Glucocorticoïden (GCs) hebben een anti-inflammatoire werking en remmen ook effectief structurele gewrichtsschade en functieverlies bij Reumatoïde Artritis (RA) (Kirwan, 1995; Mottonen, Hannonen, & Boers, 1999; van Everdingen, Jacobs, Siewertsz Van Reesema, & Bijlsma, 2002). De werking van GCs treedt snel op. Daarom kunnen GCs worden ingezet als overbruggingstherapie bij de start van disease-modifying antirheumatic drug (DMARD) therapie, wanneer er sprake is van een (lokale) opvlamming van RA, of bij verandering van DMARD therapie. GCs kunnen systemisch of lokaal worden ingezet. Voorbeelden van lokale therapie zijn een intra- articulaire of intra-tenosynoviale injectie in een ontstoken gewricht of respectievelijk peesregio. Systemische therapie kan worden gegeven in de vorm van tabletten per os, intramusculaire injectie of intraveneuze toediening. GCs hebben een breed risicoprofiel welke samenhangt met de toedieningsvorm, de (cumulatieve) dosis en de duur van therapie (Hoes, Jacobs, Verstappen, Bijlsma, & Van der Heijden, 2009). Het risicoprofiel omvat o.a. verhoogde kans op infecties, osteoporose en osteonecrose, diabetes, cataract, psychische reacties en gastro-intestinale en cardiovasculaire problematiek. Een optimale dosering en toedieningsschema (de laagst mogelijke hoeveelheid voor een zo kort mogelijke periode) alsook het opstarten van profylactische therapie in de vorm van b.v. osteoporoseprofylaxe en maagprotectie, zijn manieren om hierop anticiperen.

Op basis van de literatuur wordt geconcludeerd dat er lage kwaliteit bewijs is dat een echogeleide intratenosynoviale injectie met GCs effectiever is dan een intramusculaire steroïdinjectie, bij lokale tenosynovitis. De bewijskracht werd met 2 niveaus verlaagd gezien imprecisie van de resultaten (sparse data).

EULAR 2010 (Gorter et al., 2010):

A total of 172 publications was found, of which 11 (including three Cochrane reviews concerning 33 trials) met the criteria for detailed assessment. Evidence that GCs are effective as bridging therapy was obtained. A Cochrane review by Gotzsche and Johansen included 11 RCTs that compared GCs (dose 10 - 15mg/day) with placebo or NSAIDs in patients with RA (Gotzsche & Johansen, 2004). Significantly better clinical outcomes within 1 month were reported in the GC-treated groups for signs and symptoms, supporting the concept of bridging. In only 1 of the trials GCs were actually used to bridge the gap between the start of a DMARD and its onset (van Gestel, Laan, Haagsma, van de Putte, & van Riel, 1995). In an additional RCT increased efficacy was shown with a methylprednisolon pulse bridging therapy in addition to the initiation of methotrexate in RA (van der Veen & Bijlsma, 1993). Level of evidence (LOE): 1b.

The addition of GCs, to either csDMARD monotherapy or combinations, yields clinical benefits and inhibition of radiographic progression that may extend over many years. The addition of GCs in a dose equivalent to a maximum of 7.5mg/day to csDMARD monotherapy was studied in a number of RCTs (Capell et al., 2004; Choy et al., 2005; Hansen et al., 1999; Svensson et al., 2005; Wassenberg, Rau, Steinfeld, & Zeidler, 2005). GCs were predominantly given for a longer period (1-2 years). Overall, the addition of GCs in comparison with placebo yielded significantly better outcomes with regard to symptoms and function, and significantly reduced radiographic damage progression. LOE: 1b.

Three pivotal RCTs studied the effect of GCs as part of a strategy including csDMARD combinations versus csDMARD monotherapy: the COBRA study (Boers et al., 1997), the BeSt study (Goekoop-Ruiterman et al., 2005) and the FIN-RACo study (T. Mottonen et al., 1999). GCs were given in a step-down high dose regimen (60mg tapered in several weeks to 7.5mg and tapering to zero thereafter). The combination treatment arms in which GCs were added performed better with regard to the main clinical, functional and radiographic outcomes. Early benefits in clinical outcomes were associated with long-term benefits in radiographic progression. It is, however, difficult to conclude whether the observed effects can be solely attributed to the GCs rather than the combination of conventional synthetic DMARDs (csDMARDs), as control arms of csDMARD combinations without GCs or DMARD monotherapy with mandatory GCs were lacking. LOE: 2b.

In a large Cochrane review it was demonstrated that in RA of < 2 years duration the addition of either low-dose GCs (<7.5mg/day) or a high-dose step-down regimen to DMARDs leads to a reduction in radiographic progression (Kirwan, Bijlsma, Boers, & Shea, 2007). In a second Cochrane review in mostly longstanding RA, GCs (up to 15mg/day) improved disease activity and functional status (Criswell et al., 2000). LOE: 1a.

