Systemische behandeling

Beoordeeld: 28-11-2024

Uitgangsvraag

Wat is de plaatsbepaling van immuunmodulerende therapie van patiënten met SjS?

Deze uitgangsvraag bevat de volgende deelvragen:

Wat is de plaatsbepaling van glucocorticosteroïden in de behandeling van actieve systemische ziekte?
Wat is de plaatsbepaling van immuunmodulerende therapie bij actieve systemische ziekte? Op orgaanspecifiek niveau: constitutionele symptomen, fenomeen van Raynaud, lymfadenopathie, speekselklierzwelling/sialadenitis, artritis, pulmonaal, huidbetrokkenheid, neurologische manifestaties (musculair, perifeer zenuwstelsel, centraal zenuwstelsel), renale betrokkenheid en hematologische betrokkenheid
Hoe wordt de behandelrespons geëvalueerd?

Aanbeveling

Overweeg immuunmodulerende therapie voor de behandeling van SjD met systemische ziekteactiviteit.

Overleg zo nodig met een expertisecentrum op het gebied van SjD of met behandelaars met orgaanspecifieke expertise indien er (mogelijk) indicatie is voor behandeling van systemische ziekteactiviteit.

Gebruik glucocorticoïden in de laagst mogelijke dosis en voor de kortst mogelijke tijdsduur die nodig is om actieve systemische ziekte in remissie te brengen en te houden.

Overweeg B-celgerichte therapieën bij patiënten met ernstige, refractaire systemische ziekteactiviteit.

Als algemene regel kan de systemische orgaan specifieke behandeling bestaan uit sequentieel of gecombineerd gebruik van GC’s en DMARDs. Zie de stroomschema’s.

Stroomschema 1 sequentieel of gecombineerd gebruik van GC’s en DMARDs

Stroomschema 2 sequentieel of gecombineerd gebruik van GC’s en DMARDs

Stroomschema 3 sequentieel of gecombineerd gebruik van GC’s en DMARDs

Overwegingen

Additionele search

De aanbevelingen zijn gebaseerd op de ‘EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies’ (2019) en overwegingen die zijn opgesteld door de werkgroepleden op basis van kennis en ervaring uit de praktijk. Er is een additionele literatuursearch verricht om de meest recente klinische studies met betrekking tot systemische behandeling mee te nemen in de overwegingen. Vanuit de additionele literatuursearch zijn drie studies gevonden die voldoen aan de opgestelde PICO en die het effect van een systemische behandeling hebben onderzocht in patiënten met de ziekte van Sjögren. Hiervan hebben twee studies het effect van abatacept t.o.v. placebo (Baer, 2021; van Nimwegen, 2020) en één studie het effect van rituximab t.o.v. placebo (Bowman, 2017) vergeleken. De overall bewijskracht voor het effect van abatacept en rituximab in de geïncludeerde studies was zeer laag. Voor de verschillende uitkomstmaten werd een zeer lage bewijskracht gevonden of was de bewijskracht niet te beoordelen, onder andere vanwege het rapporteren van onvolledige of getransformeerde resultaten. Hierdoor is de klinische relevantie bij meerdere uitkomstmaten niet te bepalen. Vanwege de benoemde limitaties, kunnen deze resultaten geen richting geven aan de besluitvorming.

In de meeste studies zijn ESSDAI en ESSPRI als uitkomstmaten gebruikt met een minimal clinically important improvement (MCII). In meerdere trials werd o.b.v. deze MCII een relatief groot aantal responders (>50%) gevonden in de placebo arm, wat het moeilijk maakt om superioriteit van de actieve behandelarm aan te tonen. Momenteel worden samengestelde uitkomstmaten verder onderzocht, waarbij de respons op verschillende klinisch relevante uitkomstmaten wordt gecombineerd om klinische effectiviteit te meten in deze heterogene ziekte (Arends, 2023).

Glucocorticosteroïden in de behandeling van actieve systemische ziekte

Er zijn geen prospectieve studies naar het effect van GCs op systemische manifestaties. Op basis van retrospectieve studies wordt het gebruik van GCs niet standaard aanbevolen, mede gezien de bijwerkingen. Indien GCs worden gegeven, wordt aanbevolen de dosering en behandelduur zoveel mogelijk te beperken. Als inductietherapie voor ernstige orgaanbetrokkenheid kunnen methylprednisolon pulsen nodig zijn, gevolgd door een afbouwschema vanaf 1mg/kg/dag. Voor minder ernstige orgaanbetrokkenheid kan oraal prednison in doseringen <0,5mg/kg/dag nodig zijn. Bij ernstige orgaanmanifestaties kunnen langdurig hoge doseringen nodig zijn om schade te voorkomen. Bij remissie wordt gestreefd naar volledig afbouwen van GCs of indien dit niet mogelijk is naar een lage dosering (≤5mg/dag). Indien langdurige behandeling nodig is (> 3 maanden), wordt aanbevolen GC-sparende behandeling te starten, waarbij er geen evidence is voor voorkeur voor een bepaald immuunsuppressivum (zie ook richtlijn Osteoporose en fractuurpreventie).

Immuunmodulerende therapie bij actieve systemische ziekte

Conventionele DMARDs

Er zijn geen prospectieve studies die het effect van verschillende conventionele DMARDs op systemische manifestaties vergelijken. Bij de keuze van de therapie wordt aanbevolen rekening te houden met patiëntkarakteristieken, comorbiditeit en bijwerkingenprofiel. Hieronder worden per orgaanmanifestatie aanbevelingen gedaan, gebaseerd op prospectieve ongecontroleerde studies, retrospectieve studies, case series en expert opinion.

B-cel gerichte therapie

In de meeste RCTs met SjD-patiënten is de effectiviteit van biologicals bestudeerd, met name van B-cel gerichte therapie middels rituximab (RTX) (Meijer, 2010; Devauchelle-Pensec, 2014; Bowman, 2017). Deze RCTs zijn niet gericht op specifieke orgaanbetrokkenheid en er worden wisselende resultaten gerapporteerd. Retrospectieve en ongecontroleerde studies laten een respons van 60-100% zien van behandeling met RTX op systemische manifestaties, in het bijzonder op cryoglobuline-geassocieerde uitingen (Gottenberg, 2005; Gottenberg, 2013; Seror, 2007). In een aantal van deze studies wordt ook reductie van dagelijkse doseringen GCs beschreven. Ook in een open label studie met belimumab wordt verbetering van systemische manifestaties beschreven, waaronder bij 3 van 5 RTX refractaire patiënten (De Vita, 2015). Vanwege deze beperkte evidence wordt aanbevolen behandeling met RTX te overwegen voor ernstige orgaanmanifestaties, met name als deze cryoglobuline-geassocieerd zijn. Belimumab kan worden overwogen bij RTX-refractaire ernstige uitingen.

Aanbevelingen per systemische manifestatie

Hier volgen de aanbevelingen voor de meest voorkomende systemische manifestaties (zie ook bijlage voor een schematische weergave). In het algemeen is aan te bevelen andere oorzaken uit te sluiten, alert te zijn op overlap met andere systemische auto-immuunziekten zoals SLE, reumatoïde artritis (RA), vasculitis en systemische sclerose. En daarnaast controles en screening uit te voeren zoals aanbevolen bij de diverse immuunmodulerende therapieen.

Noot: behalve corticosteroïden zijn de middelen die staan beschreven in de samenvatting van de literatuur en aanbevelingen niet geregistreerd voor de behandeling van de ziekte van Sjögren.

Constitutionele symptomen en lymfadenopathie

Er is geen evidence voor behandeling van constitutionele symptomen of lymfadenopathie bij SjD. In het geval van koorts, nachtzweten en/of gewichtsverlies en/of lymfadenopathie wordt aanbevolen diagnostiek te doen naar lymfoom of andere verklaringen indien daar aanleiding voor is. Indien deze oorzaken redelijkerwijs zijn uitgesloten en de constitutionele symptomen/lymfadenopathie bij SjD worden geduid, wordt expectatief beleid geadviseerd. Veelal is er een wisselend beloop met spontane remissie. Indien de symptomen langdurig aanhouden en hoge ziektelast geven, kan proefbehandeling met hydroxychloroquine of lage dosis prednison worden overwogen.

Lymfoom

SjD-patiënten hebben een verhoogd risico op het ontwikkelen van lymfoom. ~5-10% van de SjD-patiënten ontwikkelt non-Hodgkinlymfoom, wat een 5-44 maal hoger risico is dan in de algemene populatie (Theander,2006; Lazarus, 2006; Ramos-Casals, 2002; Voulgarelis, 1999; Zufferey, 1995). Meest voorkomend zijn laaggradige lymfomen, met name marginale zonelymfoom van het MALT-weefsel van de parotis (vaak MALT-lymfoom genoemd). Risicofactoren zijn o.a. persisterende speekselklierzwelling, lymfadenopathie, cutane vasculitis, splenomegalie, hypocomplementemie, aanwezigheid van M-proteïne en cryoglobulinemie (Giannouli, 2014; Voulgarelis, 2008; Nocturne, 2016). Indien er sprake blijkt van lymfoom wordt de hematoloog geconsulteerd en zo nodig andere betrokken specialisten voor multidisciplinaire behandeling. De behandeling wordt afgestemd op het individu en hangt af van het (histologische) type lymfoom en de stadiëring. Bij een beperkt MALT-lymfoom van de parotis kan wait-and-see beleid worden gevoerd. Radiotherapie wordt in sommige gevallen toegepast in een lage dosis (2x 2Gy of 1x 4Gy). Bij deze dosis is het negatieve effect op de speekselklierfunctie laag. Rituximab of chemotherapieschema’s met rituximab worden voor uitgebreidere ziekte gegeven waarbij de indicatiestelling en behandelplan worden bepaald door de hematoloog.

Speekselklierzwelling

Speekselklierzwelling, met name van de parotiden, komt frequent voor bij SjD en veelal is er een wisselend beloop met spontane remissie. Bij acute pijnlijke speekselklierzwelling is het van belang de differentiaal diagnoses sialolithiasis en bacteriële sialadenitis te overwegen. Zo nodig kan de KNO-arts of MKA-chirurg worden geconsulteerd. Geef conservatieve adviezen (massage, suikervrije zuurtjes, paracetamol, NSAID). Schrijf een antibioticumkuur voor van minimaal 2 weken bij verdenking op bacteriële parotitis/sialadenitis. Bij onvoldoende respons kan de kuur verlengd worden tot 4 of 6 weken in overleg met een KNO-arts of MKA-chirurg. Indien de speekselklierzwelling bij SjD wordt geduid, kan in overleg met de patiënt een korte kuur GC worden overwogen. In uitzonderlijke gevallen kan RTX of belimumab worden overwogen. Bij persistente langdurige speekselklierzwelling wordt aanbevolen diagnostiek te doen naar lymfoom, of andere maligniteiten of oorzaken.

Artralgieën en artritis

Overweeg alternatieve diagnoses als oorzaak van artralgieën of artritis, zoals artrose of reumatoïde artritis, en indien hiervan sprake blijkt benader als zodanig. Voor artralgieën bij SjD kunnen NSAIDs worden voorgeschreven en met name bij inflammatoire artralgieën kan (proefbehandeling) hydroxychloroquine (HCQ) worden overwogen. Bij artritis kan behandeling met HCQ en GCs worden gegeven, indien dit niet effectief blijkt of bij contra-indicaties of intolerantie kan een conventionele DMARD zoals methotrexaat, leflunomide, azathioprine worden gegeven, indien dit niet effectief blijkt/contra-indicatie/intolerantie kan RTX, abatacept of anti-TNF worden overwogen.

Huidbetrokkenheid

De belangrijkste huidafwijkingen bij SjD kunnen worden onderverdeeld in xerosis cutis (zie module Siccaklachten), erythema annulare (Katayama, 2020; Brito-Zeron, 2014), cutane vasculitis (waaronder cryoglobulinemisch en urticarieel) en andere vasculaire afwijkingen (Generali, 2017; Ramos-Casals, 2004; Kittridge, 2011), Raynaud fenomeen en een grote groep “overige” huidafwijkingen waaronder ooglid dermatitis, cheilitis angularis, cutane amyloidose, livedo reticularis, diverse vormen van cutane LE en erythema multiforme.

Beoordeling en behandeling in samenwerking met een dermatoloog met ervaring met systeemziekten wordt aanbevolen. Bij beperkte vormen kan topicaal glucocorticoid of tacrolimuszalf voldoende zijn, indien er geen respons is of bij ernstigere of uitgebreidere vormen kan behandeling met HCQ, orale GCs, andere cDMARDs of RTX worden overwogen). Zie ook de module Cutane manifestaties in de richtlijn Medicamenteuze behandeling en monitoren van SLE. Bij ernstige cryoglobulinemische vasculitis waarbij onvoldoende effect is van RTX, kan cyclofosfamide of plasmaferese worden overwogen.

Longbetrokkenheid

Bij kortademigheid of persistente hoest zonder alternatieve verklaring wordt aanbevolen laagdrempelig beeldvorming en longfunctie-onderzoek te verrichten gezien het frequente voorkomen van longbetrokkenheid bij SjS-patiënten. Verschillende vormen van pulmonale betrokkenheid zijn beschreven, met name ILD-beelden (Nonspecific Interstitial Pneumonia (NSIP), Usual Interstitial Pneumonia (UIP), Lymphoid Interstitial Pneumonia
(LIP), Organizing Pneumonia (OP)), maar ook xerotrachea, xerobronchitis, bronchiolitis, amyloidose en pleurale betrokkenheid. Pulmonale hypertensie is zeldzaam. Er is een belangrijke plaats voor csDMARDs zoals azathioprine en mycofenolaatmofetil, en bij ernstige vormen kunnen RTX en cyclofosfamide worden overwogen. GCs kunnen een plaats hebben bij de behandeling van ILD ter overbrugging totdat de werking van cs/bDMARDs is bereikt. Symptomatische behandeling van xerotrachea en bronchitis/bronchiolitis middels inhalatietherapie en/of vernevelingen kan worden overwogen. De behandelstrategie moet worden bepaald in samenwerking met een longarts met ervaring met systeemziekten.

Renale betrokkenheid

Zowel tubulaire problematiek zoals TIN (tubulo-interstitiële nefritis) of RTA (renale tubulaire acidose, als glomerulonefritis (al dan niet cryoglobulinemisch) kunnen voorkomen. Bij verdenking op renale betrokkenheid wordt aanbevolen te overleggen met een nefroloog met ervaring met systeemziekten. Andere oorzaken dienen te worden uitgesloten. De behandeling kan bestaan uit symptomatische behandeling waaronder bicarbonaatsuppletie en kaliumcitraat en/of immuunsuppressieve behandeling met GCs en DMARDs zoals mycofenolaatmofetil, azathioprine en ciclosporine, en zo nodig RTX, cyclofosfamide en/of plasmaferese.

Myositis

Bij verdenking op myositis wordt overlegd met een neuroloog met ervaring met systeemziekten. Vervolgdiagnostiek mede naar alternatieve oorzaken en behandeling wordt multidisciplinair bepaald. GCs, cDMARDs zoals mycofenolaatmofetil, RTX en IVIG kunnen een plaats hebben in de behandeling. Zie ook richtlijn Myositis.

Perifeer zenuwstelsel

Verschillende manifestaties in het perifeer zenuwstelsel zijn beschreven, veel voorkomend zijn sensorische axonale polyneuropathie en dunnevezelneuropathie, waarvan de behandeling symptomatisch is. Ook de behandeling van autonome dysfunctie is symptomatisch. Daarnaast komen ook o.a. demyeliniserende neuropathie, ganglionopathie, trigeminusneuralgie en mononeuritis multiplex (met of zonder cryoglobulinemie) voor. Met name bij progressieve neuropathieën of motorische betrokkenheid wordt beoordeling door een neuroloog met ervaring met systeemziekten aanbevolen. Behandeling met GCs (zo nodig methylprednisolon pulsen), IVIG, DMARDs, RTX, cyclofosfamide en plasmaferese kunnen overwogen worden.

Centraal zenuwstelsel

Betrokkenheid van het centraal zenuwstelsel is zeldzaam, o.a. vasculitis, neuromyelitis optica spectrum disorder (NMOSD) en multiple sclerose (MS)-like beelden, myelitis transversa en lymfocytaire meningitis zijn beschreven. Beoordeling en behandeling door een neuroloog met ervaring met systeemziekten en indien van toepassing MS is aangewezen. GCs, cyclofosfamide, RTX, plasmaferese, eculizumab en specifieke MS-therapieën kunnen onderdeel zijn van de behandeling.

Cytopenieën
Neutropenie, trombopenie en hemolytische anemie kunnen voorkomen. Indien deze ernstig en/of symptomatisch zijn kan analyse en behandeling door of in overleg met de hematoloog aangewezen zijn, met bijvoorbeeld GCs, IVIG, RTX en zo nodig plasmaferese of cyclofosfamide, en G-CSF bij neutropenie (zie ook richtlijn SLE). Lymfopenie komt ook frequent voor, is meestal asymptomatisch en wordt niet behandeld.

Anti-SSA/Ro positieve vrouwen in vruchtbare leeftijd

Aanwezigheid van anti-SSA/Ro-auto-antilichamen geeft risico op congenitaal hartblock bij het ongeboren kind en neonatale lupus. Met name zwangeren met anti-Ro/SSA titer ≥50U/mL gemeten met ELISA (overeenkomstig met een titer van ≥120U/mL op de FEIA), zijn at risk voor een congenitaal hartblock (Jaeggi, 2010). Aanbevolen wordt bij zwangerschapswens te verwijzen naar een gynaecoloog voor preconceptionele counseling. Tijdens de zwangerschap is controle bij de gynaecoloog aanbevolen en kan primaire preventie met HCQ worden gegeven. Thuismonitoring van het foetale hartritme kan worden overwogen. Indien er congenitaal hartblock blijkt kan behandeling met gefluorideerde GCs (Dexamethason en Betamethason), IVIG en/of plasmaferese worden gegeven. Voor verdere informatie en evidence verwijst de werkgroep naar de NVR richtlijn Medicatiegebruik bij inflammatoire reumatische aandoeningen rondom de zwangerschap.

