf 4

E: Eff NA, Imm 2c, Saf NA

F: Eff 4. Imm 2b, Saf 4

G: Eff NA, Imm 2b, Saf 4

H: Eff NA, Imm 2b, Saf 4

I: Eff 4, Imm 2b, Saf 4

J: Eff 4, Imm 2b, Saf 2b

K: Eff NA, Imm 2b, Saf 4

L: Eff NA, Imm 2b, Saf 4

M: Eff NA, Imm 1b, Saf 1b

N: Eff NA, Imm 2b, Saf NA

O: Eff NA, Imm 2b, Saf NA

P: Eff 3, Imm 2b, Saf 4

Q: Eff NA, Imm 2b, Saf 2b

R: Eff NA, Imm 2b, Saf NA

^aStudies use multiple vaccins, so are described separately per vaccine.

_{LoE, level of evidence; Eff, Efficacy; Imm, immunogenicity Saf, Safety; NA, not analyzed; SP, seroprotection; SC, seroconversion; GMT, geometric mean titer; HC, healthy controls; pts, patients; DTP, diphtheria tetanus pertussis; IBD, inflammatory bowel disease; Thiopur, thiopurine; TNFi, tumor necrosis factor inhibitor; AE, adverse event; SAE, severe adverse event; IS, immunosuppression; JIA, juvenile idiopathic arthritis; jSLE, juvenile systemic lupus erythematosus; 6-MP, 6-mercaptopurine; AZA, azathioprine; GC, glucocorticosteroids; MTX, methotrexate; CYC, cyclosporine; bDMARD, biological disease modifying anti-rheumatic drugs; ABT, abatacept; LD, low dose; HD, high dose; TT, tetanus toxoid; MV, measles vaccine; NSAID, non steroid anti-inflammatory drug; HCQ, hydroxychloroquine; MMF, mycophenolic acid; RTX, rituximab; vacc, vaccine; AB, antibody; HAV, hepatitis A virus; HBV, hepatitis B virus; ETN, etanercept; ADA, adalimumab; TCZ, tocilizumab; IFX, infliximab; IVIG, intravenous immunoglobulines; Cy, cyclophosphamide; LEF, leflunomide; MMR(/V), measles mumps rubella (/varicella); VZV, varicella zoster virus; ANR, Anakinra; CAM, canakinumab; FMF, familial mediterranean fever; CAPS, cryopyrin-associated periodic syndrome; MKD, mevalonate kinase deficiency}

Research question: What is the efficacy, immunogenicity and safety of vaccines available for paediatric patients with juvenile idiopathic arthritis?

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Çakmak, 2022

Type of study:

Multicentre cohort study

Setting and country: Three referral centers in Turkey

Funding and conflicts of interest:

No conflict of interest and no funding.

Inclusion criteria:

Patients with JIA

Exclusion criteria:

Patients who did not complete their primary vaccination program at the time of diagnosis and patients who

received chemotherapy, immunomodulatory therapy, blood transfusions previously, and those with underlying

primary immunodeficiency were excluded from the study.

N total at baseline:

Patients: 262

Control: 274

Important prognostic factors:

Mean age ± SD:

I: 10.4 ± 4.6

C: 10.5 ± 3.6

Sex:

I: 49.2% F

C: 46.7% F

Groups comparable at baseline? Yes

Fully hepatitis B vaccinated treatment-naïve children with JIA.

Healthy children who had been vaccinated for hepatitis B according to the routine vaccination schedule.

Length of follow-up:

Efficacy

Defined as prevention of infectious disease.

Not reported.

Safety

Defined as effect on the underlying autoimmune disease or adverse events.

Not reported.

Immunogenicity

Defined as seroprotection and/or seroconversion.

Anti-Hbs antibody:

JIA patients: 59.1%

Control: 72.9%, p=0.002.

HbsAG positivity:

N=0 in both groups

Median anti-HBs titers

JIA patients: 14 (range 0-1000) IU/L

Control: 43.3 (range 0-1000) IU/L, p=0.01

Anti-nuclear antibody positivity

JIA patients: 27.1%. Among these, anti-Hbs antibody seropositivity rate was 69.1% (n=49) while this rate was 56.2% (n=104) in the remaining ANA negative cases (n=185) (p=0.04).

Four patients were negative for anti-Hbs and were receiving DMARDs (methotrexate=1, sulfasalazine=1) and biological agents (etanercept=1, adalimumab=1)

Study stratifies per age group (0-5; 5-10; >10), these data are not reported here.

Study also stratifies per subtype of JIA, these data are not reported here.