EULAR 2013:

Of 222 potentially relevant articles, five new studies relating to four RCTs were included (Bakker, Jacobs, Welsing, & Verstappen, 2012; Fedorenko, Lukina, & Sigidin Ya, 2011; Machold et al., 2010; Montecucco, Todoerti, Sakellariou, Scire, & Caporali, 2012; Todoerti et al., 2010). Two studies were RCTs with a low RoB (Bakker et al., 2012; Machold et al., 2010). In the SAVE trial a single GC (methylprednisolone 120mg) intramuscular injection in patients with very early arthritis who did not yet meet the RA 1987 classification criteria, did not result in more drug-free persistent remission after both 12 and 52 weeks (Machold et al., 2010). The CAMERA II study reported the efficacy of prednison 10mg/day added to methotrexate in a 2-year placebo-controlled double-blind RCT in RA of shorter dan 1 year duration. After 2 years there was significantly less damage progression and better American College of Rheumatology 70 (ACR70) response in the combination therapy arm (Bakker et al., 2012). Also, in this tight control strategy trial, the need for additional treatment (sc methotrexate, ciclosporin or adalimumab) was significantly lower in the methotrexate plus prednisone group. The other studies that were found were open- label trials with a high risk of bias, but also showed the clinical superiority of the combination of GCs with methotrexate. A final study which is mentioned in this update of the EULAR recommendations is the tREACH trial (de Jong et al., 2013). In this trial an intramuscular injection with methylprednisolone 120 mg or triamcinolone 80 mg or an oral GC tapering scheme (15 mg/day in the first month to 2,5mg/day after 10 weeks) were equally effective as bridging treatment (added to methotrexate, sulfasalazine and hydroxychloroquine combination).

EULAR 2016:

Efficacy of addition of GCs to csDMARDs

Of 348 hits, 4 studies were included in the analysis. A small study by Menon et al showed greater efficacy of a combination of csDMARDs with intra-articular GCs than with csDMARDs alone in patients with RA with less than 2 years disease duration, but this was an open label study with high RoB (Menon, Kothari, Gogna, & Sharma, 2014). In the CareRA trial patients with early RA, but without poor prognostic factors, benefited from the addition of GCs (COBRA-slim) to Methotrexate (MTX) with no differences in safety observed (Verschueren, De Cock, Corluy, Joos, Langenaken, Taelman, Raeman, Ravelingien, Vandevyvere, Lenaerts, Geens, Geusens, Vanhoof, Durnez, Remans, Vander Cruyssen, Van Essche, Sileghem, De Brabanter, Joly, Van der Elst, et al., 2015). The primary end point of this study was not met, since the percentage of patients achieving remission at week 16 was only numerically but not significantly higher in the GC group (65.1% vs 46.8%, p=0.08). However, this substudy analysis did not have sufficient statistical power and had a high RoB, primarily due to lack of blinding. The COBRA-light non-inferiority trial compared two different GC strategies; the COBRA-light strategy (prednisolone at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) in combination with MTX; and the COBRA strategy, using prednisolone at 60 mg/day (tapered to 7.5 mg/day in 6 weeks) in combination with both MTX and sulfasalazine. The lower dose of GCs was efficacious in suppressing clinical disease activity and improving functional ability, but non-inferiority could not be claimed formally (den Uyl et al., 2014; ter Wee et al., 2015). The degree of radiographic progression was similar in the two groups (COBRA and COBRA-light). However, this study also had a high RoB (open design), and no comparison with application of conventional GCs was performed.

In a double-blind RCT with patients with established RA, low-dose prednisone with modified release (‘chronotherapy’) added to existing DMARD treatment in patients with active disease had a significant effect on disease activity and health-related quality of life compared with placebo (Buttgereit et al., 2013). A pooled analysis could not be performed because of significant heterogeneity of the studies regarding designs, patient populations, doses and routes of administration of GCs, and outcome measures. The results of the newer RCTs are in accordance with the previously formulated standpoint that GC when added to csDMARD therapy may have beneficial effects. Safety aspects, as addressed in a separate systematic literature search (SLR), have to be taken into consideration (Ramiro et al., 2017). LOE: 1a.

Current update:

Of 355 articles 2 RCTs were found that displayed new or additional evidence for the use of GCs in RA (Ammitzbøll- Danielsen et al., 2017; Verschueren et al., 2017). Two other studies did not completely fulfill the inclusion criteria based on the PICO and will be discussed in the consideration section (Konijn et al., 2017; Safy et al., 2017). In the first RCT intramuscular versus ultrasound-guided intratenosynovial betamethasone injection was compared in 50 RA patients with stable disease and tenosynovitis in hand or ankle region (Ammitzbøll-Danielsen et al., 2017) in a double-blind placebo-controlled fashion. It was shown that after 4 weeks of follow-up, 64% versus 25% of patients achieved ultrasound defined remission (Greyscale <=1 and Dopplerscore 0) after ultrasound-guided intratenosynovial versus intramuscular injection, respectively. After 12 weeks remission percentages were 44% versus 8%, respectively. Patients in the intratenosynovial group also reported significantly less pain.