Fenomeen van Raynaud

Voor behandeling van het fenomeen van Raynaud verwijzen we naar de NIV richtlijn over het fenomeen van Raynaud (deze is in ontwikkeling en nog niet gepubliceerd (05-09-2024)).

Interstitiële cystitis

Bij verdenking op interstitiële cystitis wordt verwijzing naar een uroloog aanbevolen voor analyse en behandeling. Naast deze zeldzame uiting op urologisch gebied, komen frequenter bacteriële urineweginfecties voor bij SjD-patiënten, waarbij de vaginale droogte een risicofactor is.

Betrokkenheid van het maagdarmstelsel, lever en galwegen

Overlap met primaire biliaire cholangitis (PBC) of auto-immuunhepatitis (AIH) komt vaak voor. Indien hierop verdenking bestaat wordt verwijzing naar een MDL-arts aanbevolen.

Ook coeliakie en pernicieuze anemie komen vaker voor bij SjD-patiënten (Urbanski, 2020).

Veel patiënten met Sjögren hebben klachten van maag en darmen, hierover is weinig bekend en er is geen gerichte behandeling voor. In het algemeen wordt aanbevolen deze klachten door de huisarts te laten beoordelen tenzij er duidelijke aanwijzingen zijn voor dysmotiliteit of (MALT)-lymfoom.

Overige systemische uitingen

Er zijn andere systemische uitingen van SjD bekend, waarover in deze richtlijn geen aanbeveling kan worden gedaan, een overzicht van zeldzamere orgaanmanifestaties is o.a. beschreven in Retamozo (2019).

Evaluatie therapierespons

Tot op heden kan geen eenduidige aanbeveling worden gedaan voor een overkoepelend behandeldoel in de klinische praktijk (‘treat to target’). Behandeldoelen zijn afhankelijk van actieve systemische ziekte/orgaanbetrokkenheid. De items in de ESSDAI (Seror, 2015) geven een overzicht van de meest voorkomende orgaanmanifestaties en wat wordt beschouwd als ernstige of minder ernstige uiting. Hoewel orgaanspecifieke beoordeling en behandeling aanbevolen wordt, kan bij patiënten met een ESSDAI ≥5 systemische therapie overwogen worden, waarbij ≥3 punten daling als relevante respons wordt beschouwd (Seror, 2016) of kan worden gestreefd naar lage ziekteactiviteit (ESSDAI<5). Voor evaluatie van therapierespons van behandeling van sicca, pijn en vermoeidheid verwijzen we naar de desbetreffende modules.

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

Bij de keuze voor therapie is het van belang de specifieke patiëntfactoren mee te nemen en de wensen van de patiënt waarbij uitleg over de te verwachten therapierespons en bijwerkingen en andere voor- en nadelen moet worden gegeven. Wij adviseren de behandelkeuzes in gezamelijke besluitvorming tussen patient en zorgverlener te laten plaatsvinden.

Kosten (middelenbeslag)

Gezien er geen geregistreerde systemische immuunmodulerende behandelingen zijn voor de ziekte van Sjögren, zijn er geen gegevens over kosten en baten van systemische immuunmodulerende therapie voor de maatschappij, het ziekenhuis of het afdelingsbudget. Bij de keuze van therapie voor de individuele patiënt dient het kostenaspect te worden meegenomen, mede gezien er voor biological DMARDs geen vergoedingsindicatie is, tenzij er sprake is van specifieke orgaanbetrokkenheid voor het betreffende medicament (bv rituximab bij vasculitis). Een coulance-verzoek kan nodig zijn.

Aanvaardbaarheid, haalbaarheid en implementatie

Gezien er nog geen geregistreerde behandelingen zijn, zijn er geen gegevens over aanvaardbaarheid, haalbaarheid en implementatie.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Gezien er geen geregistreerde behandelingen zijn voor de ziekte van Sjögren zijn de aanbevelingen gebaseerd op de EULAR recommendations en op ervaringen van experts uit Nederland.

Onderbouwing

Achtergrond

Tot op heden zijn er geen geregistreerde systemische behandelingen met immuunmodulerende medicatie voor de behandeling van de klassieke trias van sicca, vermoeidheid en pijn. Een deel van de SjD-patiënten ontwikkelt orgaanbetrokkenheid waarvoor systemische behandeling kan worden gegeven. Hiervoor kunnen geen overkoepelende behandeladviezen worden gegeven en moet per patiënt en per orgaanmanifestatie worden beoordeeld wat een geschikte therapie zou kunnen zijn. Zo nodig kan dit worden besproken in een multidisciplinair overleg (ARCH) of expertisecentrum (zie hier). De items in de ESSDAI (EULAR Sjögren’s Syndrome Disease Activity Index; Seror, 2015) geven een overzicht van de meest voorkomende orgaanmanifestaties en wat wordt beschouwd als ernstige of minder ernstige uiting. Hoewel orgaanspecifieke beoordeling en behandeling aanbevolen wordt, kan bij patiënten met een ESSDAI ≥5 systemische therapie overwogen worden, waarbij ≥3 punten daling als relevante respons wordt beschouwd (Seror, 2016) of kan worden gestreefd naar lage ziekteactiviteit (ESSDAI<5). Niet alle systemische manifestaties zijn beschreven in de ESSDAI, zoals congenitaal hartblock, fenomeen van Raynaud, autonome dysfunctie en interstitiële cystitis.

Zowel glucocorticosteroïden (GCs), conventionele als biological DMARDs kunnen een plaats hebben in de behandeling van orgaanmanifestaties. Hierbij wordt een benadering aanbevolen vergelijkbaar met die bij andere systemische auto-immuunziekten zoals Systemische Lupus Erythematodes (SLE) (zie richtlijn SLE) en vasculitis, met remissie-inductie gevolgd door onderhoudsbehandeling. Er zijn geen studies naar behandelstrategieën bij de ziekte van Sjögren.

Toekomstperspectief

Er worden momenteel belangrijke stappen gezet m.b.t. systemische behandelingen voor SjD, zowel in de ontwikkeling van eindpunten (samengestelde eindpunten CRESS en STAR) als in de ontwikkeling van nieuwe systemische behandelopties – die veelbelovende resultaten laten zien (Arends, 2023). Bijv. post-hoc analyses van diverse trials laten zien dat het met de samengestelde eindpunten mogelijk is om een klinisch effect van de actieve behandeling t.o.v. placebo aan te tonen. Fase 2 trials en abstractpublicaties van recente trials rapporteren een klinisch effect van de actieve behandeling t.o.v. placebo. Veelbelovende middelen zijn dazodalidep (St Clair, 2024), ianalumab (Bowman, 2022), deucravacitinib (abstract International Symposium Sjögren’s Disease 2024), anifrolumab (Dyball, 2022) en iscalimab (Fisher, 2020; Fisher, 2024). Zie bijlage voor een overzicht van lopende trials (Arends, 2023).

Conclusies / Summary of Findings

Abatacept

Efficacy

No GRADE

Very low GRADE

Inconsistent evidence was found regarding the effect of abatacept on saliva production and patient global assessment compared to placebo in adult patients with primary Sjogren’s disease.

The evidence is very uncertain about the effect of abatacept on ESSDAI, ESSPRI, tear production and quality of life compared to placebo in adult patients with primary Sjogren’s disease.

Source: van Nimwegen, 2017

Safety

Very low GRADE

The evidence is very uncertain about the effect of abatacept on adverse events compared to placebo in adult patients with primary Sjogren’s disease.

Source: van Nimwegen, 2017

Rituximab

Efficacy

No GRADE

Very low GRADE

Inconsistent evidence was found regarding the effect of rituximab on ESSDAI, saliva production and tear production compared to placebo in adult patients with primary Sjogren’s disease.

The evidence is very uncertain about the effect of rituximab on ESSPRI and quality of life compared to placebo in adult patients with primary Sjogren’s disease.

Source: Bowman, 2017

Safety

Very low GRADE

The evidence is very uncertain about the effect of rituximab on adverse events compared to placebo in adult patients with primary Sjogren’s disease.

Source: Bowman, 2017

Samenvatting literatuur

In this module, we provide a summary of literature addressing the use of systemic medication in patients with Sjögren’s disease, as presented in the systematic review that informed the EULAR guideline for management of Sjögren’s syndrome (Brito-Zerón, 2019). Judgements about the risk of bias in this module are adopted from the systematic review (Brito-Zerón, 2019). However, as the level of evidence was not evaluated using the GRADE method, no GRADE conclusions were formulated in this module.

Results

EULAR guideline 2020

Hydroxychloroquine

We identified 12 studies that assessed hydroxychloroquine in SjS patients, with only 4 (2 prospective and 2 RCTs) carried out in primary-2002 patients. Yavuz (2011) prospectively enrolled 32 patients treated with hydroxychloroquine for at least 2 years (no data on mean length or cumulative dose) and reported, in a further 12-week control study, a significant improvement in four out of eight ocular outcomes with respect to baseline, with no information on concomitant ocular therapies. Çankaya (2010) prospectively evaluated 30 women who started on 400 mg/day of hydroxychloroquine and reported a significant

improvement in uSF rate (0.212 vs 0.162 baseline, p<0.05) but not stimulated salivary flow rate at 30 weeks, with improvement in only two of the five subjective oral VAS scores. Yoon (2016) carried out a small RCT in 26 patients and found no significant differences in dry eye

in comparison with PLA, but with no definition of the primary outcome (Yoon, 2016). The pivotal RCT was carried out by Gottenberg (2014) in 120 patients with primary-2002 SjS who were randomised to receive 400 mg/day of hydroxychloroquine (n=56) or PLA (n=64): the primary outcome was defined as a ≥30% reduction in two out of three VAS scores—dryness, fatigue, pain—without significant PLA differences at week 24 (17.6% vs 17.3%, p=0.96). For one of the secondary outcomes, hydroxychloroquine was associated with a statistical trend to improved pain (p values between 0.06 and 0.10 at 12, 24 and 48 weeks) although it was not superior to PLA for articular involvement; with respect to fatigue, no statistical differences were found (Gottenberg, 2014). No cases of retinal toxicity or severe adverse events were reported in any of these studies.

Oral GCs

The frequent use of GCs in clinical practice in primary SjS patients is not supported by reliable scientific evidence. In the absence of controlled studies in 2002 patients,

we briefly analysed the data in other SjS populations (Ramos-Casals, 2010). The first study was a very small RCT (eight patients per arm) comparing prednisone 30 mg/day with piroxicam 20 mg/day and PLA, which found significant differences in subjective symptoms but not in objective tests (Fox, 1993). However, a prospective study of 60 patients followed for a mean of nearly 4 years found that corticosteroids did not influence the progressive decrease in salivary flow rates (Pijpe, 2007). No controlled studies are published in primary-2002 patients, and only retrospective studies have reported the use of GCs for systemic disease (Gheitasi, 2015), with a high rate of GC-related adverse events, including increased appetite and weight gain (Fox, 1993), a two-fold higher frequency of diabetes mellitus (Pérez-De-Lis, 2010; Shen, 2017) and Cushing in up to 80% of patients (Shen, 2017).

Immunosuppressive agents

Seven studies have tested immunosuppressive agents in SjS patients (two studies using leflunomide and cyclophosphamide, respectively, and one study each for azathioprine,

methotrexate and mycophenolate), of which only two were carried out in primary-2002 patients. Van Woerkom (2007) carried out a prospective study using 20 mg/day of leflunomide, which showed significant improvement in 5 out of 16 efficacy parameters tested after 24 weeks of therapy (2 were components of quality of life (QoL) questionnaires and 3 analytical parameters); all 15 patients experienced adverse events (between 4 and 8 per patient), principally gastrointestinal (67%), cytopenia (47%) and lupus-like cutaneous lesions (33%). Willeke (2007) tested the use of micophenolic acid 1440 mg/day, reporting significant improvement in 8 out of 16 efficacy parameters after 24 weeks of therapy,

including VAS for sicca features (p<0.02) and mean AT use (p<0.02) (other parameters that improved included components of QoL questionnaires and analytical parameters);

adverse events were reported in 72% of patients.

Biological therapies

Of the 34 studies in which biological agents have been tested in SjS patients, we identified 6 RCTs (using infliximab (INX), anakinra and rituximab) and 10 prospective cohort studies (using etanercept, abatacept, epratuzumab, rituximab and belimumab) carried out in

primary-2002 patients.

Abatacept

Two small prospective cohort studies have tested abatacept in primary-2002 patients. The first enrolled 15 patients with early active disease who received eight intravenous abatacept infusions and reported that ESSDAI, EULAR Sjogren’s Syndrome Patient Reported Index

(ESSPRI), rheumatoid factor and IgG levels decreased significantly at 48 weeks; fatigue and health-related quality of life parameters improved significantly, while salivary and lacrimal gland function did not change; 6 (40%) patients experienced mild acute adverse events

and 10 (67%) self-reported infections (Meiners, 2014). The second study included 11 patients and reported increased saliva production (1.74 vs 1.61 g/2 min baseline, p=0.029) after 24 weeks of therapy and decreased lymphocytic foci in total (but not lymphocytic foci per mm2); one patient developed lupus-like cutaneous lesions (Adler, 2013).

Anakinra

A small RCT that randomised 26 patients (13 to anakinra and 13 to PLA) found no significant reduction in fatigue in the primary endpoint (comparison of fatigue scores at week 4, p=0.19); 2 patients experienced severe side effects (injection site reaction and gastroenteritis, respectively), 2 had a transient episode of neutropenia and 7 (54%) mild injection site reactions (Norheim, 2012).

Baminercept

St Clair (2018) have recently reported on the clinical efficacy and safety of baminercept in 52 patients with primary-2002 randomised in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching PLA. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. The change from baseline to week 24 in the SWSF rate did not differ significantly between the baminercept and the PLA groups (baseline-adjusted mean change −0.01 vs 0.07 mL/min; p=0.332). Baminercept was associated with a higher incidence of liver toxicity, including two serious adverse events.

Belimumab

The results reported by the Efficacy and Safety of Belimumab in Subjects with Primary Sjögren’s Syndrome (BELISS) open-label tria7 in 30 primary-2002 patients (all with systemic complications, early disease and/or abnormal biomarkers) showed that belimumab 10 mg/kg (weeks 0, 2 and 4, and then every 4 weeks until week 24) was associated with a higher rate of improvement in the composite outcome (improvement of at least two of the

five following items: ≥30% reduction in VAS for dryness, fatigue, musculoskeletal pain and physician systemic activity, and ≥25% reduction in any of the B-cell activation biomarkers) in patients with early disease in comparison with those with systemic disease (73% vs 47%); the mean ESSDAI score decreased from 8.8 to 5.59 (p<0.0001) and the ESSPRI score from 6.44 to 5.56 (p=0.01) (Mariette, 2015). In the 19 patients who completed 1 year of treatment, a significant improvement in some ESSDAI involvements (glandular, lymphadenopathy and articular) was maintained (De Vita, 2015). With respect to the safety profile, only one serious adverse event was reported (pneumococcal meningitis) after six drug infusions.

Epratuzumab

In 2006, a small prospective study including 15 patients with primary-2002 SjS reported a beneficial effect on VAS fatigue (<0.05), patient assessment (<0.05), physician assessment (<0.05) and tender joints (<0.05); five patients experienced severe adverse events (acute infusion reactions and infections) (Steinfeld, 2006).

Etanercept

Two studies (one RCT, one prospective) have been carried out in SjS patients; only the prospective study included primary-2002 patients and showed no significant improvements in the main sicca signs and symptoms (Zandbelt, 2004).

Infliximab

A prospective open-label study in 16 patients found significant improvements in subjective and objective measures after the administration of INF, although recently the authors have retracted the manuscript (Steinfeld, 2013). In 2004, Mariette (2004) conducted an RCT including 103 patients and found no significant differences in the primary outcome, defined as improvement in at least 30% of the joint pain, fatigue and dryness VAS at 22 weeks (INF 20.4% vs PLA 16.7%, p=0.62) or in the majority of secondary outcomes (symptoms, salivary flow rates, ocular tests, QoL and salivary biopsy), with improvement only in fatigue and some analytical parameters in comparison with PLA.