Ziv, 2022

Type of study:

Observational cohort study

Setting and country:

Data from Clalit Health Services, Israel

Funding and conflicts of interest:

No funding and no conflicts of interest.

Inclusion criteria:

Eligibility criteria

were adolescents aged 12–18 years, who were members

of Clalit Health Services (CHS) and had a documented

diagnosis of JIA, SLE or FMF [according to International

Classification of Diseases, ninth edition (ICD-9) codes or Clalit diagnostic criteria] during the 6 months preceding

data extraction.

Exclusion criteria:

Not reported.

N total at baseline:

IRD: 1639, of which 380 (23.2%) JIA

Control: 524.471

Important prognostic factors:

Not reported

Groups comparable at baseline? Not reported

Adolescents aged 12-18 years with IRD, either vaccinated or not vaccinated against COVID-19 with the BNT162b2 mRNA vaccine.

Adolescents aged 12-18 years without IRD, either vaccinated or not vaccinated against COVID-19 with the BNT162b2 mRNA vaccine.

Length of follow-up:

The median follow-up times after receiving vaccination

for the study cohort were 21.6 weeks [interquartile range

(IQR) 14.7–39.1], 19.0 weeks (IQR 13.6–36.9) and

8.9 weeks (IQR 7.3–11.6) after one, two and three doses

of vaccine, respectively.

Loss-to-follow-up:

Efficacy

Defined as prevention of infectious disease.

COVID-19 infection after one dose of vaccination

JIA: 0%

Control: 12.6%

P<0.01

COVID-19 infection with no vaccination

No difference in JIA and controls (p=0.36).

COVID-19 infection with two doses of vaccination

No difference in JIA and controls (p=0.14)

COVID-19 infection with three doses of vaccination

No difference in JIA and controls (p=0.53)

Safety

Defined as effect on the underlying autoimmune disease or adverse events.

Hospitalization

One patient with JIA (0.12%) was hospitalized due to COVID-19 infection, compared with 0.08% in the control group.

Immunogenicity

Defined as seroprotection and/or seroconversion.

Not reported.

Udaondo, 2022

Type of study:

Prospective observational exploratory study

Setting and country:

One hospital in Madrid, Spain.

Funding and conflicts of interest: This work has been partially supported by a grant from Merck & Co (USA) MISP

Call, Reference # 60465. The authors declare no conflict of interest.

Inclusion criteria:

Inclusion criteria for all groups was having received the

full SARS-CoV-2 vaccination schedule, with the BNT162b2 mRNA vaccine. Children aged between 12 to 18 years with rheumatic diseases (RD)

were recruited into the study.

Exclusion criteria:

Exclusion criteria for controls were history

or suspicion of chronic disease affecting the immune response and immunosuppressive treatment including

corticosteroids.

No exclusion criteria for RD patients were reported.

N total at baseline:

Patients with RD: 40

JIA: 26

Control: 24

Important prognostic factors:

Median age (range):

I: 14 (13-16)

C: 13 (12-14)

Sex:

I: 55% F

C: 50% F

Groups comparable at baseline? Yes

Children aged between 12 to 18 years with rheumatic diseases (RD), fully vaccinated against COVID-19.

Medication: 35 immunosuppressive treatment, 11 adalimumab, 9 etanercept, 3 infliximab, 5 mycophenolate mofetil, 5 baricitinib, 1 cyclosporine, 14 methotrexate between 10 and 15 mg/m2/weekly combined with other treatment.

The control group included children aged between 12

to 18 years, receiving vaccination against COVID-19 in our hospital.

Length of follow-up:

3 weeks after complete vaccination regime

Lost to follow-up

Not reported

Efficacy

Defined as prevention of infectious disease.

Not reported.

Safety

Defined as effect on the underlying autoimmune disease or adverse events.

Disease activity

No inflammatory arthritis flares in JIA patients were reported, in the context of either vaccination time points.

Immunogenicity

Defined as seroprotection and/or seroconversion.

Not reported.

Erguven, 2010

Type of study:

Cohort study

Setting and country:

Two clinics in Turkey

Funding and conflicts of interest: Not reported

Inclusion criteria:

Children with JIA, negative anti-HAV IgG.

Exclusion criteria:

Children with chronic disease other than JIA and children who did not regularly come to follow-up.

N total at baseline:

JIA: 47

Control: 67

Important prognostic factors:

Mean age ± SD:

JIA: 10.73 ± 3.89

Control: 9.41 ± 3.80

Sex:

JIA: 51.1% F

Control: 46.3% F

Groups comparable at baseline? Yes

Children with JIA, with negative anti-HAV IgG. Children were vaccinated with two doses of hepatitis A vaccine at 6-month intervals.