In the Belgian CareRA trial, a randomized pragmatic open-label superiority trial, DMARD-inexperienced patients with RA less than 1 year duration were stratified into a high-risk and a low-risk group on the basis of erosions, rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) and disease activity score 28 (DAS28) (Verschueren et al., 2017). High-risk patients (n=289) were randomized into either COBRA Classic (MTX, sulfasalazine and prednisone step-down from 60mg), COBRA Slim (MTX, prednisone step-down from 30mg), or COBRA Avant Garde (MTX, leflunomide, prednisone step-down from 30mg). Low-risk patients (n=90) were randomised into MTX tight step-up (monotherapy without GCs) or COBRA Slim. A low prednison dosage (7.5mg/day in Classic and 5mg/day in Slim) was maintained until week 28.

The results after 16 weeks were described previously in the EULAR systematic review. High-risk patients did not benefit more from combination of MTX with other csDMARDs in comparison to MTX monotherapy (both combined with glucocorticoids), after 16 weeks of follow-up (Verschueren, De Cock, Corluy, Joos, Langenaken, Taelman, Raeman, Ravelingien, Vandevyvere, Lenaerts, Geens, Geusens, Vanhoof, Durnez, Remans, Vander Cruyssen, Van Essche, Sileghem, De Brabanter, Joly, Meyfroidt, et al., 2015). In our update, we identified the one- year follow-up results of the CareRA trial (Verschueren et al., 2017). It was shown that in the high-risk group, there was no difference in DAS28 CRP remission percentages between the groups receiving either the COBRA Slim, Classic, or Avant Garde regiment (60%, 64% and 62%, respectively). No significant differences were found for secondary outcomes health assessment questionnaire (HAQ), EULAR responses and radiographic progression. Hence, there was no superiority of csDMARD combination therapy in comparison to MTX monotherapy, all combined with GCs. Furthermore, step-down from 60mg prednisone had no advantage in comparison to step- down from 30mg but was associated with more side effects. On the other hand, more GC injections and treatment adaptations were needed in the Slim group. In the low-risk RA group, there was no difference in DAS28 CRP remission between COBRA slim and MTX tight step-up after one year of follow-up (67% versus 57%, respectively), although in the group receiving COBRA Slim, time-to-remission was shorter. Also, the power in this subgroup was low.

Bewijskracht van de literatuur

Op basis van de literatuur wordt geconcludeerd dat er hoge kwaliteit bewijs is dat overbruggingstherapie met GCs naast csDMARDs effectief is ten aanzien van verbetering van ziekteactiviteit en remming van radiologische schade, zowel op korte als lange termijn.

Op basis van de literatuur wordt geconcludeerd dat er hoge kwaliteit bewijs is dat overbruggingstherapie met GCs effectief is in verschillende doseringsschema’s via orale of intramusculaire toediening.

Om de uitgangsvraag te kunnen beantwoorden is er een systematische literatuuranalyse verricht naar de volgende zoekvraag:

Wat is de effectiviteit van GCs bij patiënten met RA naast DMARD behandeling?

Relevante uitkomstmaten

De werkgroep achtte ziekteactiviteit, functie en radiologische schade kritieke uitkomstmaten; en patiënt- gerapporteerde uitkomstmaten (PROMs) zoals pijn en moeheid belangrijke uitkomstmaten.

De werkgroep definieerde niet a priori de genoemde uitkomstmaten, maar hanteerde de in de studies gebruikte definities.

Zoeken en selecteren (Methode)

In de databases Medline (via OVID), Embase (via Embase.com) en de Cochrane CENTRAL Library (via Wiley) is op 18-12-2017 met relevante zoektermen gezocht naar randomized controlled trial (RCTs), gepubliceerd na 2016 (voortbordurend op de evidence die reeds samengevat is door de European League Against Rheumatism (EULAR) tot 2016). De zoekverantwoording is weergegeven onder het tabblad Verantwoording. De literatuurzoekactie leverde na verwijdering van duplicaten 8546 treffers op. Studies werden geselecteerd op grond van de volgende selectiecriteria:

• Volwassen patiënten met een diagnose RA
• Behandeling met GCs (in bepaalde dosis of toedieningsroute) naast DMARD therapie
• In vergelijking met geen GCs of GCs in een andere toedieningsroute of dosis
• Uitkomstmaten: ziekteactiviteit, functie, radiologische schade, PROM’s
• Studie design: gerandomiseerd gecontroleerd onderzoek

Op basis van titel en abstract werden uit 355 artikelen in eerste instantie 12 studies voorgeselecteerd. Na raadpleging van de volledige tekst, werden vervolgens 10 studies geëxcludeerd (zie exclusietabel onder het tabblad Verantwoording), en 2 studies definitief geselecteerd. Daarnaast zijn twee studies geëxcludeerd omdat ze lange termijn follow-up data beschreven van reeds voor 2016 gepubliceerde RCTs die al in de bestaande EULAR aanbevelingen zijn verwerkt. Desalniettemin werden deze follow-up data wel meegenomen in de overwegingen.

Twee studies zijn opgenomen in de literatuuranalyse. De belangrijkste studiekarakteristieken en resultaten zijn opgenomen in de evidencetabellen. De beoordeling van de individuele studieopzet (risk of bias) is opgenomen in de risk of bias (RoB) tabellen.