Rituximab

Rituximab has been tested in three prospective cohort studies (Pijpe, 2005; Devauchelle-Pensec, 2007; St Clair, 2013), one case-control study (Carubbi, 2013) and four RCTs (Meijer, 2010; Dass, 2008; Devauchelle-Pensec, 2014; Bowman, 2017). A summary of the significant improvements reported with respect to baseline in the prospective cohort studies showed improvement in VAS for dryness (Devauchelle-Pensec, 2007; Carubbi, 2013) ,fatigue (Devauchelle-Pensec, 2007; St Clair, 2013; Carubbi, 2013) and pain/tender point count (Devauchelle-Pensec, 2007), while no significant improvements were reported for objective oral and ocular tests (except in the study by Pijpe (2005) in a subset of patients). In the case-control study, Carubbi (2013) compared the therapeutic effect of rituximab (n=22) and conventional immunosuppressive therapy (n=19) and found a significant improvement in patients treated with rituximab in the ESSDAI (<0.05), global VAS (<0.05), fatigue VAS (<0.01), dryness VAS (<0.01), physician VAS (<0.05), uSF (<0.01) and Schirmer test (<0.05) at the end of follow-up (120 weeks); the authors reported a complete lack of reported adverse events in either of the two arms in spite of the long-term nature of the study. With respect to the two small RCTs, Dass (2008) randomised 17 primary-2002 patients to receive rituximab (n=8) or PLA (n=9) and found no significant results in the primary outcome (improvement >20% VAS fatigue at 6 months, rituximab 87% vs PLA 56%, p=0.36), while Meijer (2010) randomised 30 primary-2002 patients to receive rituximab (n=20) or PLA (n=10) with no significant results for the primary outcome (improvement in SWSF rate at 48 weeks, p>0.05). Two large RCTs have recently been reported. Devauchelle-Pensec (2014) randomised 122 primary- 2002 patients to receive rituximab (n=63) or PLA (n=57) and found no significant results in the primary outcome (≥30 mm improvement at week 24 on at least 2 out of 4 VAS scores—dryness, fatigue, pain, global, 23% vs 22%, p=0.91), while Bowman (2017) randomised 133 primary-2002 patients to receive rituximab (n=67) or PLA (n=66) and found no significant results in the primary outcome (reduction ≥30% at week 48 in either fatigue or oral dryness VAS, rituximab 39.3% vs PLA 36.8%, p=0.76). Two recent meta-analyses including the four RCTs have confirmed the lack of significant between-group differences in mean improvements between baseline and week 24 values for fatigue VAS, oral dryness VAS, salivary flow rate and Schirmer test, and no significant difference between groups for the main adverse events (Letaief, 2018; Chu, 2020).

Additional search

A total of sixteen studies were included in literature analysis. Of these studies, twelve studies were Phase II trials (Bowman, 2022; Capacio 2018; Dorner, 2019; Felten, 2021; Fisher, 2020; He, 2022; Juarez, 2021; Mariëtte, 2022; Price, 2022; St Clair, 2018; van der Heijden, 2020; Xu, 2023). The other three studies were Phase III trials (Baer, 2001; Bowman, 2017; van Nimwegen, 2020). The Phase II trials (together with the study of Karagozoglu (2018)) will not be further analysed according to the GRADE method. An overview of the study characteristics and results of interest can be found in Table 1.

Description of Phase III studies

Baer (2021) performed a double-blind randomized controlled trial in multiple countries (at least Europe and Asia, not fully clear) to evaluate the efficacy and safety of abatacept in patients with active primary Sjogren’s Syndrome (SS). A total of 187 patients were randomized 1:1 to receive either abatacept 125 mg weekly for 24 weeks or placebo. After 24 weeks, patients from both treatment groups were enrolled in an open-label phase were both groups received abatacept (not further considered). The total follow-up period was 52 weeks. Study groups did not differ regarding mean age (I: 51.2 ± 12.3, C: 52.9 ± 13.5) and proportion of males (I: 7.6%, C: 3.2%). Study outcomes of interest included ESSDAI, ESSPRI, (un)stimulated salivary flow rate, Schirmer’s test, patient global assessment, and adverse events. The study was limited by absence of information on the allocation method.

Bowman (2017) performed a double-blind randomized controlled trial in the UK (multi-center) to determine the effectiveness of rituximab in improving symptoms of fatigue and oral dryness in patients with primary SS. A total of 133 patients were randomized 1:1 to receive either rituximab (1000 mg in 250 ml saline) as intervention or a placebo (250 ml saline) in two courses at baseline, at week 2, 24 and 26. To reduce the risk of infusion reactions, patients also received methylprednisolone, acetaminophen and chlorpheniramine pre-infusion. They also received oral prednisolone post infusion 60 mg/day tapered to 15 mg/day over 7 days post-infusion. The total follow-up period was 48 weeks. Study groups did not differ regarding mean age (I: 54.3 ± 11.5, C: 54.4 ± 11.6) or proportion of males (I: 7.6%, C: 6%). Study outcomes of interest included ESSDAI, ESSPRI, unstimulated salivary flow rate, Schirmer’s test, quality of life and adverse events. The study was limited by use of an inadequate randomization method, substantial difference in loss-to-follow-up between groups and no full outcome data reported for stimulated salivary flow and SSDDI.

Van Nimwegen (2020) performed a double-blind randomized controlled trial in the Netherlands (single-center) to assess the safety and efficacy of abatacept compared with placebo in patients with primary SS. A total of 80 patients were randomized 1:1 to receive either abatacept 125 mg weekly for 24 weeks or placebo. Patients were allowed to use concomitant low-dose prednisone (≤ 10 mg/day). After 24 weeks, patients from both treatment groups were enrolled in an open-label phase were both groups received abatacept (not further considered). The total follow-up period was 48 weeks. Study groups did not differ regarding mean age (I: 48 ± 15, C: 49 ± 16) and proportion of males (I: 8%, C: 8%). Study outcomes of interest included ESSDAI, ESSPRI, (un)stimulated salivary flow rate, Schirmer’s test, patient global assessment, quality of life and adverse events. The study was limited by the use of an inadequate allocation method.

Table 1. Overview and results of Phase II trials according to PICO since 2017, all randomized controlled trials.

Study	Study characteristics	Results
Bowman, 2022	Multi centre, Europe/North America No. patients: 27 Intervention a (Ia): Ianalumab 5 mg subcutaneous every four weeks, n = 47 Intervention b (Ib): ‘’ 50 mg, n = 47 Intervention c (Ic): ‘’ 300mg, n = 47 Control: Placebo, n = 49 Baseline characteristics - Mean age (SD): Ia: 52.5 (13.6), Ib: 51.0 (11.1), Ic: 49.1 (15.4), C: 47.9 (12.4) - Sex (% males): Ia: 2%, Ib: 13%, Ic: 2%, C: 4% Follow-up period: 24 weeks	ESSDAI¹: Mean difference in score (95%CI) (intervention minus control) -1.92 (-4.15 to 0.32) ESSPRI¹: Mean difference in score (95%CI) (intervention minus control) -0.06 (-0.86 to 0.74) Stimulated salivary flow rate (ml/min)¹: Mean difference (95%CI) (intervention minus control) 0.20 (0.01 to 0.38) Unstimulated salivary flow rate (ml/min)¹: Mean difference (95%CI) (intervention minus control) -0.01 (-0.10 to 0.07) Patient global asessment¹: Mean difference (95%CI) (intervention minus control) -4.77 (-14.2 to 4.7) SF-361: Mean difference in score (95%CI) (intervention minus control) Physical component score: 1.8 (-0.8 to 4.5) Mental component score: 1.00 (-2.5 to 4.5) Adverse events (% of patients): Ia: 85%, Ib: 83%, Ic: 94%, C: 84%. SAE: Ia: 0%, Ib: 4%, Ic: 0%, C: 8% ¹Results were only reported for effect of ianalumab 300 mg compared to placebo.
Dorner, 2019	Single centre, Switzerland No. patients: 27 Intervention a (Ia): Ianalumab single infusion 3 mg/kg, n = 6 Intervention b (Ib): ‘’ 10 mg/kg, n = 12 Control: Placebo, n = 9 Baseline characteristics - Median age (range): Ia: 49.0 (32 to 56), Ib: 58.5 (25 to 70), C: 50.0 (28 to 58) - Sex (% males): Ia: 16.7%, Ib: 8.3%, C:22.8% Follow-up period: 24 weeks plus follow-up until B-cell recovery (range 39 to 154 weeks)	ESSDAI: No detailed data available. Large variability in follow-up scores for intervention groups. ESSPRI: No detailed data available. No reduction in Ia group. Mean reduction (95%CI) of 1.55 points (9-0.03 to -3.08) at week 12 and mean reduction of 1.92 (0.33 to 3.52) in Ib group compared to control group. Adverse events: Ia group: 14 events, Ib group: 17 events, placebo: 11 events.
Capaccio, 2018	Multi centre, Italy No. patients: 22 Intervention: Interventional sialendoscopy plus repeated outpatients intraductal steroid irrigations, n = 12 Control: Interventional sialendoscopy solely, n = 10 Intervention was performed once at start of the study. Baseline characteristics - Mean age (SD): I: 66.6 (11.6), C: 72.9 (7.2) - Sex (% of males) I: 8.3%, C: 20% Follow-up period: Six months	ESSPRI: Mean score (SD) after follow-up: Intervention: 3.0 (0.6) Control: 4.0 (0.8)
Felten, 2021	Multi centre, France No. patients: 110 Intervention: Tocilizumab infusion monthly 8 mg/kg, n = 55 Control: Placebo at baseline and at week 20, n = 55 Baseline characteristics - Mean age (SD): I: 50.9 (12.8), C: 51.0 (11.9) - Sex (% males): I: 1.8%, C: 9.1% Follow-up period: 44 weeks (24 weeks of intervention)	ESSDAI: Mean difference in score (95%CI) (intervention minus control) Week 12: -10.9 (-30.7 to 9.4) Week 24: 11.0 (-9.0 to 30.6) Week 32 -11.1 (-31.2 to 9.4) Week 44: 3.8 (-17.4 to 24.9) ESSPRI: Mean score (SD): Week 12: I: 5.9 (1.8), C: 6.0 (1.8) Week 24: I: 5.8 (2.0), C: 6.2 (2.1) Stimulated salivary flow rate: Mean (ml/min) (SD) Week 24: I: 0.9 (1.1), C: 0.6 (0.8) Tear production (Schirmer’s test): Mean score (SD): Week 24: I 7.8 (8.3), C: 9.5 (11.7) SF-36: Mean score (SD): Physical component score Week 24: 212.0 (80.4), C: 203.1 (86.9) Mental component score Week 24: 208.3 (82.3), C: 200.3 (93.6) Adverse events (SAE until week 24, % of patients): I: 25.5%, C: 10.9%
Fisher, 2020	Multi centre, Europe No. patients: 44 Cohort 1: Intervention a (Ia): Iscalimab subcutaneous 3 mg/kg, n = 8 Control: Placebo, n = 4 Cohort 2: Intervention b (Ib): Iscalimab intravenous 10 mg/kg, n = 21 Control: placebo, n = 11 Intervention given every two weeks until week 8, followed by iscalimab until week 20 according to intervention in the respective cohort. Baseline characteristics - Mean age (SD) Cohort 1: Ia: 56.5 (12.2), C: 48.8 (3.3) Cohort 2: Ib: 51.7 (14.3), C: 50.6 (12.4) - Sex (% males): Only males (n = 2, 10%) in Ib group of cohort 2. Follow-up period: 32 weeks	ESSDAI: Cohort 1: Mean reduction (95%CI) of 0.41 points (-2.89 to 3.70) at week 12 in intervention group compared to control. Cohort 2: Mean reduction of 5.21 points (-0.96 to 9.46) ‘’ ESSPRI: Cohort 1: No results reported Cohort 2: Mean reduction (95%CI) of 0.95 points (-0.50 to 2.41) at week 12 in intervention group compared to control. SF-36: Cohort 1: No results reported Cohort 2: Physical component score: Mean increase (95%CI) of 3.83 points (-1.81 to 9.48) at week 12 in intervention group compared to control. Mental component score: Mean increase (95%CI) of 2.52 points (-4.50 to 9.53) ‘’ Adverse events (number of events, % of patients): Cohort 1: Intervention group: n = 34 (88%), control group: n = 17 (100%). SAE: 1 event, 1 patient in control group. Cohort 2: Intervention group: n = 23 (33%), control group: n = 14 (55%). SAE: none
He, 2022	Single centre, China No. patients: 60 Intervention: Low-dose interleukin 2 (LD-IL-2) subcutaneous 1 million IU, n = 30 Control: Placebo, n = 30 Intervention given every other day for two weeks, followed 2-week break as one treatment cycle. Total of three cycles. Baseline characteristics - Mean age (SD): I: 47.6 (12.8), C: 51.0 (11.9) - Sex (% males): no males Follow-up period: 24 weeks	ESSDAI: Mean reduction (95%CI) of 1.33 points (-2.27 to -0.20) at week 12 and mean reduction of 2.47 (-3.75 to -1.18) at week 24 in intervention group compared to control. ESSPRI: Patients (%) with ≥1 point decrease: Intervention group: 83.3% at week 12, 83.3% at week 24. Control group: 46.7% at week 12, 63.3% at week 24. Patients (%) with 15% decrease in score: Intervention group: 86.7% at week 12, 46.7% at week 24. Control group: 83.3% at week 12, 53.3% at week 24. STAR: Patients (%) with ≥3 points improvement Mean difference (intervention minus placebo, (95%CI)) in percentage 3.25 (0.89 to 11.90) at week 12, 6.54 (1.97 to 21.74) at week 24 SF-36: Mean difference (intervention minus control, (95%CI)) in score Physical component score: 0.26 (-0.11 to 0.62) at week 12, 0.26 (-0.16 to 0.68) at week 24. Mental component score: -0.58 (-0.97 to -0.19) at week 12, -0.58 (-1.03 to -0.13) at week 24.
Juarez, 2021	Multi centre, Europe No. patients: 27 Intervention: Seletalisib oral 45 mg/day for 12 weeks, n =13 Control: Placebo for 12 weeks, n = 14 Baseline characteristics - Mean age (SD): I: 52.2 (16.1), C: 60.2 (9.9) - Sex: one male in both study groups Follow-up period: 16 weeks	ESSDAI: Mean reduction (95%CI) of 2.59 points (-7.30 to 2.11) at week 12 in intervention group compared to control. ESSPRI: Mean reduction (95%CI)of 1.55 points (-3.39 to 0.28) at week 12 in intervention group compared to control. Individual domains (mean reduction (95%CI)): Fatigue: –2.48 (-4.22 to -0.75) at week 12 in intervention group compared to control. Dryness: -0.92 (–3.47 to 1.63) ‘’ Limb pain: -1.22 (-3.80 to 1.36) ‘’ Stimulated salivary flow rate: Mean difference (intervention minus control, (95%CI)) in ml/min: 0.02 (-0.27 to 0.31) at week 12 Unstimulated salivary flow rate ‘’ -0.02 (-010 to 0.06) ‘’ Tear production (Schirmer’s test): Mean difference (intervention minus control) in score: -1.41 (-10.35 to 7.52) at week 12. Adverse events: all patients, except for one patient in placebo group. Drug-related AEs: 10 (77%) patients in intervention group, 3 (21%) patients in control group. SAEs: 3 (23%) patients in intervention group, 1 (7%) patient in control group.
Karagozoglu, 2018³	Single centre, Netherlands No. patients: 51 Intervention a (Ia): Sialendoscopy using saline, n = 16 Intervention b (Ib): Sialendoscopy + 40 mg/mL triamcinolone acetonide in 5 ml saline, n = 19 Control: placebo, n = 16 Intervention was performed once at start of the study. Control patients were not blinded. Baseline characteristics - Mean age (SD) of overall study population: 59 (10.37) - Sex (% of males): 12.2% Follow-up period: 24 weeks	ESSPRI: Mean score (SD) for subdomain dryness after follow-up: Week 16: Ia: 6.22 (2.10) Ib: 6.40 (1.91) Control: 8.53 (1.19) Week 24: Ia: 6.28 (1.83) Ib: 6.50 (2.26) Control: 8.01 (1.49) Stimulated salivary flow rate (ml/min), median (IQR). Week 16: Ia: 0.33 (0.09 to 0.68) Ib: 0.64 (0.17 to 0.90) Control: 0.24 (0.10 to 0.56) Week 24: Ia: 0.30 (0.09 to 0.81) Ib: 0.61 (0.19 to 0.80) C: 0.25 (0.11 to 0.67) Unstimulated salivary flow rate ‘’ Week 16: Ia: 0.13 (0.04 to 0.45) Ib: 0.11 (0.05 to 0.27) Control: 0.10 (0.02 to 0.28) Week 24: Ia: 0.16 (0.07 to 0.38) Ib: 0.12 (0.08 to 0.27) C: 0.12 (0.03 to 0.22) ³Study reports data for five timepoints (baseline, week 1, week 8, week 16, week 24). Only data for week 16 and week 24 reported in the current table. No substantial differences in week 1 and week 8 were found.
Mariette, 2022	Single centre, Switzerland No. patients: 27 Intervention a (Ia): Belimumab 200 mg subcutaneous weekly for 52 weeks, n = 24 Intervention b (Ib): Rituximab 1000 mg intravenous at week 8 and week 10, n = 25 Intervention c (Ic): Combination of Ia and Ib, n = 24 Control: placebo, n = 13 Baseline characteristics - Mean age (SD): Ia: 52.0 (11.49), Ib: 55.2 (15.07), Ic: 45.1 (10.93), C: 52.7 (12.67) - Sex (% of males) Ia: 8.3%, Ib: 8%, Ic: 8.3%, C: 0% Follow-up period: 69 weeks	ESSDAI: Mean difference (SE) in score from baseline Ia: -3.9 (0.87) at week 24, -4.8 (0.85) at week 52, -3.9 (0.92) at week 69. Ib: -5.3 (0.94) ‘’, –4.3 (0.92) ‘’, -4.4 (0.99) ‘’ Ic: -5.3 (0.91) ‘’, -5.7 (0.89) ‘’, -5.7 (0.96) ‘’ Control: -2.9 (1.32) ‘’, -2.9 (1.29) ‘’, –1.8 (1.40) ‘’ ESSPRI: No detailed data available. No notable differences reported according to authors. Adverse events: All patients, except for one patient from Ia and Ib group. SAE’s: Ia: two events, Ib: seven events control: none
Price, 2022	Multi centre, Europe No. patients: 150 Intervention a (Ia): Filgotinib 200 mg oral once daily, n = 38 Intervention b (Ib): Lanraplenib 30 mg oral once daily, n = 37 Intervention c (Ic): Tirabrutinib 40 mg oral once daily, n = 39 Control: Placebo, n = 36 Intervention given 48 weeks. Placebo group received filgotinib, lanraplenib or tirabrutinib (randomized 1:1:1) from week 24 on. Baseline characteristics - Mean age (SD): Ia: 52.2 (10.5), Ib: 56.2 (9.7), Ic: 55.8 (10.1), C: 53.2 (10.3) - Sex (% of males) ‘ Ia: 0%, Ib: 2.7%, Ic: 5.1%, C: 2.8% Follow-up period: 52 weeks	ESSDAI: Mean difference (SD) in score from baseline Ia: -4.7 (0.72) at week 12, -5.4 (0.75) at week 24. Ib: -2.5 (0.76) ’’, -4.3 (0.81) ‘’. Ic: -3.2 (0.73) ‘’, -4.0 (0.75) ‘’. Control: -3.9 (0.76) ‘’, -4.2 (0.78) ‘’. ESSPRI: Mean difference (SD) in score from baseline Ia: -1.4 (0.33) at week 12, -0.8 (0.31)) at week 24. Ib: -1.0 (0.34) ‘’, -1.1 (0.34) ‘’. Ic: -1.4 (0.33) ‘’, -1.2 (0.31) ‘’. Control: -0.8 (0.31) ‘’, -0.9 (0.33) ‘’. Stimulated and unstimulated salivary flow rate (ml/min): No difference from baseline in all study groups, see Supplementary data of Price (2022) for result of different timepoints. Tear production (Schirmer’s test): Mean difference (SE) (intervention minus control) in score Ia: 3.01 (2.037) at week 12, 2.92 (1.740) at week 24. Ib: 4.57 (2.050) ‘’, 3.68 (1.764) ‘’. Ic: 3.72 (2.021) ‘’, 3.14 (1.712)’’. Adverse events (n of patients): Ia: 3 (ten drug-related), Ib: 29 (ten drug-related), Ic: 29 (five drug-related), control: 27 (six drug-related). SAEs (n of patients): Ia: 3, Ib: 3, Ic: 1, control: 2
St. Clair, 2018	Multi center, Europe No. patients: 52 Intervention: Baminercept 100 mg subcutaneous weekly for 24 weeks, n = 33 Control: Placebo, n = 19 Baseline characteristics - Mean age (SD): I: 50 (10.9), C: 55 (11.0) - Sex (% of males) I: 6%, C: 5% Follow-up period: 48 weeks	ESSDAI: Mean difference (95%CI) in score from baseline: Intervention: -1.23 (-2.03 to -0.43) Control: -0.15 (-1.18 to 0.87) Stimulated salivary flow rate: mean difference (95%CI) from baseline (ml/min). Intervention: -0.01 (-0.10 to 0.09) Control: 0.07 (-0.06 to 0.19) Unstimulated salivary flow rate ‘’ Intervention: 0.06 (0.00 to 0.12) Control: 0.07 (-0.01 to 0.15) Tear production (Schirmer’s test): mean difference (95%CI) from baseline Intervention: Right eye: 0.80 (-1.60 to 3.21), left eye: 0.75 (-2.73 to 4.23) Control: Right eye: -3.48 (-6.63 to -0.34) Patient global assessment: mean difference (95%CI) from baseline Intervention: 2.51-13.88 (-23.11 to -4.65), control: -9.75 (-21.81 to 2.30) SF-36: mean difference (95%CI) from baseline Physical component: Intervention: 2.51 (-0.19 to 5.22), control: -0.63 (-4.18 to 2.91) Mental component: Intervention: -1.04 (-4.82 to 2.75), control: -0.59 (-5.53 to 4.35) Adverse events (number of events, % of patients): Intervention group: n = 356 (100%) of which 177 AEs related to drug treatment, control group: n = 204 (100%) of which 100 AEs related to drug treatment. SAE: Intervention: 5 (15%), control: 1 (5%)
van der Heijden, 2020²	Single centre, Netherlands No. patients: 29 Intervention: Leflunomide 20 mg and hydroxychloroquine 400 mg (200 mg twice or 200 mg once if body weight was < 60 kg) oral once daily for 24 weeks, n = 21 Control: Placebo ‘’, n = 8 Baseline characteristics - Mean age (SD): I: 54.7 (12.4), 53.5 (15.2) - Sex (% of males) Only 1 male in intervention group Follow-up period: 24 weeks	ESSDAI: Mean difference in score (95%CI) (intervention minus control) Week 16: -3.50 (-6.27 to -0.72) Week 24: -4.29 (-7.06 to -1.53) ESSPRI: Mean difference in score (95%CI) (intervention minus control) Week 16: -1.66 (-2.90 to -0.41) Week 24: -1.11 (-2.35 to 0.13) Individual domains (mean reduction (95%CI)): Fatigue: Week 16: -2.44 (-4.17 to -0.70) Week 24: -1.78 (-3.51 to -0.05) Pain: Week 16: -1.76 (-3.38 to -0.13) Week 24: -1.23 (-2.84 to 0.39) Dryness: Week 16: -1.06 (-2.85 to 0.72) Week 24: -0.64 (-2.42 to 1.14) Stimulated salivary flow rate: mean difference (95%CI) (intervention minus control) (μL/5 min) Week 16: 13.1 (1.5 to 24.80) Week 24: 9.81 (-1.89 to 21.51) Unstimulated salivary flow rate: mean difference (95%CI) (intervention minus control) (μL/5 min) Week 16: 4.24 (-4.15 to 12.64) Week 24: 10.57 (2.21 to 18.93) Tear production (Schirmer’s test): mean difference (95%CI) (intervention minus control) Week 16: 4.79 (-1.95 to 11.5) Week 24: 3.02 (-3.71 to 9.74) Patient global assessment: mean difference (95%CI) (intervention minus control) Week 16: -14.01 (-33.66 to 5.64) Week 24: -18.80 (-38.39 to 0.78) Adverse events: I: 100 events, C: 19 events. SAE: two events in placebo group. ²Study reports data for four timepoints (baseline, week 8, week 16, week 24). Only data for week 16 and week 24 reported in the current table.
Xu, 2023	Multi centre, China No. patients: 42 Intervention a (Ia): Telitacicept subcutaneously 160 mg/week, n = 14 Intervention b (Ib): ‘’ 240 mg/week, n = 14 Control: placebo, n = 16 Baseline characteristics - Mean age (SD): Ia: 47.4 (12.4), Ib: 52.1 (11.8), C: 48.7 (13.5) - Sex (% of males): Ia: 7.1%, Ib 0%, C: 7.1% Follow-up period: 24 weeks	ESSDAI: Mean difference (SD) in score from baseline: Week 12 Ia: -3.1 (2.80) Ib: -1.9 (3.43) C: 0.4 (4.67) Week 24 Ia: -3.3 (2.73) Ib: -1.3 (4.14) C: 0.6 (4.55) ESSPRI, unstimulated salivary flow rate, tear production, patient global assessment, SF-36: No significant differences reported. Full outcome data not available. Adverse events (% of patients): Ia: 85.7%, Ib: 100%, C: 92.9%