Healthy children, with negative anti-HAV IgG. Children were vaccinated with two doses of hepatitis A vaccine at 6-month intervals.

Length of follow-up:

On average 2 months after the second dose.

Lost to follow-up:

Not reported.

Efficacy

Defined as prevention of infectious disease.

Not reported.

Safety

Defined as effect on the underlying autoimmune disease or adverse events.

Adverse events

No side effects were encountered in any of the patients. No reactivation was seen and there was no increment in CHAQ scores.

Immunogenicity

Defined as seroprotection and/or seroconversion.

Positive anti-HAV IgG (n (%)):

JIA: 43 (91.5%)

Control: 67 (100%)

_{JIA, juvenile idiopathic arthritis; SD, standard deviation; F, female; IgG, immunoglobulin G; Anti-Hbs, anti-hepatitis B surface; HbsAG, hepatitis B surface antigen; MMR, measles mumps rubella; NA, not analyzed; TBE, tick-borne-encephalitis; TBEV, tick-borne-encephalitis virus; RAI, relative avidity index; SFU, spot forming units; IRD, immune rheumatic diseases; RD, rheumatic diseases; HAV, hepatitis A virus; CHAQ, Childhood Health}

_{Assessment Questionnaire}

Risk of bias table for interventions studies (cohort studies based on risk of bias tool by the CLARITY Group at McMaster University)

Author, year

Selection of participants

Was selection of exposed and non-exposed cohorts drawn from the same population?

Exposure

Can we be confident in the assessment of exposure?

Outcome of interest

Can we be confident that the outcome of interest was not present at start of study?

Confounding-assessment

Can we be confident in the assessment of confounding factors?

Confounding-analysis

Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these confounding variables?

Assessment of outcome

Can we be confident in the assessment of outcome?

Follow up

Was the follow up of cohorts adequate? In particular, was outcome data complete or imputed?

Co-interventions

Were co-interventions similar between groups?

Overall Risk of bias

Definitely yes, probably yes, probably no, definitely no

Low, Some concerns, High

Studies retrieved from Jansen (2022)

Brunner, 2020

Definitely yes

Unexposed and exposed were both the same population; both children with JIA.

For outcome safety:

Probably no

Not described how outcome is measured.

For outcome immunogenicity: Definitely yes

A single blood sample was used.

Definitely no

Patients already received the vaccination prior to enrolment, so the oucomes were present at the start.

For outcome safety:

Probably no

Not described how outcome is measured.

For outcomes immunogenicity: Definitely yes

Blood samples from all patients were used.

Probably yes

Participants were part of a substudy, and were very similar based on patient characteristics. Nothing is mentioned about matching or adjusting for confounders.

For outcome safety:

Probably no

Not described how outcome is measured.

For outcome immunogenicity: Definitely yes

Outcomes were assessed from a blood sample.

Definitely yes

One patient discontinuted.

Probably no

Patients were part of the substudy, but it is unclear whether they were all in the intervention or control group.

High

(safety)

Some concerns

(immunogenicity)

Ingelman-Sundberg, 2016

Definitely yes

Unexposed were treated in the same hospital or siblings.

Definitely yes

Sample titre analysis were used.

Definitely no

Patients were already vaccinated before enrolment, so the outcomes were present at the start of the study.

Probably no

Serum IgG avidity, flow cytometry and ELISpot analysis were only performed in a subgroup of samples, but this was not equally divided between groups.

Probably no

Controls were age-matched, but the exact duration between vaccination and inclusion was not clear in all cases.

Definitely yes

Outcomes were assessed from serum titre samples.

Definitely no

Due to sample limitations, a subgroup of samples is used for analysis of serum IgG avidity, flow cytometry and ELISpot analysis.

Probably no

11 children in the control group received a minor surgery.

High (immunogenicity)

Heijstek, 2012

Definitely no

Controls were an historical cohort, so not from the same time frame as patients.

Probably yes

IgG serum levels were determined, but it is not completely clear how this blood was obtained, especially in the historical cohort. Vaccination data of patients were also obtained from parents.

Definitely no

Patients already received the vaccination prior to enrolment, so the oucomes were present at the start.

Definitely yes

Vaccination data of healty controls were obtained from a previous study, data of patients were retrieved from parents and the national vaccination registration database.

Definitely yes

Clinical data concerning confounders were collected, multivariable linear regression analysis was performed to correct for age and number of vaccinations.