Results of the additional search

Abatacept

Two studies reported on the efficacy of abatacept compared to placebo (Baer, 2021; van Nimwegen, 2020). For the study by Baer (2021), the clinical relevance could not be evaluated for all outcome measures but adverse events, as results were reported as difference in mean change from baseline instead of difference in follow-up score. For the study van Nimwegen, the clinical relevance of the results could not be calculated for the outcome measures saliva production and patient global assessment, as baseline and follow-up results were only reported as median (IQR).

Efficacy

ESSDAI

Both Baer (2021) and van Nimwegen (2020) reported on the outcome ESSDAI.

Baer (2021) reported on ESSDAI as adjusted mean treatment difference (difference in mean change from baseline) between intervention and placebo. The mean difference (95%CI) in score change at week 24 was 0.5 (-0.7 to 1.6) in favor of the control group. Baer (2021) also reported on the mean difference (intervention minus placebo) in percentage of patients with minimally clinically improvement (improvement in ESSDAI total score ≥ 3) after 24 weeks. The reported mean difference (95%CI) was -2.7% (-17.2% to 11.7%), in favor of the control group.

Van Nimwegen (2020) reported on ESSDAI as adjusted mean difference (intervention minus placebo) in score. At week 12, the mean difference (95%CI) was -2.4 (-4.7 to -0.1) in favor of the intervention group, which is not clinically relevant. At week 24, the mean difference (95%CI) was -1.3 (-4.1 to 1.6) in favor of the intervention group, which is not clinically relevant.

ESSPRI

Both Baer (2021) and van Nimwegen (2020) reported on the outcome ESSPRI as total score and the individual scores for the subdomains dryness, fatigue and pain. Baer (2021) reported on ESSPRI as adjusted mean treatment difference (difference in mean change from baseline) between intervention and placebo. Table 1 provides an overview of the results.

Table 1 ESSPRI at week 24 (Baer, 2021)

Mean difference in score change (95%CI)	Clinical relevance
Total score
0.3 (-0.3 to 0.8), in favor of control	Not measurable
Dryness
0.2 (-0.5 to 0.8), in favor of control	Not measurable
Fatigue
0.3 (-0.4 to 0.9), in favor of control	Not measurable
Pain
0.3 (-0.3 to 1.0), in favor of control	Not measurable

Baer (2021) also reported on the mean difference (intervention minus placebo) in percentage of patients with minimally clinically improvement (improvement in ESSPRI total score ≥ 1) after 24 weeks. The reported mean difference (95%CI) was -11.2% (-25.6% to 3.2%), in favor of the control group.

Van Nimwegen (2020) reported on ESSPRI as adjusted mean difference (intervention minus placebo) in score. Table 1 provides an overview of the results. For the total score and subscores on fatigue and pain, results were reported by van Nimwegen (2020) as transformed to the second power, due to skewness. In Table 1, these results are backtransformed into the original values.

Table 2 ESSPRI at week 12 and week 24 (van Nimwegen, 2020)

Timepoint	Mean difference in score (95%CI)	Clinical relevance
Total score
Week 12	-2.2 (-3.5 to 1.7), in favor of intervention	Yes
Week 24	-2.2 (-3.6 to 1.7), in favor of intervention	Yes
Dryness
Week 12	-0.3 (-0.9 to 0.4), in favor of intervention	No
Week 24	-0.3 (-0.9 to 0.4), in favor of intervention	No
Fatigue
Week 12	-1.4 (-3.5 to 2.9), in favor of intervention	Yes
Week 24	-1.6 (-3.8 to 3.0), in favor of intervention	Yes
Pain
Week 12	-2.1 (-3.8 to 2.4), in favor of intervention	Yes
Week 24	-2.3 (-3.8 to 2.0), in favor of intervention	Yes

Saliva production

Both Baer (2021) and van Nimwegen (2020) reported on the outcome saliva production, as unstimulated (UWSF) and stimulated (SWSF) whole salivary flow (ml/min). Baer (2021) reported on UWSF and SWSF as adjusted mean treatment difference (difference in mean change from baseline) between intervention and placebo. The mean difference in UWSF change (95%CI) at week 24 was -0.1 (-0.2 to 0.1) in favor of the control group. The mean difference in SWSF change (95%CI) at week 24 was -0.004 (-0.03 to 0.03) in favor of the intervention group.

Van Nimwegen (2020) reported on USWF and SWSF as adjusted mean difference (intervention minus placebo). Table 3 provides an overview of the results.

Table 3 Saliva production (unstimulated and stimulated salivary flow rate) at week 12 and 24 (van Nimwegen, 2020)

Timepoint	Mean difference in ml/min (95%CI)	Clinical relevance
UWSF
Week 12	-0.01 (-0.04 to 0.03) in favor of control	Not measurable
Week 24	0.02 (-0.02 to 0.05) in favor of intervention	Not measurable
SFWS
Week 12	0.03 (-0.05 to 0.10) in favor of intervention	Not measurable
Week 24	0.01 (-0.08 to 0.09) in favor of intervention	Not measurable

Tear production

Both Baer (2021) and van Nimwegen (2020) reported on the outcome tear production, using the Schirmer’s test (in mm/5 min). Baer (2021) reported on the Schirmer’s test as adjusted mean treatment difference (difference in mean change from baseline) between intervention and placebo. The mean difference in change (95%CI) at week 24 was 0.7 (-1.5 to 2.9) in favor of the intervention group.

Van Nimwegen (2020) reported on the Schirmer’s test as adjusted mean difference (intervention minus placebo) in mm/5 min. At week 12, the mean difference (95%CI) was 0.1 (-2.9 to 3.2) in favor of the intervention group, which is not clinically relevant. At week 24, the mean difference (95%CI) was 1.1 (-1.2 to 3.3) in favor of the intervention group, which is not clinically relevant.

Patient global assessment

Both Baer (2021) and van Nimwegen (2020) reported on the outcome patient global assessment. Baer (2021) reported on the outcome as patient global assessment score using a 0-100 scale (100 indicating worse outcome) and reported results as adjusted mean treatment difference (difference in mean change from baseline) between intervention and placebo. The mean difference in change (95%CI) at week 24 was -1.1 (-7.4 to 5.1) in favor of the intervention.

Van Nimwegen (2020) reported on the outcome as patient global disease activity using a 0-10 scale (10 indicating worse outcome) and reported results as adjusted mean difference (intervention minus placebo) in score. At week 12 the mean difference (95%CI) was -0.8 (-1.7 to 0.0) in favor of the intervention. At week 24 the mean difference (95%CI) was -0.4 (-1.3 to 0.6) in favor of the intervention.

Quality of life

Van Nimwegen reported on quality of life using the SF-36 score (0-100 scale). Results were reported as adjusted mean difference (intervention minus placebo) in score for both the physical and mental component score. Table 4 provides an overview of the results.

Table 4 Quality of life (SF-36, physical and mental component) at week 12 and 24 (van Nimwegen, 2020)

Timepoint	Mean difference in score (95%CI)	Clinical relevance
Physical component score
Week 12	2.5 (-0.2 to 5.2) in favor of intervention	No
Week 24	2.0 (-0.7 to 4.7) in favor of intervention	No
Mental component score
Week 12	-1.9 (-5.5 to 1.8) in favor of control	No
Week 24	-1.0 (-4.6 to 2.6) in favor of control	No

Safety

Adverse events

Both Baer (2021) and van Nimwegen (2020) reported on the outcome adverse events (AE). Baer (2021) reported on AE as number of patients with AE. A total of 79/92 (85.9%) patients in the intervention group experienced AE, compared to 68/95 (71.6%) patients in the control group. The corresponding risk ratio (RR, 95%CI) is 1.20 (1.03 to 1.40) in favor of the control group, which is not clinically relevant.

Regarding serious adverse events (SAE), 9/92 (9.8%) patients in the intervention group experienced SAE, compared to 3/95 (3.2%) patients in the control group. The corresponding risk ratio (RR, 95%CI) is 3.10 (0.87 to 11.08) in favor of the control group, which is clinically relevant.

Van Nimwegen (2020) reported on AE both as number of events as well as number of patients. A total of 103 AE were reported in the intervention group and 87 AE in the control. This involved 38/40 (95%) patients in the intervention group, compared to 38/40 (95%) patients in the control group. The corresponding risk ratio (RR, 95%CI) is 1.00 (0.90 to 1.11) indicating no favor for one of the study groups.

The number of SAE was 1 in the intervention group and 4 in the control group. This involved 1/40 (3%) patients in the intervention group, compared to 4/40 (10%) patients in the control group. The corresponding risk ratio (RR, 95%CI) is 0.25 (0.03 to 2.14) in favor of the intervention group, which is clinically relevant.

See study articles of the studies for details on type of events (Baer, 2021; van Nimwegen, 2020).

Rituximab

One study reported on the efficacy of rituximab compared to placebo (Bowman, 2017). The clinical relevance could not be calculated for the outcome measures ESSDAI, saliva production and tear production, as results were log-transformed.

Efficacy

ESSDAI

Bowman (2017) reported on the outcome ESSDAI as mean difference (intervention minus placebo) in score. Table 5 provides an overview of the results.

Table 5 ESSDAI at week 12, 24, 36 and 48 (Bowman, 2017)

Timepoint	Mean difference (log-transformed) in score (95%CI)¹	Clinical relevance
Week 16	0.85 (0.64 to 1.11) in favor of intervention	Not measurable
Week 24	0.94 (0.73 to 1.22) in favor of intervention	Not measurable
Week 36	0.74 (0.55 to 0.98) in favor of intervention	Not measurable
Week 48	0.75 (0.55 to 1.03) in favor of intervention	Not measurable
¹ Bowman (2017) reported that raw values were highly positively skewed and were therefore log-transformed for analysis and then backtransformed for presentation. Mean differences reported are rather ratios on the original scale than differences on the logarithmic scale.

ESSPRI

Bowman (2017) reported on the outcome ESSPRI as mean difference (intervention minus placebo) in total score. Table 6 provides an overview of the results.

Table 6 ESSPRI at week 16, 24, 36 and 48 (Bowman, 2017)

Timepoint	Mean difference in score (95%CI)	Clinical relevance
Week 16	0.19 (-0.45 to 0.82) in favor of control	No
Week 24	0.94 (0.73 to 1.22) in favor of control	No
Week 36	0.55 (0.01 to 1.09) in favor of control	No
Week 48	0.54 (-0.12 to 1.20) in favor of control	No

Saliva production

Bowman (2017) reported on the outcome saliva production, as unstimulated (UWSF) whole salivary flow (ml/min in mean difference (intervention minus placebo). Table 7 provides an overview of the results.

Table 7 Saliva production (unstimulated salivary flow rate) at week 16, 24, 36 and 48 (Bowman, 2017).

Timepoint	Mean difference in ml/min (log-transformed) (95%CI)	Clinical relevance
Week 16	1.36 (0.99 to 1.88) in favor of intervention	Not measurable
Week 24	1.25 (0.91 to 1.72) in favor of intervention	Not measurable
Week 36	1.56 (1.11 to 2.18) in favor of intervention	Not measurable
Week 48	1.71 (1.23 to 2.37) in favor of intervention	Not measurable
¹Bowman (2017) reported that raw values were highly positively skewed and were therefore log-transformed for analysis. Mean differences reported are rather ratios on the original scale than differences on the logarithmic scale.

Tear production

Bowman (2017) reported on the outcome tear production, using the Schirmer’s test (in mm/5 min). Table 8 provides an overview of the results.

Table 8. Tear production (Schirmer’s test) at week 16, 24, 36 and 48 (Bowman, 2017)

Timepoint	Mean difference in mm/5 min (log-transformed) (95%CI)	Clinical relevance
Week 16	1.19 (0.88 to 1.61) in favor of intervention	Not measurable
Week 24	1.01 (0.75 to 1.35) in favor of intervention	Not measurable
Week 36	1.09 (0.79 to 1.51) in favor of intervention	Not measurable
Week 48	1.16 (0.84 to 1.61) in favor of intervention	Not measurable
¹Bowman (2017) reported that raw values were highly positively skewed and were therefore log-transformed for analysis. Mean differences reported are rather ratios on the original scale than differences on the logarithmic scale.

Quality of life

Bowman (2017) reported on the outcome quality of using the SF-36 score. Results were reported as mean difference (intervention minus placebo) in score for both the physical and mental component score. Table 9 provides an overview of the results.

Table 9 Quality of life (SF-36, physical and mental component) at week 24 and 48 (van Nimwegen, 2020)

Timepoint	Mean difference in score (95%CI)	Clinical relevance
Physical component score
Week 24	-1.86 (-4.15 to 0.43) in favor of control	No
Week 48	-0.79 (-3.25 to 1.67) in favor of control	No
Mental component score
Week 24	-0.64 (-3.81 to 2.54) in favor of control	No
Week 48	0.12 (-3.58 to 3.82) in favor of intervention	No

Safety

Adverse events

Bowman reported on the outcome as SAE. A total of 10/66 (15.2%) patients in the intervention group experienced SAE, compared to 10/67 (14.9%) patients in the control group. The corresponding risk ratio (RR, 95%CI) is 1.02 (0.45 to 2.28) in favor of the control group, which is not clinically relevant.

See study article of the study for details on type of events (Bowman, 2017).

Level of evidence of the literature

EULAR guideline 2020

As evidence was adapted from the systematic review of Brito-Zerón (2019), and level of evidence was not evaluated using the GRADE method in this review, no GRADE conclusions were formulated.

Additional search

The level of evidence came from RCT’s and therefore started as high.

Abatacept

For all outcome measures but adverse events, only the results of the study by van Nimwegen were used, as the study by Baer (2021 only reported results as difference in mean change from baseline instead of difference in follow-up score.

Efficacy

No GRADE level could be calculated for the outcome measures saliva production and patient global assessment as results for the individual study groups were only reported as median (IQR).

The level of evidence regarding the outcome measure ESSDAI was downgraded by 3 levelsto very low, because of study limitations (no or inadequate allocation method, downgraded1 level for risk of bias) and imprecision (effect estimate crosses lower boundary of clinical relevance, optimal information size (OIS) not reached, downgraded 2 levels for imprecision).

The level of evidence regarding the outcome measure ESSPRI was downgraded by 3 levels to very low, because of study limitations (no or inadequate allocation method, downgraded 1 level for risk of bias) and imprecision (effect estimate crosses upper and lower boundary of clinical relevance, downgraded 2 levels for imprecision).

The level of evidence regarding the outcome measure tear production and quality of life was downgraded by 3 levels to very low because of study limitations no or inadequate allocation method, downgraded 1 level for risk of bias) and imprecision (OIS not reached, downgraded 2 levels for imprecision).

Safety

The level of evidence regarding the outcome measure adverse events was downgraded by 3 levels to very low, because of study limitations (no or inadequate allocation method, downgraded 1 level for risk of bias) and imprecision (OIS not reached, downgraded 2 levels for imprecision).

Rituximab

Efficacy

No GRADE level could be calculated for the outcome measures ESSDAI, saliva production and tear production as results were log-transformed and the clinical relevance could not be calculated.

The level of evidence regarding the outcome measure ESSPRI and quality of life was downgraded by 3 levels to very low, because of study limitations (incorrect randomization method, missing results for several outcomes in study by Bowman (2017), downgraded 1 level for risk of bias) and imprecision (OIS not reached, downgraded 2 levels for imprecision).

Safety

The level of evidence regarding the outcome measure adverse events was downgraded by 3 levels to very low, because of study limitations (incorrect randomization method, missing results for several outcomes in study by Bowman (2017), downgraded 1 level for risk of bias) and imprecision (OIS not reached, downgraded 2 levels for imprecision).

Zoeken en selecteren

To answer the clinical question the 2020 update of the European Alliance of Associations for Rheumatology (EULAR) guideline for the management of Sjögren’s syndrome with topical and systemic therapies was used (Ramos-Casals, 2020). In this module we refer to a systematic review that informed the EULAR recommendations for the management of Sjögren’s syndrome (Brito-Zerón, 2019).

An additional literature search was performed to search for more recent studies published after the 2020 EULAR guideline. However, the detailed search strategy of the 2020 update of the EULAR guideline stated above was not available. Therefore, a systematic review of the literature was performed to answer the following question:

What is the (in)effectivity of a systemic treatment compared to placebo, standard care or other systemic treatments in patients with Sjögren’s disease?

P:	adult primary SjS patients fulfilling the 2002 AECG criteria (stated in the manuscript as ‘primary- 2002’ patients) or the 2016 ACR/EULAR criteria
I:	Systemic treatment (inc. oral therapy, omega-3 fatty acids, antimalarials, csDMARDS, bDMARDS, tsDMARDS)
C:	Placebo, standard care, other systemic treatments
O:	Efficacy (ESSDAI, ESSPRI, tear production, saliva production, patient global assessment, quality of life, STAR, CRESS, SSDDI, organ-specific improvement); and safety (adverse events)

Relevant outcome measures

Additional search

The guideline development group considered efficacy (ESSDAI, ESSPRI) as a critical outcome measure for decision making; and efficacy (other) and safety as an important outcome measure for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

The working group defined the following cut-offs as a minimal clinically (patient) important difference:

ESSDAI: Difference of ≥ 3 points in score (Seror, 2016)

ESSPRI: Difference of ≥ 1 points in score (Seror, 2016)

Tear production: Schirmer’s test: Difference of 5 mm

Quality of life (SF-36), both physical and mental score: Difference of 4 points (Ogura, 2021).

For the outcome measures and safety (adverse events), the working group defined the GRADE standard limit of 25% difference for the dichotomous outcome safety (adverse events) and 0.5 SD for the continuous outcomes saliva production (unstimulated and stimulated salivary flow rate) and patient global assessment as a minimal clinically important difference.

Search and select (Methods)

EULAR guideline 2020

The databases Medline, Embase and the Cochrane CENTRAL databases were searched with relevant search terms from 1 January 1986 to 31 December 2017. Studies were selected based on the following criteria:

Participants: adult primary SjS patients fulfilling the 2022 criteria (stated in the manuscript as ‘primary- 2002’ patients) or the 2016 ACR/EULAR criteria;
Intervention: topical or systemic medications;
Comparators: placebo or other therapeutic interventions;
Outcomes: the effect of the therapeutic intervention (efficacy) and safety profile;
Study design: randomised controlled trials (RCTs), cohort studies (prospective non-PLA-controlled, non-randomised studies and those with quasi-experimental designs), case-control studies (comparing therapeutic options) and meta-analyses; case series (descriptive/retrospective therapeutic studies) were considered in the absence of other studies.

A total of 1373 records were identified by Brito-Zerón (2019) in the systematic search. 104 studies were initially selected based on title and abstract screening. After reading the full text, 67 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 37 studies were included in the qualitative synthesis to inform the EULAR recommendations.

Additional literature search

The databases Medline (via OVID) and Embase (via Embase.com)]were searched with relevant search terms from 2016 until 10 October 2023. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 279 hits. Studies were selected based on the following criteria: systematic reviews or RCTs (Phase II or Phase III trials). A total of 57 studies were initially selected based on title and abstract screening. After reading the full text, 41 studies were excluded (see the table with reasons for exclusion under the tab Methods), and sixteen studies were included.

Results

EULAR guideline 2020

In this module we refer to a systematic literature review that informed the EULAR recommendations for the management of Sjögren’s syndrome (Brito-Zerón, 2019). In addition to that, an additional literature search was performed.

Additional literature search

A total of sixteen studies were included in literature analysis. Of these studies, twelve studies were Phase II trials (Bowman, 2022; Capacio 2018; Dorner, 2019; Felten, 2021; Fisher, 2020; He, 2022; Juarez, 2021; Mariëtte, 2022; Price, 2022; St Clair, 2018; van der Heijden, 2020; Xu, 2023). One study did not report in which trial phase the study was conducted (Karagozoglu, 2018). Due to the small sample size, this study was further considered as Phase II trial. Due to the high risk of bias and imprecision, the Phase II trials will not be analyzed in detail. The remaining three studies were Phase III trials (Baer, 2001; Bowman, 2017; van Nimwegen, 2020). Important study characteristics and results of the Phase III trials are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias table.