Probably yes

Outcomes were assessed using samples and from the healthy cohort from a previous study.

Definitely yes

No missing outcome data.

Probably yes

No cointerventions were described.

Some concerns

(immunogenicity)

Heijstek, 2014

Probably yes

Patients were recruited in the hospital and controls via two sencondary schools.

For outcome safety:

Probably yes

Standardized diary for 14 days after vaccination was used.

For outcome immunogenicity: Definitely yes

Blood samples were used.

Definitely yes

Patients received the vaccination in the study period, so the outcomes could not have been present before.

Definitely yes

Blood samples and self-reported diary was used of all participants at the start of the study.

Probably yes

Controls were age matched.

Definitely yes

Outcomes were assessed from titers of blood samples and systemtatically diary.

Probably no

One healthy control was lost to follow-up and seven patients. This is not evenly balanced, and no correction was made for this.

Probably yes

No cointerventions were described.

Low

(safety and immunogenicity)

Esposito, 2014

Definitely yes

Both groups were recruited from the same hospital in the same period.

For outcome safety:

Probably yes

Subjects were observed 30 min after vaccination and recorded a diary card for the following 14 days. Disease activity was assessed during clinical visits using the JADAS-27.

For outcome immunogenicity: Definitely yes

Serum was analyzed.

Definitely yes

No patient had HPV-specific antibodies or a history of positive HPV DNA test at enrolment.

Definitely yes

Blood samples and self-reported diary was used of all participants.

Definitely yes

Participants were matched based on age distribution and gender.

Definitely yes

Outcomes were assessed from titers of blood samples and systemtatically diary.

Probably yes

No missing outcome data was reported.

Probably yes

No cointerventions were described.

Low

(safety & immunogenicity)

Stoof, 2014

Definitely yes

Unexposed and exposed were from the same time frame.

Definitely yes

Serum samples were used for determining antibody concentrations.

Definitely no

Patients already received the vaccination prior to enrolment, so the outcomes were present at the start.

Probably no

Estimated IgG values from patients were compared with measured values from healthy patients.

Probably no

No matching was performed. The article states that there were no statistical differences between groups.

Definitely yes

Outcomes were assessed from a serum sample.

Definitely yes

No missing outcome data.

Probably yes

No cointerventions were described.

Some concerns (immunogenicity)

Aikawa, 2015

Definitely yes

Both groups consisted of JIA patients.

For outcome immunogenicity and efficacy:

Definitely yes

Blood samples were used.

For outcome safety:

Probably yes

A weekly diary and questionnaires were used.

Definitely yes

Patients were vaccinated after start of the study, a baseline measurement was performed and patients with a previous vaccination were excluded.

For outcome immunogenicity and efficacy:

Definitely yes

Blood samples from all patients were used.

For outcome safety:

Probably yes

A weekly diary and questionnaires were used three times.

Probably no

Article does not state anything about matching and no statistical correction is performed. It only states that the groups were comparable on possible confounding factors and include a p-value.

For outcome immunogenicity and efficacy:

Definitely yes

Outcomes were assessed from a blood sample.

For outcome safety:

Probably no

Self-report was used.

Probably no

18% lost to follow-up, which is high in relation to the amount of patients included and in the other group.

Probably yes

No cointerventions were described.

Some concerns (efficacy and immunogenicity)

High

(safety)

Aikawa, 2012

Definitely yes

Both groups were from the same centre and at the same time.

Definitely yes

Serum was used.

Definitely yes

Patients were vaccinated after start of the study and patients with a previous vaccination were excluded.

Definitely yes

Serum from all patients were used.

Definitely yes

Controls were age-matched.

Definitely yes

Outcomes were assessed from a serum sample.

Definitely yes

No patients lost to follow-up.

Probably yes

No cointerventions were described.

Low

(immunogenicity)

Aikawa, 2013

Definitely yes

Both groups were from the same centre and at the same time.

For outcome safety:

Probably yes

21-day personal diary card was used.

For outcome immunogenicity: Definitely yes

Serum was used.

Probably yes

Patients were vaccinated after start of the study, so outcomes were probably not present.

For outcome safety:

Probably yes

A 21-day diary card was used.

For outcome immunogenicity and efficacy:

Definitely yes

Serum from all patients was used.

Definitely no

The article does not state anything about matching or statistically adjustment.

For outcome safety:

Probably yes

Outcomes were assessed from a 21-day diary.

For outcome immunogenicity: Definitely yes

Outcomes were assessed from serum.

Probably yes

The article does not state anything about how many patients are lost to follow-up.

Probably yes

No cointerventions were described.

High

(safety)

Some concerns

(immunogenicity)

Carvalho, 2013

Probably no

No description about whether the groups were drawn from the same population. Both groups received the vaccination at the same time.

For outcome efficacy:

Probably yes

Efficacy was determined by repeated telephone contact with the participants, participants were instructed to contact medical staff, medical records were analyzed, and swabs were tested.

For outcome safety:

Probably no

No description in the article how flares and disease activity were measured.

For outcome immunogenicity: Definitely yes

Titers were used.

Probably no

Patients were vaccinated during the 2^nd surveillance period, so the outcomes could have been present.

For outcome efficacy:

Definitely yes

All participants had the telephone contact and records were analysed

For outcome safety:

Probably no

Unclear

For outcome immunogenicity: Definitely yes

Titers from all patients were used.

Definitely yes

Statistical methods (Fisher’s exact test and logistic regression model) were used to adjust for confounders.

For outcome efficacy:

Probably yes

Outcomes were assessed from swabs, medical records and telephone calls.

For outcome safety:

Probably no

Not clear how outcomes were assessed.

For outcome immunogenicity: Definitely yes

Outcomes were assessed from titers.

Definitely no

Between surveillance 1 and 2, n=6 lost to follow-up, and in surveillance period 2, n=19 lost to follow up.

Probably yes

No cointerventions were described.

Some concerns

(efficacy)

High

(safety)

Some concerns

(immunogenicity)

Toplak, 2012

Definitely yes

All three groups were vaccinated at the same time and the control groups were patients from the same clinic.

For outcome efficacy:

Probably yes

Dairy, nasal and oral swabs, and survey were used to determine efficacy.

For outcome safety:

Probably yes

Measured by using a diary (adverse events) and at three time points using a paediatric core set for rheumatology.

For outcome immunogenicity: Definitely yes

Titers were used.

Definitely yes

Children were vaccinated after start of the study, so the outcomes were probably not present at start of the study.

For outcome efficacy:

Definitely yes

Multiple methods were used by every participant.

For outcome safety:

Definitely yes

Multiple methods were used by every participant.

For outcome immunogenicity: Definitely yes

Titers from all patients were used.

Definitely no

The article does not describe that participants were matched and no statistical adjustment is described.

For outcome efficacy:

Probably no

Outcomes were assessed using self-report.

For outcome safety:

Probably no

Outcomes were assessed using self-report.

For outcome immunogenicity: Definitely yes

Outcomes were assessed using titers.

Probably yes

Article describes no missing outcome data and it is not possible to extract this.

Probably yes

No cointerventions were described.

Some concerns

(efficacy, safety, and immunogenicity)

Woerner, 2011

Probably yes

Both groups were recruited at the same time.

For outcome safety:

Probably no

Parents were instructed to inform the study team, so no repeated interview or diary was used.

For outcome immunogenicity: Definitely yes

Serum was used.

Definitely yes

Children were vaccinated after start of the study, so the outcomes were probably not present at start of the study.

For outcome safety:

Definitely no

Not all patients perfomed self-report, only the patients with adverse events.

For outcome immunogenicity: Definitely yes

Serum from all patients was used.

Probably yes

Participants were matched for age and did not significantly differ in gender.

For outcome safety:

Probably no

Outcomes were assessed by self-report, but not regularly.

For outcome immunogenicity: Definitely yes

Outcomes were assessed using serum.

Probably yes

No missing outcome data reported.

Probably yes

No cointerventions were described.

High

(safety)

Low

(immunogenicity)

Dell’Era, 2012

Definitely yes

Exposed and unexposed were both from the same clinic and included at the same time.

For outcome safety:

Probably yes

Adverse outcomes were assessed in 30 min observation after vaccination and diary card for the following 14 days, and disease activity was assessed three times.

For outcome immunogenicity: Definitely yes

Serum samples were used.

Definitely yes

Children were vaccinated after start of the study, so the outcomes were probably not present at start of the study.

For outcome safety:

Probably yes

All patients and parents needed to fill in the diary and were observed.

For outcome immunogenicity: Definitely yes

Serum from all patients was used.

Definitely yes

Healthy subjects were of similar age and gender.

For outcome safety:

Probably yes

Outcomes were regularly assessed by self-report.

For outcome immunogenicity: Definitely yes

Outcomes were assessed using serum.

Definitely yes

No lost to follow-up.

Probably no

Healthy subjects received minor surgery and the two groups with JIA use different medication.