Referenties

Adler S, Körner M, Förger F, Huscher D, Caversaccio MD, Villiger PM. Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjögrens syndrome: a pilot study. Arthritis Care Res (Hoboken). 2013 Nov;65(11):1862-8. doi: 10.1002/acr.22052. PMID: 23740889.
Arends S, Verstappen GM, de Wolff L, Pringle S, Kroese FGM, Vissink A, Bootsma H. Why do drug treatments fail in Sjögren's disease? Considerations for treatment, trial design and interpretation of clinical efficacy. Expert Rev Clin Immunol. 2023 Jul-Dec;19(10):1187-1194. doi: 10.1080/1744666X.2023.2234641. Epub 2023 Aug 8. PMID: 37551702.
Baer AN, Gottenberg JE, St Clair EW, Sumida T, Takeuchi T, Seror R, Foulks G, Nys M, Mukherjee S, Wong R, Ray N, Bootsma H. Efficacy and safety of abatacept in active primary Sjögren's syndrome: results of a phase III, randomised, placebo-controlled trial. Ann Rheum Dis. 2021 Mar;80(3):339-348. doi: 10.1136/annrheumdis-2020-218599. Epub 2020 Nov 9. PMID: 33168545; PMCID: PMC7892395.
Bowman SJ, Everett CC, O'Dwyer JL, Emery P, Pitzalis C, Ng WF, Pease CT, Price EJ, Sutcliffe N, Gendi NST, Hall FC, Ruddock SP, Fernandez C, Reynolds C, Hulme CT, Davies KA, Edwards CJ, Lanyon PC, Moots RJ, Roussou E, Giles IP, Sharples LD, Bombardieri M. Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren's Syndrome. Arthritis Rheumatol. 2017 Jul;69(7):1440-1450. doi: 10.1002/art.40093. Epub 2017 Jun 5. Erratum in: Arthritis Rheumatol. 2020 Oct;72(10):1748. PMID: 28296257.
Bowman SJ, Fox R, Dörner T, Mariette X, Papas A, Grader-Beck T, Fisher BA, Barcelos F, De Vita S, Schulze-Koops H, Moots RJ, Junge G, Woznicki JN, Sopala MA, Luo WL, Hueber W. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet. 2022 Jan 8;399(10320):161-171. doi: 10.1016/S0140-6736(21)02251-0. Epub 2021 Nov 30. PMID: 34861168.
Brito-Zerón P, Retamozo S, Kostov B, Baldini C, Bootsma H, De Vita S, Dörner T, Gottenberg JE, Kruize AA, Mandl T, Ng WF, Seror R, Tzioufas AG, Vitali C, Bowman S, Mariette X, Ramos-Casals M. Efficacy and safety of topical and systemic medications: a systematic literature review informing the EULAR recommendations for the management of Sjögren's syndrome. RMD Open. 2019 Oct 28;5(2):e001064. doi: 10.1136/rmdopen-2019-001064. PMID: 31749986; PMCID: PMC6827762.
Brito-Zerón P, Retamozo S, Akasbi M, Gandía M, Perez-De-Lis M, Soto-Cardenas MJ, Diaz-Lagares C, Kostov B, Bove A, Bosch X, Perez-Alvarez R, Siso A, Ramos-Casals M. Annular erythema in primary Sjogren's syndrome: description of 43 non-Asian cases. Lupus. 2014 Feb;23(2):166-75. doi: 10.1177/0961203313515764. Epub 2013 Dec 10. PMID: 24326481.
Cankaya H, Alpöz E, Karabulut G, Güneri P, Boyacioglu H, Kabasakal Y. Effects of hydroxychloroquine on salivary flow rates and oral complaints of Sjögren patients: a prospective sample study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Jul;110(1):62-7. doi: 10.1016/j.tripleo.2010.02.032. PMID: 20610299.
Capaccio P, Canzi P, Torretta S, Rossi V, Benazzo M, Bossi A, Vitali C, Cavagna L, Pignataro L. Combined interventional sialendoscopy and intraductal steroid therapy for recurrent sialadenitis in Sjögren's syndrome: Results of a pilot monocentric trial. Clin Otolaryngol. 2018 Feb;43(1):96-102. doi: 10.1111/coa.12911. Epub 2017 Jun 26. PMID: 28585263.
Carubbi F, Cipriani P, Marrelli A, Benedetto P, Ruscitti P, Berardicurti O, Pantano I, Liakouli V, Alvaro S, Alunno A, Manzo A, Ciccia F, Gerli R, Triolo G, Giacomelli R. Efficacy and safety of rituximab treatment in early primary Sjögren's syndrome: a prospective, multi-center, follow-up study. Arthritis Res Ther. 2013 Oct 30;15(5):R172. doi: 10.1186/ar4359. PMID: 24286296; PMCID: PMC3979092.
Chu LL, Cui K, Pope JE. Meta-Analysis of Treatment for Primary Sjögren's Syndrome. Arthritis Care Res (Hoboken). 2020 Jul;72(7):1011-1021. doi: 10.1002/acr.23917. Epub 2020 Jun 7. PMID: 31058469.
Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, Richards A, Rauz S, Emery P. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis. 2008 Nov;67(11):1541-4. doi: 10.1136/ard.2007.083865. Epub 2008 Feb 14. PMID: 18276741.
Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A. Improvement of Sjögren's syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum. 2007 Mar 15;57(2):310-7. doi: 10.1002/art.22536. PMID: 17330280.
De Vita S, Quartuccio L, Seror R, Salvin S, Ravaud P, Fabris M, Nocturne G, Gandolfo S, Isola M, Mariette X. Efficacy and safety of belimumab given for 12 months in primary Sjögren's syndrome: the BELISS open-label phase II study. Rheumatology (Oxford). 2015 Dec;54(12):2249-56. doi: 10.1093/rheumatology/kev257. Epub 2015 Aug 4. PMID: 26242856.
Dörner T, Posch MG, Li Y, Petricoul O, Cabanski M, Milojevic JM, Kamphausen E, Valentin MA, Simonett C, Mooney L, Hüser A, Gram H, Wagner FD, Oliver SJ. Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019 May;78(5):641-647. doi: 10.1136/annrheumdis-2018-214720. Epub 2019 Mar 2. PMID: 30826774.
Felten R, Devauchelle-Pensec V, Seror R, Duffau P, Saadoun D, Hachulla E, Pierre Yves H, Salliot C, Perdriger A, Morel J, Mékinian A, Vittecoq O, Berthelot JM, Dernis E, Le Guern V, Dieudé P, Larroche C, Richez C, Martin T, Zarnitsky C, Blaison G, Kieffer P, Maurier F, Dellal A, Rist S, Andres E, Contis A, Chatelus E, Sordet C, Sibilia J, Arnold C, Tawk MY, Aberkane O, Holterbach L, Cacoub P, Saraux A, Mariette X, Meyer N, Gottenberg JE. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double-blind randomised placebo-controlled trial. Ann Rheum Dis. 2021 Mar;80(3):329-338. doi: 10.1136/annrheumdis-2020-218467. Epub 2020 Nov 18. PMID: 33208345.
Fisher, B. A., Szanto, A., Ng, W. F., Bombardieri, M., Posch, M. G., Papas, A. S., ... & Gergely, P. (2020). Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study.?The Lancet Rheumatology,?2(3), e142-e152.
Fisher BA, Mariette X, Papas A, Grader-Beck T, Bootsma H, Ng WF, van Daele PLA, Finzel S, Noaiseh G, Elgueta S, Hermann J, McCoy SS, Akpek E, Bookman A, Sopala M, Montecchi-Palmer M, Luo WL, Scheurer C, Hueber W; TWINSS study group. Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study. Lancet. 2024 Aug 10;404(10452):540-553. doi: 10.1016/S0140-6736(24)01211-X. Epub 2024 Jul 31. PMID: 39096929.
Fox PC, Datiles M, Atkinson JC, Macynski AA, Scott J, Fletcher D, Valdez IH, Kurrasch RH, Delapenha R, Jackson W. Prednisone and piroxicam for treatment of primary Sjögren's syndrome. Clin Exp Rheumatol. 1993 Mar-Apr;11(2):149-56. PMID: 8508556.
Generali E, Costanzo A, Mainetti C, Selmi C. Cutaneous and Mucosal Manifestations of Sjögren's Syndrome. Clin Rev Allergy Immunol. 2017 Dec;53(3):357-370. doi: 10.1007/s12016-017-8639-y. PMID: 28871434.
Gheitasi H, Kostov B, Solans R, Fraile G, Suárez-Cuervo C, Casanovas A, Rascón FJ, Qanneta R,Pérez-Alvarez R, Ripoll M, Akasbi M, Pinilla B, Bosch JA, Nava-Mateos J, Díaz-López B, Morera-Morales ML, Retamozo S, Ramos-Casals M, Brito-Zerón P; SS Study Group, Autoimmune Diseases Study Group (GEAS), Spanish Society of Internal Medicine (SEMI). How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients. Int Immunopharmacol. 2015 Aug;27(2):194-9. doi: 10.1016/j.intimp.2015.03.027. Epub 2015 Apr 18. PMID: 25899085.
Gottenberg JE, Ravaud P, Puéchal X, Le Guern V, Sibilia J, Goeb V, Larroche C, Dubost JJ, Rist S, Saraux A, Devauchelle-Pensec V, Morel J, Hayem G, Hatron P, Perdriger A, Sene D, Zarnitsky C, Batouche D, Furlan V, Benessiano J, Perrodeau E, Seror R, Mariette X. Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. JAMA. 2014 Jul 16;312(3):249-58. doi: 10.1001/jama.2014.7682. PMID: 25027140.
He J, Chen J, Miao M, Zhang R, Cheng G, Wang Y, Feng R, Huang B, Luan H, Jia Y, Jin Y, Zhang X, Shao M, Wang Y, Zhang X, Li J, Zhao X, Wang H, Liu T, Xiao X, Zhang X, Su Y, Mu R, Ye H, Li R, Liu X, Liu Y, Li C, Liu H, Hu F, Guo J, Liu W, Zhang WB, Jacob A, Ambrus JL Jr, Ding C, Yu D, Sun X, Li Z. Efficacy and Safety of Low-Dose Interleukin 2 for Primary Sjögren Syndrome: A Randomized Clinical Trial. JAMA Netw Open. 2022 Nov 1;5(11):e2241451. doi: 10.1001/jamanetworkopen.2022.41451. PMID: 36355371; PMCID: PMC9650609.
Jaeggi ET, Laskin C, Hamilton R, Kingdom J, Silverman ED. The importance of the level of maternal Anti-Ro/SSA antibodies as prognostic marker of the development of cardiac neonatal lupus erythematosus. Journal of the American College of Cardiology 2010;55 (24): 2778-2784
Juarez M, Diaz N, Johnston GI, Nayar S, Payne A, Helmer E, Cain D, Williams P, Devauchelle-Pensec V, Fisher BA, Giacomelli R, Gottenberg JE, Guggino G, Kvarnström M, Mariette X, Ng WF, Rosas J, Sánchez Bursón J, Triolo G, Barone F, Bowman SJ. A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren's syndrome. Rheumatology (Oxford). 2021 Mar 2;60(3):1364-1375. doi: 10.1093/rheumatology/keaa410. PMID: 32949140.
Karagozoglu KH, Vissink A, Forouzanfar T, Brand HS, Maarse F, Jager DHJ. Sialendoscopy enhances salivary gland function in Sjögren's syndrome: a 6-month follow-up, randomised and controlled, single blind study. Ann Rheum Dis. 2018 Jul;77(7):1025-1031. doi: 10.1136/annrheumdis-2017-212672. Epub 2018 Feb 23. PMID: 29475854.
Katayama I, Kotobuki Y, Kiyohara E, Murota H. Annular erythema associated with Sjögren's syndrome: review of the literature on the management and clinical analysis of skin lesions. Mod Rheumatol. 2010 Apr;20(2):123-9. doi: 10.1007/s10165-009-0257-y. Epub 2010 Jan 8. PMID: 20054701.
Kittridge A, Routhouska SB, Korman NJ. Dermatologic manifestations of Sjögren syndrome. J Cutan Med Surg. 2011 Jan-Feb;15(1):8-14. doi: 10.2310/7750.2010.09033. PMID: 21291650.
Letaief H, Lukas C, Barnetche T, Gaujoux-Viala C, Combe B, Morel J. Efficacy and safety of biological DMARDs modulating B cells in primary Sjögren's syndrome: Systematic review and meta-analysis. Joint Bone Spine. 2018 Jan;85(1):15-22. doi: 10.1016/j.jbspin.2017.06.004. Epub 2017 Jun 30. PMID: 28673789.
Mariette X, Barone F, Baldini C, Bootsma H, Clark KL, De Vita S, Gardner DH, Henderson RB, Herdman M, Lerang K, Mistry P, Punwaney R, Seror R, Stone J, van Daele P, van Maurik A, Wisniacki N, Roth DA, Tak PP. A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome. JCI Insight. 2022 Dec 8;7(23):e163030. doi: 10.1172/jci.insight.163030. PMID: 36477362; PMCID: PMC9746921.
Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J. Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS). Arthritis Rheum. 2004 Apr;50(4):1270-6. doi: 10.1002/art.20146. PMID: 15077311.
Mariette X, Seror R, Quartuccio L, Baron G, Salvin S, Fabris M, Desmoulins F, Nocturne G, Ravaud P, De Vita S. Efficacy and safety of belimumab in primary Sjögren's syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015 Mar;74(3):526-31. doi: 10.1136/annrheumdis-2013-203991. Epub 2013 Dec 17. PMID: 24347569.
Meiners PM, Vissink A, Kroese FG, Spijkervet FK, Smitt-Kamminga NS, Abdulahad WH, Bulthuis-Kuiper J, Brouwer E, Arends S, Bootsma H. Abatacept treatment reduces disease activity in early primary Sjögren's syndrome (open-label proof of concept ASAP study). Ann Rheum Dis. 2014 Jul;73(7):1393-6. doi: 10.1136/annrheumdis-2013-204653. Epub 2014 Jan 28. PMID: 24473674.
Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, Brouwer E, Kallenberg CG, Bootsma H. Effectiveness of rituximab treatment in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010 Apr;62(4):960-8. doi: 10.1002/art.27314. PMID: 20131246.
Norheim KB, Harboe E, Gøransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary Sjögren's syndrome--a double blind, randomised clinical trial. PLoS One. 2012;7(1):e30123. doi: 10.1371/journal.pone.0030123. Epub 2012 Jan 10. PMID: 22253903; PMCID: PMC3254637.
Ogura K, Bartelstein MK, Yakoub MA, Nikolic Z, Boland PJ, Healey JH. Minimal clinically important differences in SF-36 global score: Current value in orthopedic oncology. J Orthop Res. 2021 Oct;39(10):2116-2123. doi: 10.1002/jor.24944. Epub 2020 Dec 20. PMID: 33617087; PMCID: PMC9348556.
Pérez-De-Lis M, Akasbi M, Sisó A, Diez-Cascon P, Brito-Zerón P, Diaz-Lagares C, Ortiz J, Perez-Alvarez R, Ramos-Casals M, Coca A. Cardiovascular risk factors in primary Sjögren's syndrome: a case-control study in 624 patients. Lupus. 2010 Jul;19(8):941-8. doi: 10.1177/0961203310367504. PMID: 20581017.
Pijpe J, van Imhoff GW, Spijkervet FK, Roodenburg JL, Wolbink GJ, Mansour K, Vissink A, Kallenberg CG, Bootsma H. Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study. Arthritis Rheum. 2005 Sep;52(9):2740-50. doi: 10.1002/art.21260. PMID: 16142737.
Pijpe J, Kalk WW, Bootsma H, Spijkervet FK, Kallenberg CG, Vissink A. Progression of salivary gland dysfunction in patients with Sjogren's syndrome. Ann Rheum Dis. 2007 Jan;66(1):107-12. doi: 10.1136/ard.2006.052647. Epub 2006 May 25. PMID: 16728458; PMCID: PMC1798390.
Price E, Bombardieri M, Kivitz A, Matzkies F, Gurtovaya O, Pechonkina A, Jiang W, Downie B, Mathur A, Mozaffarian A, Mozaffarian N, Gottenberg JE. Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren's syndrome: a randomized, phase 2, double-blind, placebo-controlled study. Rheumatology (Oxford). 2022 Nov 28;61(12):4797-4808. doi: 10.1093/rheumatology/keac167. PMID: 35377447; PMCID: PMC9707320.
Ramos-Casals M, Tzioufas AG, Stone JH, Sisó A, Bosch X. Treatment of primary Sjögren syndrome: a systematic review. JAMA. 2010 Jul 28;304(4):452-60. doi: 10.1001/jama.2010.1014. PMID: 20664046.
Ramos-Casals M, Brito-Zerón P, Bombardieri S, Bootsma H, De Vita S, Dörner T, Fisher BA, Gottenberg JE, Hernandez-Molina G, Kocher A, Kostov B, Kruize AA, Mandl T, Ng WF, Retamozo S, Seror R, Shoenfeld Y, Sisó-Almirall A, Tzioufas AG, Vitali C, Bowman S, Mariette X; EULAR-Sjögren Syndrome Task Force Group. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Ann Rheum Dis. 2020 Jan;79(1):3-18. doi: 10.1136/annrheumdis-2019-216114. Epub 2019 Oct 31. PMID: 31672775.
Ramos-Casals M, Anaya JM, García-Carrasco M, Rosas J, Bové A, Claver G, Diaz LA, Herrero C, Font J. Cutaneous vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore). 2004 Mar;83(2):96-106. doi: 10.1097/01.md.0000119465.24818.98. PMID: 15028963.
Seror R, Bootsma H, Saraux A, Bowman SJ, Theander E, Brun JG, Baron G, Le Guern V, Devauchelle-Pensec V, Ramos-Casals M, Valim V, Dörner T, Tzioufas A, Gottenberg JE, Solans Laqué R, Mandl T, Hachulla E, Sivils KL, Ng WF, Fauchais AL, Bombardieri S, Priori R, Bartoloni E, Goeb V, Praprotnik S, Sumida T, Nishiyama S, Caporali R, Kruize AA, Vollenweider C, Ravaud P, Meiners P, Brito-Zerón P, Vitali C, Mariette X; EULAR Sjögren's Task Force. Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum Dis. 2016 Feb;75(2):382-9. doi: 10.1136/annrheumdis-2014-206008. Epub 2014 Dec 5. PMID: 25480887.
Seror R, Bowman SJ, Brito-Zeron P, Theander E, Bootsma H, Tzioufas A, Gottenberg JE, Ramos-Casals M, Dörner T, Ravaud P, Vitali C, Mariette X, Asmussen K, Jacobsen S, Bartoloni E, Gerli R, Bijlsma JW, Kruize AA, Bombardieri S, Bookman A, Kallenberg C, Meiners P, Brun JG, Jonsson R, Caporali R, Carsons S, De Vita S, Del Papa N, Devauchelle V, Saraux A, Fauchais AL, Sibilia J, Hachulla E, Illei G, Isenberg D, Jones A, Manoussakis M, Mandl T, Jacobsson L, Demoulins F, Montecucco C, Ng WF, Nishiyama S, Omdal R, Parke A, Praprotnik S, Tomsic M, Price E, Scofield H, L Sivils K, Smolen J, Laqué RS, Steinfeld S, Sutcliffe N, Sumida T, Valesini G, Valim V, Vivino FB, Vollenweider C. EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide. RMD Open. 2015 Feb 20;1(1):e000022. doi: 10.1136/rmdopen-2014-000022. PMID: 26509054; PMCID: PMC4613159.
Shen Y, Xie J, Lin L, Li X, Shen P, Pan X, Ren H, Chen N. Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren's Associated Chronic Interstitial Nephritis. Am J Nephrol. 2017;46(6):473-480. doi: 10.1159/000484903. Epub 2017 Dec 14. PMID: 29241210.
St Clair EW, Levesque MC, Prak ET, Vivino FB, Alappatt CJ, Spychala ME, Wedgwood J, McNamara J, Moser Sivils KL, Fisher L, Cohen P; Autoimmunity Centers of Excellence. Rituximab therapy for primary Sjögren's syndrome: an open-label clinical trial and mechanistic analysis. Arthritis Rheum. 2013 Apr;65(4):1097-106. doi: 10.1002/art.37850. PMID: 23334994; PMCID: PMC3618621.
St Clair EW, Baer AN, Wei C, Noaiseh G, Parke A, Coca A, Utset TO, Genovese MC, Wallace DJ, McNamara J, Boyle K, Keyes-Elstein L, Browning JL, Franchimont N, Smith K, Guthridge JM, Sanz I, James JA; Autoimmunity Centers of Excellence. Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ? Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2018 Sep;70(9):1470-1480. doi: 10.1002/art.40513. Epub 2018 Jul 18. PMID: 29604186; PMCID: PMC6115299.
Steinfeld SD, Tant L, Burmester GR, Teoh NK, Wegener WA, Goldenberg DM, Pradier O. Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study. Arthritis Res Ther. 2006;8(4):R129. doi: 10.1186/ar2018. PMID: 16859536; PMCID: PMC1779377.
Steinfeld SD, Demols P, Salmon I, Kiss R, Appelboom T. Notice of retraction of two articles (Infliximab in patients with primary Sjögrens syndrome: a pilot study and Infliximab in patients with primary Sjögrens syndrome: one-year followup). Arthritis Rheum. 2013 Mar;65(3):814. PMID: 23565525.
Urbanski G, Chabrun F, Schaepelynck B, May M, Loiseau M, Schlumberger E, Delattre E, Lavigne C, Lacombe V. Association of Primary Sjögren's Syndrome and Vitamin B12 Deficiency: A Cross-Sectional Case-Control Study. J Clin Med. 2020 Dec 16;9(12):4063. doi: 10.3390/jcm9124063. PMID: 33339380; PMCID: PMC7765802.
van der Heijden, E. H. M., Blokland, S. L. M., Hillen, M. R., Lopes, A. P. P., van Vliet-Moret, F. M., Rosenberg, A. J. W. P., ... & van Roon, J. A. G. (2020). Leflunomidehydroxychloroquine combination therapy in patients with primary Sjögren's syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial.?The Lancet Rheumatology,?2(5), e260-e269.
van Nimwegen, J. F., Mossel, E., van Zuiden, G. S., Wijnsma, R. F., Delli, K., Stel, A. J., ... & Bootsma, H. (2020). Abatacept treatment for patients with early active primary Sjögren's syndrome: a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study).?The Lancet Rheumatology,?2(3), e153-e163.
van Woerkom JM, Kruize AA, Geenen R, van Roon EN, Goldschmeding R, Verstappen SM, van Roon JA, Bijlsma JW. Safety and efficacy of leflunomide in primary Sjögren's syndrome: a phase II pilot study. Ann Rheum Dis. 2007 Aug;66(8):1026-32. doi: 10.1136/ard.2006.060905. Epub 2007 Jan 12. PMID: 17223657; PMCID: PMC1954693.
Willeke P, Schlüter B, Becker H, Schotte H, Domschke W, Gaubitz M. Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial. Arthritis Res Ther. 2007;9(6):R115. doi: 10.1186/ar2322. PMID: 17986340; PMCID: PMC2246233.
Xu D, Fang J, Zhang S, Huang C, Huang C, Qin L, Li X, Chen M, Liu X, Liu Y, Li Z, Hu J, Bao C, Wei W, Tian J, Duan X, Zeng X. Efficacy and safety of telitacicept in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled, phase 2 trial. Rheumatology (Oxford). 2023 Jul 3:kead265. doi: 10.1093/rheumatology/kead265. Epub ahead of print. PMID: 37399108.
Yavuz S, Asfuro?lu E, Bicakcigil M, Toker E. Hydroxychloroquine improves dry eye symptoms of patients with primary Sjogren's syndrome. Rheumatol Int. 2011 Aug;31(8):1045-9. doi: 10.1007/s00296-010-1415-4. Epub 2010 Mar 23. PMID: 20309693.
Yoon CH, Lee HJ, Lee EY, Lee EB, Lee WW, Kim MK, Wee WR. Effect of Hydroxychloroquine Treatment on Dry Eyes in Subjects with Primary Sjögren's Syndrome: a Double-Blind Randomized Control Study. J Korean Med Sci. 2016 Jul;31(7):1127-35. doi: 10.3346/jkms.2016.31.7.1127. Epub 2016 Apr 20. PMID: 27366013; PMCID: PMC4901007.
Zandbelt MM, de Wilde P, van Damme P, Hoyng CB, van de Putte L, van den Hoogen F. Etanercept in the treatment of patients with primary Sjögren's syndrome: a pilot study. J Rheumatol. 2004 Jan;31(1):96-101. PMID: 14705226.

Evidence tabellen

Evidence tables

Research question: What is the (in)effectivity of a systemic treatment compared to placebo, standard care or other systemic treatments in patients with Sjögren’s syndrome?