Low

(safety)

Low

(immunogenicity)

Camacho-Lovillo, 2017

Definitely yes

Patients and healthy controls were siblings.

For outcome safety:

Probably yes

Questionnaire every 3 months and actively monitoring was used.

For outcome immunogenicity: Definitely yes

Serum samples at three time points were used.

Definitely yes

Children were vaccinated after start of the study and children with an acute infection were excluded, so the outcomes were probably not present at start of the study.

Definitely yes

All patients were questioned, monitored, and serum was measured.

Definitely no

No matching or statistical adjustment was performed.

For outcome safety:

Probably yes

Outcomes were regularly assessed by questionnaire.

For outcome immunogenicity: Definitely yes

Outcomes were assessed using serum.

Definitely no

67% lost to follow-up after one year and lost to follow-up in control group is not reported.

Probably yes

No cointerventions reported.

Some concerns

(safety)

High

(immunogenicity)

Groot, 2017

Probably yes

No information about inclusion of patients. Patients were included after 2008, but healthy controls not.

For outcome safety:

Probably yes

JADAS-71 score by parents was used.

For outcome efficacy and immunogenicity: Definitely yes

Serum was used.

Probably yes

Patients received vaccination after start of the study.

Probably yes

All parents completed the JADAS-71 score and were asked to do this two times.

Definitely no

No information provided about matching or statistical adjustments.

For outcome safety:

Probably yes

Outcomes were assessed with JADAS-71 score.

For outcome efficacy and immunogenicity: Definitely yes

Outcomes were assessed using serum.

Probably yes

Article does not describe incomplete outcome data.

Probably no

No other vaccines were administered during the study, but some patients (n=21) received a second dose with another vaccine brand, and all controls received one vaccination.

High

(safety)

Some concerns

(efficacy and immunogenicity)

Studies retrieved from additional search

Çakmak, 2022

Probably yes

Unexposed and exposed were both from the same clinics and probably the same time frame.

Definitely yes

Medical records were used, and when this was incomplete, parents were asked for clarification.

Definitely no

Children were already vaccinated at the start of the study, so the outcomes were present at the start.

Definitely yes

Charts were reviewed and could be reproduced.

Probably yes

Controls were age and sex-matched.

Definitely yes

Outcomes were assessed from titers of blood samples.

Definitely yes

No missing data.

Probably no

Children in the IG did not have a surgery and children in the CG had after measuring blood levels.

Low

(immunogenicity)

Ziv, 2022

Definitely yes

Patients and control were both adolescent menbers of CHS.

Definitely yes

Data of CHS and CHS prescription system were used.

Probably no

This was an observational study, so participants could have the COVID-19 infection at the start of the study.

Definitely yes

Data from a database was used and could be reproduced.

Probably yes

Controls were age matched.

Definitely yes

Outcome was COVID-19 infection based on a positive PCR test and hospitalization,and this was retrieved from the charts.

Definitely yes

No missing data.

Probably yes

No cointerventions were described.

Low

(efficacy)

Low

(safety)

Udaondo, 2022

Definitely yes

Patients and controls were from the same hospital.

For outcome immunogenicity: definitely yes

Blood samples were used.

For outcome safety: Definitely no

Self-report of adverse events.

Definitely yes

Participants were vaccinated at the start of the study, so the outcomes could not be present. Previous COVID-19 infection was confirmed by PCR of antigen test.

For outcome immunogenicity: Probably yes

Charts were used and could be reproduced.

For outcome safety:

Probably no

Not all patients completed the self-report.

Probably yes

Controls were age matched.

For outcome immunogenicity: Definitely yes

Outcome was IgG COVID-19 was based on antigen titer, and this was retrieved from the charts.

For outcome safety: Definitely no

Self-report

For outcome immunogenicity: Definitely yes

No missing data

For outcome safety: Definitely no

Several ‘not reported’, which is also not in balance between the two groups.

Probably yes

No cointerventions were described.

High

(safety)

Low

(imunogenicity)

Erguven, 2010

Definitely yes

Patients and controls were from the same clinics and included in the same time frame.

For outcome safety:

Probably no

CHAQ questionnaire was used, but it is not described when and how often.

For outcome immunogenicity: Definitely yes

Titers were used.

Definitely yes

Participants were vaccinated in the study and they were tested at baseline for anti-HAV IgG, so the outcomes were not present at the start of the study.

For outcome safety:

Probably no

Unclear how questionnaire was used.

For outcome immunogenicity: Definitely yes

Titers of all patients were used.

Probably yes

Controls had a similar age and sex.