Study reference	Study characteristics	Patient characteristics ²	Intervention (I)	Comparison / control (C) ³	Follow-up	Outcome measures and effect size ⁴	Comments
Baer, 2021	Type of study: Randomized controlled trial, double-blind Setting and country: Europe/Asia (not fully clear), multicentre Funding and conflicts of interest: Commercial funding, potential conflicts of interest (grants from pharmaceutical companies received by authors)	Inclusion criteria: Diagnosis of primary SS (defined by ACR/EULAR 2016 criteria), moderate-to-severe disease activity with ESSDAI score ≥ 5, refractory to symptomatic or local therapy, positive for anti-SS-related antigen A/anti-Ro antibody. Exclusion criteria: Other systemic autoimmune disease, inflammatory conditions, severe fibromyalgia, other medical conditions associated with clinical features of pSS that could interfere with assessment of treatment response; use of corticosteroids (exc. oral) within 4 weeks prior to randomisation, rituximab or belimumab within 12 months, other biological therapy or methotrexate within 12 weeks. More in supplementary appendix of Baer (2021). N total at baseline: Intervention: 92 Control: 95 Important prognostic factors²: Mean age ± SD: I: 51.2 ± 12.3 C: 52.9 ± 13.5 Sex: I: 7.6% M C: 3.2% M Groups comparable at baseline.	Abatacept subcutaneous, 125 mg weekly for 24 weeks (reported as 169 days).	Placebo ‘’	Length of follow-up: 52 weeks Loss-to-follow-up: Intervention: 81/92 (88%) patients completed treatment. Reasons for discontinue: adverse events (n = 2), patient withdrew consent (n = 5), poor/non-compliance (n =1), patient no longer meets study criteria (n = 1), other (n = 2) Control: 87/95 (91.6%) patients completed treatment. Reasons for discontinue: lack of efficacy (n = 3), adverse events (n = 2), patient withdrew consent (n = 1), poor/non-compliance (n =1), patient request to discontinue (n = 1), other (n = 1) Incomplete outcome data: See ‘Loss-to-follow-up’	Efficacy All reported mean differences below are the adjusted mean treatment differences (difference in mean change from baseline) between intervention and placebo (95%CI) at week 24 ESSDAI 0.5 (-0.7 to 1.6) Percentage of patients with minimally clinically improvement (improvement in score ≥ 3: -2.7 (17.2 to 11.7) ESSPRI Total score: 0.3 (-0.3 to 0.8) Dryness: 0.2 (-0.5 to 0.8) Fatigue: 0.3 (-0.4 to 0.9) Pain: 0.3 (-0.3 to 1.0) Percentage of patients with minimally clinically improvement (improvement in score ≥ 1: -11.2 (-25.6 to 3.2) Saliva production Unstimulated salivary flow ml/min: -0.1 (-0.2 to 0.1) Stimulated salivary flow ml/min: -0.004 (-0.03 to 0.03) Tear production Schirmer’s test (mm/5 mm): 0.7 (-1.5 to 2.9) Patient global disease assessment score Scale of 0-100 -1.1 (-7.4 to 5.1) Safety Adverse events Overall: I: 79 (85.9%) C: 68/95 (71.6%) Serious adverse events: I: 9/92 (9.8%) C: 3/95 (3.2%)	Authors report that abatacept has no significant clinical effect compared to placebo, although a positive effect was seen for specific disease-relevant biomarkers (not reported). Intervention period was followed by an open-label treatment period where all patients received abatacept.
Bowman, 2017	Type of study: Randomized controlled trial, double-blind Setting and country: United Kingdom, multicentre Funding and conflicts of interest: Non-commercial funding, potential conflicts of interest (grants from pharmaceutical companies received by authors)	Inclusion criteria: Diagnosis of primary SS, aged 18-80 years, positive for anti Ro-antibodies, some (>0) unstimulated salivary flow, symptomatic fatigue, oral dryness worse than 5 of 10 on self-completed Likert scale. Patients had to be receiving a stable dose of corticosteroids, NSAIDs, DMARDs, pilocarpine and antidepressants for 4 weeks prior to an throughout the study. Exclusion criteria: Secondary SS, hepatitis B or C infection, tuberculosis, HIV infection, prior use of rituximab or other monoclonal antibody, malignancy within previous 5 years, recent organ transplant, major surgery planned or within last three months, pregnancy/lactation N total at baseline: Intervention: 67 Control: 66 Important prognostic factors²: Mean age ± SD: I: 54.3 ± 11.5 C: 54.4 ± 11.6 Sex: I: 7.6% M C: 6% M Groups comparable at baseline.	Rituximab 1000 mg in 250 ml saline, in two courses at baseline, at week 2, 24 and 26.	Placebo in 250 ml saline ‘’	Length of follow-up: 48 weeks Loss-to-follow-up: Intervention: 8/66 (12.1%) patients did not attend 48-week final visit. 55/66 (83%) received all four infusions. Control: 4/67 (6.0%) patients did not attend 48-week final visit. 54/67 (80.6%) patients received all four infusions. Incomplete outcome data: Intervention: 10/66 (15.2%) Reasons: no baseline measurements (n = 1), no follow-up (48-week) measurements (n = 8), no outcome for VAS (n = 1) Control: 6/67 (9.0%) Reasons: no baseline measurements (n = 1), no follow-up (48-week) measurements (n = 4), no outcome for VAS (n = 1)	Efficacy All reported mean differences below are the mean difference of intervention minus placebo (95%CI) ESSDAI Week 16: 0.85 (0.64 to 1.11) Week 24: 0.94 (0.73 to 1.22) Week 36: 0.74 (0.55 to 0.98) Week 48: 0.75 (0.55 to 1.03) ESSPRI Week 16: 0.19 (-0.45 to 0.82) Week 24: 0.55 (0.01 to 1.09) Week 36: -0.21 (-0.90 to 0.49) Week 48: 0.54 (-0.12 to 1.20) Saliva production Unstimulated salivary flow ml per 15 minutes (log-transformed) Week 16: 1.36 (0.99 to 1.88) Week 24 1.25 (0.91 to 1.72) Week 36: 1.56 (1.11 to 2.18) Week 48: 1.71 (1.23 to 2.37) Tear production Schirmer’s test (mm/5 mm) (lof-transformed): Week 16: 1.19 (0.88 to 1.61) Week 24: 1.01 (0.75 to 1.35) Week 36: 1.09 (0.79 to 1.51) Week 48: 1.16 (0.84 to 1.61) Quality of life SF-36 Physical component score Week 24: -1.86 (-4.15 to 0.43) Week 48: -0.79 (-3.25 to 1.67) Mental component score Week 24: -0.64 (-3.81 to 2.54) Week 48: 0.12 (-3.58 to 3.82) Safety Adverse events: 10 serious adverse events in both study groups. No data on other adverse events.	The authors report that no significant benefit of rituximab was found, only a significant difference found for the ESSDAI score on week 36 between the intervention and control group. Next to the intervention or placebo, patients also received methylprednisolone, acetaminophen and chlorpheniramine pre-infusion to reduce the risk of infusion reactions. They also received oral prednisolone post infusion 60 mg/day tapered to 15 mg/day over 7 days post-infusion. Several results were log-transformed due to skewed data. No outcomes reported for the relevant outcome measures stimulated salivary flow and SSDDI.
van Nimwegen, 2020	Type of study: Randomized controlled trial, double-blind Setting and country: Netherlands, single-center Funding and conflicts of interest: Commercial funding, potential conflicts of interest (grants from pharmaceutical companies received by authors)	Inclusion criteria: Diagnosis of primary SS (defined by ACR/EULAR 2016 criteria), aged ≥18, positive gland biopsy, diagnosis of SS of ≤7s years, baseline ESSDAI score of ≥5. Exclusion criteria: Prednisone use (≥ 10 mg/day), use of cs/tDMARDs including HCQ or pilocarpine for ≤1 month before enrolment. Patients who previously used abatacept (≥ 6 months before inclusion) or rituximab (≥12 months before inclusion) were allowed to participate. N total at baseline: Intervention: 40 Control: 40 Important prognostic factors²: Mean age ± SD: I: 48 ± 15 C: 49 ± 16 Sex: I: 8% M C: 8% M Groups comparable at baseline.	Abatacept subcutaneous, 125 mg weekly for 24 weeks.	Placebo ‘’	Length of follow-up: 48 weeks (inc. open-label phase with abatacept treatment). Loss-to-follow-up: Intervention: none Control: 2/40 (5%) Reasons: autoimmune hepatitis (n = 1), pulmonary and renal involvement (n = 1) Incomplete outcome data: See ‘Loss-to-follow-up’	Efficacy All reported mean differences below are the mean difference of intervention minus placebo (95%CI) ESSDAI Week 12: -2.4 (-4.7 to -0.1) Week 24: -1.3 (-4.1 to 1.6) ESSPRI Total score: Week 12: -4.7 (-12.5 to 3.0) Week 24: -5.0 (-12.7 to 2.8) Dryness: Week 12: -0.3 (-0.9 to 0.4) Week 24: -0.3 (-0.9 to 0.4) Fatigue: Week 12: -2.0 (-12.5 to 8.6) Week 24: -2.6 (-14.1 to 9.0) Pain: Week 12: -4.5 (-14.7 to 5.7) Week 24: -5.2 (-14.5 to 4.2) Saliva production Unstimulated salivary flow (ml/min) Week 12: -0.01 (-0.04 to 0.03) Week 24: 0.02 (-0.02 to 0.05) Stimulated salivary flow (ml/min) Week 12: 0.03 (-0.05 to 0.10) Week 24: 0.01 (-0.08 to 0.09) Tear production Schirmer’s test (mm/5 min): Week 12: 0.1 (-2.9 to 3.2) Week 24: 1.1 (-1.2 to 3.3) Patient global disease activity score Scale of 0-10 Week 12: -0.8 (-1.7 to 0.0) Week 24: -0.4 (-1.3 to 0.6) Quality of life SF-36 Physical component score Week 12: 2.5 (-0.2 to 5.2) Week 24: 2.0 (-0.7 to 4.7) Mental component score Week 12: -1.9 (-5.5 to 1.8) Week 24: -1.0 (-4.6 to 2.6) Safety Adverse events Total: Intervention: 103 events, 38/40 (95%) patients Control: 87 events, 38/40 (95%) patients Serious adverse events: Intervention 1 event (3% of patients) Control: 4 events, 4/40 (10%) of patients	Authors conclude that abatacept is well tolerated by primary SS patients, but the beneficial use as standard care could not be supported. Use of concomitant prednisone (≤ 10 mg/day) was allowed. After 24 weeks, patients from both treatment groups were enrolled in an open-label phase were both groups received abatacept (not further considered) Several results (ESSPRI total score and subscore for fatigue, pain) were transformed to second power due to skewed data.

Risk of bias table

Research question: What is the (in)effectivity of a systemic treatment compared to placebo, standard care or other systemic treatments in patients with Sjögren’s syndrome?

Study reference (first author, publication year)	Was the allocation sequence adequately generated? Definitely yes Probably yes Probably no Definitely no	Was the allocation adequately concealed? Definitely yes Probably yes Probably no Definitely no	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? Definitely yes Probably yes Probably no Definitely no	Was loss to follow-up (missing outcome data) infrequent? Definitely yes Probably yes Probably no Definitely no	Are reports of the study free of selective outcome reporting? Definitely yes Probably yes Probably no Definitely no	Was the study apparently free of other problems that could put it at a risk of bias? Definitely yes Probably yes Probably no Definitely no	Overall risk of bias If applicable/necessary, per outcome measure LOW Some concerns HIGH
Baer, 2021	Definitely yes Reason: Central randomization with global stratification of current corticosteroid use, current HCQ use, enrolment in Japan and level of stimulated salivary flow.	No information	Probably yes Reason: ‘Double-blind study design’, no more information reported.	Definitely yes Reason: Infrequent loss-to-follow-up in both study groups (9-12%). Use of ITT-analysis.	Definitely yes Reason: All relevant outcomes were reported;	Probably yes Reason: Commercial funding and potential conflicts of interest. However, no beneficial effect for abatacept reported in conclusion.	Some concerns (all outcomes) Reason: No information on allocation method.
Bowman, 2017	Probably no Reason: Randomization by minimization, assigning the patient with 80% probability to the study arm that reduces the between-group imbalance.	Probably yes Reason: The pharmacy of each study site received details of the participant allocation. Bags with intervention and control products received were identical.	Probably yes Reason: ‘Double-blind study design’, no more information reported. Independent study board had access to unblinded data for safety monitoring.	Probably no Reason: Loss to follow-up in intervention group twice as large compared to control group (12.1% vs. 6%). Use of ITT-analysis.	Definitely yes Reason: Data for stimulated salivary flow not reported and SSDDI.	Probably yes Reason: Potential conflicts of interest. However, no beneficial effect for rituximab reported in conclusion.	Some concerns (all outcomes) Reason: Incorrect randomization method, substantial difference in loss-to-follow-up between groups, no full outcome data reported for stimulated salivary flow and SSDDI.
van Nimwegen, 2020	Definitely yes Reason: Use of block randomization in blocks of four	Definitely no Reason: Block size was prespecified in the protocol and could be known to the investigators and outcome assessors.	Probably yes Reason: ‘Double-blind study design’, no more information reported. An independent data and safety monitoring board reviewed the unblinded study data for safety monitoring and overall study conduction.	Definitely yes Reason: Infrequent loss-to-follow-up in both study groups (0-5%). Use of ITT-analysis.	Definitely yes Reason: All relevant outcomes were reported;	Probably yes Reason: Commercial funding and potential conflicts of interest. However, no beneficial effect for abatacept reported in conclusion.	Some concerns (all outcomes) Reason: Inadequate allocation method.

Table of excluded studies (additional search)