For outcome safety:

Definitely no

Unclear whether all participants completed the questionnaire.

For outcome immunogenicity: Definitely yes

Outcomes were assessed using antibody titers.

Probably yes

The article does not report anything about missing data but it seems from the results that no patient is lost to follow-up. Although children who did not regularly come to follow-up were excluded.

Probably yes

No cointerventions were described.

High

(safety)

Low

(immunogenicity)

Risk of bias table for intervention studies (randomized controlled trials; based on Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University)

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Was the allocation adequately concealed?

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Was loss to follow-up (missing outcome data) infrequent?

Are reports of the study free of selective outcome reporting?

Was the study apparently free of other problems that could put it at a risk of bias?

Overall risk of bias

If applicable/necessary, per outcome measure

Heijstek, 2013

Definitely yes

Computer generated sequence operated by an independent research organization was used.

Probably yes

Not reported how allocation was concealed.

Definitely no

Patients, clinical staff, and research staff was not masked. Laboratory staff were masked.

Definitely no

In both the intervention and control group, samples were available of 47 of the 63 patients at 12 months.

Definitely yes

Outcomes in article are also described in the protocol.

Definitely yes

No other problems noted; the study was funded but the sponsor had no role in the study.

Some concerns

(safety and immunogenicity)

Table of excluded studies

Reference	Reason for exclusion
Keller, 2022	Broader PICO. A part of the studies is also in the review of Jansen. The other studies will be judged seperately
Fridman, 2021	Russian article
Sahn, 2022	No subgroup analysis in JIA patients
Yeo, 2023	No suitable subgroup analysis in JIA patients
Alexeeva, 2020	Study only reports results and limitations, remaining is in Russian + study compares sJIA remission with sJIA active (wrong comparison) + wrong population (SJIA)
Kostik, 2021	Cross-sectional study
Prelog, 2021	Cross-sectional study
Jensen, 2021	Study also includes patients with other diseases and no subgroup analysis is performed.
Borte, 2009^a	Publication in February 2009, before the search date of Jansen in September 2009
Kasapcopur, 2004^a	Publication in 2004, before the search date of Jansen in September 2009
Zonneveld-Huijssoon, 2007^a	Publication in February 2007, before the search date of Jansen in September 2009
Shinoki, 2012^a	Wrong population; patients with SJIA
Farmaki, 2010^a	Wrong comparison; studying the effect of anti-TNF treatment
Maritsi, 2017^b	Case-control study
Maritsi, 2013^b	No full text available
Szczyglieska, 2020^b	No control group, cross sectional study.
Nerome, 2016^b	No control group, compares patients with biologicals with patients with no biologicals.
Szczygielska, 2015^b	Wrong population; includes patients with AIRDs and performs no subgroup analysis.
Uziel, 2020^b	Wrong population; includes a broader group of patients and performs no subgroup analysis.
Jeyaratnam, 2018^b	Case reports, no control group, and broader population.
Toplak, 2014^b	No control group.

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld : 17-02-2025

Laatst geautoriseerd : 17-02-2025

Geplande herbeoordeling :

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Kindergeneeskunde

Geautoriseerd door:

Nederlandse Internisten Vereniging
Nederlandse Vereniging voor Kindergeneeskunde
Nederlandse Vereniging voor Reumatologie
Artsen Jeugdgezondheidszorg Nederland
Jeugdreuma Vereniging Nederland
Youth-R-Well

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS).

De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2022 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor kinderen met JIA.

Werkgroep

Dr. M.H.A. (Marc) Jansen, kinderarts reumatoloog/immunoloog, werkzaam in het UMC Utrecht, NVK
Dr. I. (Ivette) Essers, reumatoloog, werkzaam Maastricht Universitair Medisch Centrum+, NVR
Dr. M.A.J. (Marion) van Rossum, kinderarts-reumatoloog/immunoloog, werkzaam in het Amsterdam UMC en detachering naar Reade Reumatologie, NVK (voorzitter)
Dr. M.W. (Marloes) Heijstek, internist allergoloog/immunoloog, werkzaam in het UMC Utrecht, NIV
Dr. L.M. (Lilly) Verhagen, kinderarts- infectioloog/immunoloog, werkzaam in het Radboudumc, NVK
Dr. C.G. (Casper) Schoemaker, adviseur patiëntenparticipatie, werkzaam in het UMC Utrecht en bij INVOLV, Jeugdreumavereniging
Drs. E. (Elizabeth) Legger, kinderarts-reumatoloog-immunoloog, werkzaam in het UMCG, persoonlijke titel
Dr. W. (Wendy) Wagenaar, senior onderzoeker, werkzaam bij Tranzo, Tilburg Universiteit, Youth-R-Well

Klankbordgroep

Drs. A.M. (Annemiek) van Woudenberg, arts M&G, werkzaam bij de GGD Amsterdam, AJN Jeugdartsen Nederland
Prof dr. E.A.M. (Lieke) Sanders, kinderarts, werkzaam in het UMC Utrecht, RIVM

Met ondersteuning van

Dr. J. (Janneke) Hoogervorst-Schilp, senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. A.J. (Bart) Versteeg, senior adviseur, Kennisinstituut van de Federatie Medsich Specialisten
Dr. T. (Tim) Christen, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Drs. L. (Liza) van Mun, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van (kern)werkgroepleden en klankbordgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

Betrokkenen	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
Werkgroep
Van Rossum*	Kinderarts reumatoloog/immunoloog Amsterdam UMC en detachering naar Reade reumatologie Amsterdam	Geen	Geen	Geen actie
*Essers*	Reumatoloog in reumacentrum Genk en ziekenhuis oost Limburg Genkt (België)	Geen	Geen	Geen actie
*Schoemaker*	Adviseur patiëntenparticipatie in het UMC Utrecht en bij INVOLV	Lid WAC Longfonds (onbetaald) Vrijwilliger Jeugdreuma Vereniging Nederland	Geen	Geen actie
*Heijstek*	Internist allergoloog/immunoloog UMC Utrecht	Immunostart project deelname (preventie voor start immunosuppressie, oa met vaccinaties)	Sprekersvergoeding (2019): Roche Pharma	Geen actie
*Verhagen*	Kinderarts infectioloog/immunoloog Radboudumc, Nijmegen	Onderzoeker	Hypatia tenure track grant (onderwerp: mucosale immuunsysteem in luchtweginfecties) ZonMW VENI (onderwerp mucosale immuuncellen in luchtweginfecties) Stichting Kiddy Goodpills (onderwerp: het nut van onderhoudsantibiotica bij terugkerende luchtweginfecties). PI van genoemde onderzoeken.	Geen actie
*Legger*	Kinderarts reumatoloog/immunoloog UMCG	NVK- subrichtlijn JIA	1. Novartis: leveren datamanager Eurofever, projectleider. 2. Sobi: leveren datamanager Eurofever, projectleider	Geen actie
*Wagenaar*	Senior onderzoeker Tranzo, Tilburg Universiteit	Trainer patiëntenparticipatie bij INVOLV (betaald) Vrijwilliger Youth-R	Ikzelf en vrienden met jeugdtreuma	Geen actie
*Jansen*	Kinderarts reumatoloog/immunoloog UMC Utrecht	Chief Science PReS vaccination working party (onbetaald) Myositis richtlijn (onbetaald)	Biomarkers in JDM (copromoter), valt buiten scope van deze richtlijn	Geen actie

* Voorzitter

Klankbordgroep

Van Woudenberg

Directeur de Jeugdzaak, GGD Amsterdam, Lid werkgroep via AJN

Geen

Geen actie

Sanders

Adviseur RIVM, 1,0 fte.

Hoogleraar UMC Utrecht, WKZ, 0,2 fte

Geen

Geen actie

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door afvaardiging vanuit de Jeugdreumavereniging en Youth-R-Well in de werkgroep. De conceptrichtlijn is tevens voor commentaar voorgelegd aan Jeugdreumavereniging en Youth-R-Well en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).

Module	Uitkomst raming	Toelichting
Module Vaccinaties bij JIA	Geen financiële gevolgen	Uit de toetsing volgt dat de aanbeveling(en) niet breed toepasbaar zijn (<5000 patiënten) en zal daarom naar verwachting geen substantiële financiële gevolgen hebben voor de collectieve uitgaven.

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 en Richtlijnen 3.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

Beoordelen van de kracht van het wetenschappelijke bewijs

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

GRADE	Definitie
Hoog	er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Redelijk	er is redelijke zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Laag	er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Zeer laag	er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; de literatuurconclusie is zeer onzeker.

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

	Sterke aanbeveling	Zwakke (conditionele) aanbeveling
Voor patiënten	De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.	Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.
Voor behandelaars	De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.	Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.
Voor beleidsmakers	De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.	Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

Organisatie van zorg

In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

Literatuur

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html

Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

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Richtlijnendatabase

Juveniele idiopathische artritis (JIA)

Juveniele idiopathische artritis (JIA)

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