Reference	Reason for exclusion
Collins, A. and Lendrem, D. and Wason, J. and Tarn, J. and Howard-Tripp, N. and Bodewes, I. and Versnel, M. A. and Gottenberg, J. E. and Seror, R. and Mariette, X. and Ng, W. F. Revisiting the JOQUER trial: stratification of primary Sjögren’s syndrome and the clinical and interferon response to hydroxychloroquine. Rheumatology International. 2021; 41 (9) :1593-1600	Primary study (of 2014) already included in EULAR
Fang W, Qingqing Z, Qihui L, Bing Z, Xinyue H, Jie X. Safety and Efficacy of Oral Hydroxychloroquine in the Treatment of Ophthalmic Disease Associated with Sjögren's Syndrome. Altern Ther Health Med. 2023 Nov;29(8):656-662. PMID: 37678871.	Specific on opthalmy
Yoon, C. H. and Lee, H. J. and Lee, E. Y. and Lee, E. B. and Lee, W. W. and Kim, M. K. and Wee, W. R. Effect of Hydroxychloroquine Treatment on Dry Eyes in Subjects with Primary Sjögren's Syndrome: a Double-Blind Randomized Control Study. Journal of Korean medical science. 2016; 31 (7) :1127-1135	Specific on opthalmy
Cornec D, Jousse-Joulin S, Costa S, Marhadour T, Marcorelles P, Berthelot JM, Hachulla E, Hatron PY, Goeb V, Vittecoq O, Nowak E, Pers JO, Devauchelle-Pensec V, Saraux A. High-Grade Salivary-Gland Involvement, Assessed by Histology or Ultrasonography, Is Associated with a Poor Response to a Single Rituximab Course in Primary Sjögren's Syndrome: Data from the TEARS Randomized Trial. PLoS One. 2016 Sep 23;11(9):e0162787. doi: 10.1371/journal.pone.0162787. PMID: 27662653; PMCID: PMC5035078.	Primary study (of 2014) already included in EULAR
Jain, A. and Srinivas, B. H. and Emmanuel, D. and Jain, V. K. and Parameshwaran, S. and Negi, V. S. Renal involvement in primary Sjogren’s syndrome: a prospective cohort study. Rheumatology International. 2018; 38 (12) :2251-2262	No outcomes of interest
Martínez-Sánchez, N. and Pérez-Pinto, S. and Robles-Marhuenda, Á and Arnalich-Fernández, F. and Martín Cameán, M. and Hueso Zalvide, E. and Bartha, J. L. Obstetric and perinatal outcome in anti-Ro/SSA-positive pregnant women: a prospective cohort study. Immunologic Research. 2017; 65 (2) :487-494	Very specific study population, although broad disease group. No outcomes of interest
Mutha, V. and Gupta, Y. and Gupta, N. and Vanathi, M. and Sen, S. and Kumar, U. and Tandon, R. Evaluation of oral rebamipide as a potential therapy for Sjögren syndrome-related dry eye and mouth. Indian Journal of Rheumatology. 2021; 16 (1) :49-56	No outcomes of interest
Reina, D. and Roig Vilaseca, D. and Torrente-Segarra, V. and Cerdà, D. and Castellví, I. and Díaz Torné, C. and Moreno, M. and Narváez, J. and Ortiz, V. and Blavia, R. and Martín-Baranera, M. and Corominas, H. Sjögren's syndrome-associated interstitial lung disease: A multicenter study. Reumatologia Clinica. 2016; 12 (4) :201-205	No full outcome data reported
Gonçalves, C. M. and Cordeiro, L. R. and de Andrade, C. A. F. and de Carvalho, J. F. Lymphocytic Interstitial Pneumonia Associated with Sjögren Syndrome: Case-Based Review. Current Rheumatology Reviews. 2023; 19 (1) :1-6	No comparison study
Kaegi, C. and Steiner, U. C. and Wuest, B. and Crowley, C. and Boyman, O. Systematic review of safety and efficacy of belimumab in treating immune-mediated disorders. Allergy: European Journal of Allergy and Clinical Immunology. 2021; 76 (9) :2673-2683	Only two studies on SS, of which one included separately and one study without control group.
Barsalou, J. and Costedoat-Chalumeau, N. and Berhanu, A. and Fors-Nieves, C. and Shah, U. and Brown, P. and Laskin, C. A. and Morel, N. and Levesque, K. and Buyon, J. P. and Silverman, E. D. and Izmirly, P. M. Effect of in utero hydroxychloroquine exposure on the development of cutaneous neonatal lupus erythematosus. Annals of the Rheumatic Diseases. 2018; 77 (12) :1742-1749	Study on infants with cutaneous neonatal lupus
Boujnah, Y. and Mouchel, R. and El-Chehab, H. and Dot, C. and Burillon, C. and Kocaba, V. [Prospective, monocentric, uncontrolled study of efficacy, tolerance and adherence of cyclosporin 0.1 % for severe dry eye syndrome]. Etude prospective, monocentrique, non controlee de l'efficacite, de la tolerance et de l'adhesion au traitement par ciclosporine 0,1 % au cours des secheresses oculaires severes.. 2018; 41 (2) :129-135	Article in French
Chighizola, Cecilia Beatrice and Ong, Voon H. and Meroni, Pier Luigi The Use of Cyclosporine A in Rheumatology: a 2016 Comprehensive Review. Clinical reviews in allergy & immunology. 2017; 52 (3) :401-423	Narrative review
de Wolff L, van Nimwegen JF, Mossel E, van Zuiden GS, Stel AJ, Majoor KI, Olie L, Los LI, Vissink A, Spijkervet FKL, Verstappen GMPJ, Kroese FGM, Arends S, Bootsma H. Long-term abatacept treatment for 48 weeks in patients with primary Sjögren's syndrome: The open-label extension phase of the ASAP-III trial. Semin Arthritis Rheum. 2022 Apr;53:151955. doi: 10.1016/j.semarthrit.2022.151955. Epub 2022 Jan 10. PMID: 35091325.	Secondary analysis of previous trial (van Nimwegen, 2020) with no comparison.
Fasano, Serena and Isenberg, David A. Present and novel biologic drugs in primary Sjogren's syndrome. Clinical and experimental rheumatology. 2019; 37 (3) :167-174	Narrative review
Fisher, B. A. and Everett, C. C. and Rout, J. and O'Dwyer, J. L. and Emery, P. and Pitzalis, C. and Ng, W. F. and Carr, A. and Pease, C. T. and Price, E. J. and Sutcliffe, N. and Makdissi, J. and Tappuni, A. R. and Gendi, N. S. T. and Hall, F. C. and Ruddock, S. P. and Fernandez, C. and Hulme, C. T. and Davies, K. A. and Edwards, C. J. and Lanyon, P. C. and Moots, R. J. and Roussou, E. and Richards, A. and Sharples, L. D. and Bombardieri, M. and Bowman, S. J. Effect of rituximab on a salivary gland ultrasound score in primary Sjögren's syndrome: Results of the TRACTISS randomised double-blind multicentre substudy. Annals of the Rheumatic Diseases. 2018; 77 (3) :412-416	Incorrect outcome (salivary gland ultrasound)
Grigoriadou, Sofia and Chowdhury, Farzana and Pontarini, Elena and Tappuni, Anwar and Bowman, Simon J. and Bombardieri, Michele B cell depletion with rituximab in the treatment of primary Sjogren's syndrome: what have we learnt?. Clinical and experimental rheumatology. 2019; 37 (3) :217-224	Narrative review
Kedor, C. and Zernicke, J. and Hagemann, A. and Gamboa, L. M. and Callhoff, J. and Burmester, G. R. and Feist, E. A phase II investigator-initiated pilot study with low-dose cyclosporine A for the treatment of articular involvement in primary Sjögren’s syndrome. Clinical Rheumatology. 2016; 35 (9) :2203-2210	No control group
Nocturne, G. and Cornec, D. and Seror, R. and Mariette, X. Use of Biologics in Sjögren's Syndrome. Rheumatic Disease Clinics of North America. 2016; 42 (3) :407-417	Narrative review
Othman, Tageldin M. and Mousa, Ahmed and Gikandi, Priscilla W. and AbdelMabod, Mohamed and Abdelrahman, Ahmed M. Efficacy and safety of using topical cyclosporine A for treatment of moderate to severe dry eye disease. Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society. 2018; 32 (3) :217-221	Patients with dry eye disease, no subgroup analysis for patients with Sjögren.
Sambataro, Domenico and Sambataro, Gianluca and Dal Bosco, Ylenia and Polosa, Riccardo Present and future of biologic drugs in primary Sjogren's syndrome. Expert opinion on biological therapy. 2017; 17 (1) :63-75	Narrative review, focus on expert opinion.
Saraux, A. and Pers, J. O. and Devauchelle-Pensec, V. Treatment of primary Sjögren syndrome. Nature Reviews Rheumatology. 2016; 12 (8) :456-471	Only single studies until 2010 included.
Al Hamad, A. and Lodi, G. and Porter, S. and Fedele, S. and Mercadante, V. Interventions for dry mouth and hyposalivation in Sjögren’s syndrome: A systematic review and meta-analysis. Oral Diseases. 2019; 25 (4) :1027-1047	Only one recent study (Bowman, 2017), listed above.
Álvarez-Rivas, N. and Sang-Park, H. and Díaz del Campo, P. and Fernández-Castro, M. and Corominas, H. and Andreu, J. L. and Navarro-Compán, V. Efficacy of belimumab in Primary Sjögren's syndrome: A systematic review. Reumatologia Clinica. 2021; 17 (3) :170-174	Older search data, potential studies already included in EULAR.
Choudhary, Ruchika and Reddy, Sujatha S. and Nagaraju, Rakesh and Nagi, Ravleen and Rathore, Pooja and Sen, Ritu Effectiveness of pharmacological interventions for Sjogren syndrome - A systematic review. Journal of clinical and experimental dentistry. 2023; 15 (1) :e51-e63	No studies of interest reported, due to older study date (already in EULAR) or no systemic treatment
Chu, L. L. and Cui, K. and Pope, J. E. Meta-Analysis of Treatment for Primary Sjögren's Syndrome. Arthritis Care and Research. 2020; 72 (7) :1011-1021	No studies after 2017 included.
Souza FB, Porfírio GJ, Andriolo BN, Albuquerque JV, Trevisani VF. Rituximab Effectiveness and Safety for Treating Primary Sjögren's Syndrome (pSS): Systematic Review and Meta-Analysis. PLoS One. 2016 Mar 21;11(3):e0150749. doi: 10.1371/journal.pone.0150749. PMID: 26998607; PMCID: PMC4801187.	Search data until 2015.
Fox, R. I. and Fox, C. M. and McCoy, S. S. Emerging treatment for Sjögren’s disease: a review of recent phase II and III trials. Expert Opinion on Emerging Drugs. 2023; 28 (2) :107-120	Narrative review
Garlapati, K. and Kammari, A. and Badam, R. K. and B. E, S. and Boringi, M. and Soni, P. Meta-analysis on pharmacological therapies in the management of xerostomia in patients with Sjogren’s syndrome. Immunopharmacology and Immunotoxicology. 2019; 41 (2) :312-318	Only older studies included (until 2003), focus on xerostomia.
Gueiros, L. A. and France, K. and Posey, R. and Mays, J. W. and Carey, B. and Sollecito, T. P. and Setterfield, J. and Woo, S. B. and Culton, D. and Payne, A. S. and Lodi, G. and Greenberg, M. S. and De Rossi, S. World Workshop on Oral Medicine VII: Immunobiologics for salivary gland disease in Sjögren's syndrome: A systematic review. Oral Diseases. 2019; 25 :102-110	No studies after 2017 included
Hermans, A. M. and Vulsteke, J. B. and Lenaerts, J. and De Langhe, E. Can We Expect Any Effect of Rituximab on Fatigue in Primary Sjögren Syndrome?: A Systematic Review and Critical Appraisal. Journal of Clinical Rheumatology. 2021; 27 (8) :E510-E515	Full tekst not available, single studies already included
Letaief, H. and Lukas, C. and Barnetche, T. and Gaujoux-Viala, C. and Combe, B. and Morel, J. Efficacy and safety of biological DMARDs modulating B cells in primary Sjögren's syndrome: Systematic review and meta-analysis. Joint Bone Spine. 2018; 85 (1) :15-22	No detailed search methods and no exclusion table (not fulfilling criteria for inclusion of SR), only data on 4 RCT on RTX
Liampas, A. and Parperis, K. and Erotocritou, M. F. and Nteveros, A. and Papadopoulou, M. and Moschovos, C. and Akil, M. and Coaccioli, S. and Hadjigeorgiou, G. M. and Hadjivassiliou, M. and Zis, P. Primary Sjögren syndrome-related peripheral neuropathy: A systematic review and meta-analysis. European Journal of Neurology. 2023; 30 (1) :255-265	Diagnostic study on prevalence of peripheral neuropathy.
MacIsaac, J. and Siddiqui, R. and Jamula, E. and Li, N. and Baker, S. and Webert, K. E. and Evanovitch, D. and Heddle, N. M. and Arnold, D. M. Systematic review of rituximab for autoimmune diseases: a potential alternative to intravenous immune globulin. Transfusion. 2018; 58 (11) :2729-2735	No studies on SS after 2017 reported.
Marshall, L. L. and Roach, J. M. Treatment of dry eye disease. Consultant Pharmacist. 2016; 31 (2) :96-106	Narrative review
Miyamoto, S. T. and Lendrem, D. W. and Ng, W. F. and Hackett, K. L. and Valim, V. Managing fatigue in patients with primary sjögren’s syndrome: Challenges and solutions. Open Access Rheumatology: Research and Reviews. 2019; 11 :77-88	Narrative review
Ringheim GE, Wampole M, Oberoi K. Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures. Front Immunol. 2021 Nov 3;12:662223. doi: 10.3389/fimmu.2021.662223. PMID: 34803999; PMCID: PMC8595937.	Narrative review
Shih KC, Lun CN, Jhanji V, Thong BY, Tong L. Systematic review of randomized controlled trials in the treatment of dry eye disease in Sjogren syndrome. J Inflamm (Lond). 2017 Nov 21;14:26. doi: 10.1186/s12950-017-0174-3. PMID: 29200970; PMCID: PMC5698951.	Older review with no studies included after 2017. Focus on dry eye disease.
Wang SQ, Zhang LW, Wei P, Hua H. Is hydroxychloroquine effective in treating primary Sjogren's syndrome: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2017 May 12;18(1):186. doi: 10.1186/s12891-017-1543-z. PMID: 28499370; PMCID: PMC5427554.	Older review with no studies included after 2017.
Wang X, Lin X, Su Y, Wang H. Systematic review with meta-analysis: Efficacy and safety of biological treatment on salivary gland function in primary Sjögren's syndrome. Front Pharmacol. 2023 Feb 14;14:1093924. doi: 10.3389/fphar.2023.1093924. PMID: 36865919; PMCID: PMC9972580.	Several studies of interest, included separately. Focus on salivary gland production with several outcomes of interest not reported.
Wang X, Zhang T, Guo Z, Pu J, Riaz F, Feng R, Fang X, Song J, Liang Y, Wu Z, Pan S, Tang J. The Efficiency of Hydroxychloroquine for the Treatment of Primary Sjögren's Syndrome: A Systematic Review and Meta-Analysis. Front Pharmacol. 2021 Sep 7;12:693796. doi: 10.3389/fphar.2021.693796. PMID: 34588979; PMCID: PMC8475756.	Review with no studies included after 2017, except for Hernandez-Molina (2018), listed above.

Verantwoording

Beoordelingsdatum en geldigheid

Laatst beoordeeld : 28-11-2024

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Reumatologie

Geautoriseerd door:

Nederlands Oogheelkundig Gezelschap
Nederlandse Internisten Vereniging
Nederlandse Vereniging voor Reumatologie
Nederlandse Vereniging voor Mond- Kaak- en Aangezichtschirurgie
Nationale Vereniging Sjögrenpatiënten

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 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 patiënten met de ziekte van Sjögren en ervaringsdeskundigen vanuit de patiëntenvereniging (NVSP).

Werkgroep

Drs. M. Smits (voorzitter), Reumatoloog, werkzaam in het Bernhoven ziekenhuis, NVR.
Prof. Dr. H. Bootsma, Reumatoloog, werkzaam in Universitair Medisch Centrum Groningen, NVR.
Dr. J. L. G. Vosters, Reumatoloog, werkzaam in Meander Medisch Centrum, NVR.
Dr. S. L. M. Blokland, AIOS reumatologie, werkzaam in Universitair Medisch Centrum Utrecht, NVR.
Dr. L. van den Hoogen, AIOS reumatologie, werkzaam in Radboud UMC en Sint Maartenskliniek, NVR.
Dr. G. A. W. Bruyn, Reumatoloog, werkzaam in Reumakliniek Lelystad en Tergooi MC, NVR.
Dr. B. van den Bergh, MKA-chirurg, werkzaam in MKA Kennemer en Meer B.V. en Spaarne Gasthuis, NVMKA.
Prof. Dr. A. Vissink, MKA-chirurg, werkzaam in Universitair Medisch Centrum Groningen, NVMKA.
Dr. Z. Brkić, Internist-allergoloog/klinisch immunoloog, werkzaam in Erasmus Medisch Centrum, NIV/NVvAKI.
Drs. M. Rietbergen, Oogarts, werkzaam in Medisch Centrum Leeuwarden, NOG.
Drs. M. Y. Visser – Noordegraaf, ervaringsdeskundige, NVSP.
A. M. Baert – Jansen, Ervaringsdeskundige, NVSP.

Klankbordgroep

Dr. M. Wintzen, Dermatoloog, werkzaam in Amsterdam Universitair Medisch Centrum, NVDV.
Dr. K. Mansour, Oogarts, werkzaam in Tjongerschans ziekenhuis Heerenveen, NOG.
Dr. D. H. J. Jager, Tandarts, werkzaam in Amsterdam Universitair Medisch Centrum, KNMT
Prof. Dr. R. Geenen, Emeritus Hoogleraar, Universiteit Utrecht

Met ondersteuning van

Dr. A.N. Nguyen, Adviseur, Kennisinstituut van Federatie Medisch Specialisten.
Drs. L. Niesink-Boerboom, Literatuurspecialist, Kennisinstituut van 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, onderzoek financiering) 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 werkgroepleden 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.

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
Drs. M. Smits, voorzitter van de werkgroep	Reumatoloog	Geen	Geen	Geen actie vereist
Prof. Dr. H. Bootsma	Reumatoloog	Voorzitter stafconvent UMCG; Hoofd expertisecentrum van Sjögren; Afdelingshoofd; Hoogleraar.	Extern gefinancierd onderzoek; Hoofd researchlijn Sjögren; Vooraanstaande rol internationaal onderzoek ziekte van Sjögren; Medische Adviesraad: NVSP, Europese patiëntenvereniging ziekte van Sjögren, Sjögrens foundation (USA)	Restricties ten aanzien van besluitvorming rondom medicamenteuze behandeling van de ziekte van Sjögren
Dr. J. L. G. Vosters	Reumatoloog	Geen	Geen	Geen actie vereist
Dr. L. van den Hoogen	AIOS	Geen	Geen	Geen actie vereist
Dr. G. A. W. Bruyn	Reumatoloog	Directeur RUKL; Schrijver; Docent.	Ontvangt royalties van geschreven boeken (Sjögren and the Salivary Glands; Introduction to Musculoskeletal Ultrasound for the Rheumatologist).	Geen actie vereist
Dr. S. L. M. Blokland	AIOS Reumatologie	Secretaris landelijke ARCH werkgroep Sjögren	Medisch adviseur NVSP	Geen actie vereist
Dr. B. van den Bergh	MKA-chirurg	Secretaris MKA Kennemer en Meer B.V. Haarlem	Geen	Geen actie vereist
Prof. Dr. A. Vissink	MKA-chirurg	Betaald: - Lid Centraal Tuchtcollege voor de Gezondheidszorg - Lid Centraal Tuchtcollege voor de Gezondheidszorg van het Caraïbisch Gebied - Editor European Journal of Oral Sciences - Directeur Ter Stal Onroerengoed Niet betaald: - Associate editor Oral Diseases - Editorial board Journal of Clinical Medicine, Int J Environ Res Public Health, International Journal of Oral and Maxillofacial Surgery, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, International Journal of Case Reports in Medicine, World Journal of Methodology, Journal of the Indian Society of Periodontology, Clinical and Experimental Rheumatology	Extern gefinancierd onderzoek.	Geen actie vereist
Dr. Z. Brkić	Internist-allergoloog / Klinisch Immunoloog	Voorzitter landelijke werkgroep Sjögren binnen ARCH (onbetaald) Speaker Fee Novartis, Jansen, AstraZeneca en Santen.	Geen	Geen betaalde presentaties te geven gedurende de richtlijnontwikkeling.
Drs. M. Rietbergen	AIOS Oogheelkunde, UMCG Groningen	Speaker fee Tramedico	Geen	Geen actie vereist
Drs. M. Y. Visser – Noordegraaf	Ervaringsdeskundige	Geen	Geen	Geen actie vereist
A. M. Baert – Jansen	Ervaringsdeskundige	Geen	Geen	Geen actie vereist

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door samenwerking met de Patiëntenfederatie Nederland. Hiertoe zullen de betrokken patiëntenverenigingen ook benaderd worden, zoals Reuma Nederland en de Nationale Vereniging Sjögren Patiënten.

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 Systemische behandeling	Geen financiële gevolgen	Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten), volgt ook uit de toetsing dat het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet. Er worden daarom geen financiële gevolgen verwacht.

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010). Bij deze richtlijn is er sprake van een versnelde adaptatie van een internationale richtlijn naar de Nederlandse praktijk. Daarvoor zijn de stappen gevolgd conform het advies “Adapteren van internationale richtlijnen naar de Nederlandse praktijk” (RK-17.07.07, bijlage bij adviesrapport ‘Adapteren van internationale richtlijnen naar de Nederlandse praktijk. Opgesteld door de adviescommissie richtlijnen, en vastgesteld op 27 juni 2017).

Knelpuntenanalyse en uitgangsvragen

Conform de verkorte adaptatieprocedure [RK-17.07.07 Advies Adapteren van internationale richtlijnen 24 juni 2017] vervalt de knelpuntenanalyse. Echter is er wel binnen de NVR en de commissie kwaliteit besproken of de uitgangsvragen in de internationale richtlijn: 1) aansluiten bij de knelpunten in de Nederlandse praktijk, 2) er nog knelpunten ontbreken die opgenomen moeten worden in de richtlijn en, 3) of er bepaalde uitgangsvragen een update behoeven. Deze vragen zullen ook worden gesteld aan de richtlijnwerkgroep.

Uitkomstmaten

Relevante uitkomstmaten werden overgenomen zoals geformuleerd in de internationale richtlijn.

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Search and select’. Deze beschrijving en beoordeling zijn overgenomen van de internationale EULAR-richtlijn en waar nodig aangevuld met nieuwe studies die geselecteerd zijn bij het updaten van desbetreffende richtlijnmodules. 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 een op een 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 nul effect) 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 Kwaliteit. 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.

Richtlijnendatabase

Topicale en systemische behandeling van de ziekte van Sjögren

Topicale en systemische behandeling van de ziekte van Sjögren

Systemische behandeling

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Achtergrond

Conclusies / Summary of Findings

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Beoordelingsdatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Module

Werkwijze

Bijlagen