Towards the lowest efficacious dose (toledo): results of a multicenter non-inferiority randomized open-label controlled trial assessing tocilizumab or abatacept injection spacing in rheumatoid arthritis patients in remission
2 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
3 SU - Sorbonne Université
4 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
5 SAINBIOSE - Santé Ingénierie Biologie Saint-Etienne
6 BPH - Bordeaux population health
7 CRI-IMIDIATE Clinical Research Network
8 Service de Rhumatologie [Orléans]
9 CIRID - Composantes innées de la réponse immunitaire et différenciation
10 Service de rhumatologie [Rennes] = Rheumatology [Rennes]
11 UNH - Unité de Nutrition Humaine
12 Service Rhumatologie [CHU Clermont-Ferrand]
13 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
14 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
15 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
16 CPTP - Centre de Physiopathologie Toulouse Purpan
17 Service de Rhumatologie [CH Le Mans]
18 Hôpital Louis Pasteur [Chartres]
19 Hôpital Maison Blanche
20 Hôpitaux Sud - Rhumatologie [Sainte- Marguerite - APHM]
21 Service de rhumatologie [Strasbourg]
22 Hopital Réné Dubos
23 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
24 LBAI - Lymphocytes B, Autoimmunité et Immunothérapies
25 CHU - BREST - Rhumato - CHRU Brest - Service de Rhumatologie
26 GREPI - Groupe de Recherche et d'Etude du Processus Inflammatoire
27 CHD Vendée - Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon
28 CHU Trousseau [APHP]
29 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
30 IMVA-HB - Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes
31 CRSA - Centre de Recherche Saint-Antoine
32 Centre Hospitalier Victor Jousselin [Dreux]
33 Service de rhumatologie [Nantes]
34 Service de Rhumatologie (CHU de Dijon)
35 BIOSCAR (UMR_S_1132 / U1132) - Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques
36 Hôpital Lariboisière-Fernand-Widal [APHP]
37 Rhumatologie [CHU Amiens]
38 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
39 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
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Résumé
Background: Biologic Disease Modifying Anti-Rheumatic Drugs (bDMARD) tapering is possible in rheumatoid arthritis (RA) patients in sustained remission. However, only minimal data are available on progressive tapering of non-TNF bDMARD such as tocilizumab (TCZ) or abatacept (ABA). Objectives: The TOLEDO (Towards the Lowest Efficacious Dose) trial aimed to assess the impact on disease activity of progressive spacing of TCZ or ABA in RA patients in sustained remission compared to their maintenance at full dose. Methods: In this multicenter open-label non-inferiority randomized controlled trial, patients fulfilling ACR-EULAR 2010 criteria for RA were included if they were 1) treated with ABA or TCZ for ≥ 1 year (monotherapy or in combination with csDMARD, corticosteroid allowed at a dose ≤ 5 mg/day), 2) in DAS28VS remission (DAS28 <2.6) for ≥ 6 months and 3) with no X-ray damage progression in the year before inclusion. They were randomized into 2 arms: TCZ or ABA maintenance at full dose or DAS28-driven progressive injection spacing arm adapted in which bDMARD IV or SC injections were progressively spaced out every 3 months according to a predetermined 4-step algorithm up to bDMARD discontinuation at step 4. Spacing was reversed to the previous interval in case of relapse. The primary outcome was the evolution of disease activity according to DAS44 during the 2-year follow-up, which was analyzed with a linear mixed-effect model. Relapse and durable relapse rates (respectively defined as DAS28 > 3.2, and DAS28 >3.2 not recovered at the following visit despite bDMARD escalation at previous step) were also compared between the 2 arms. Analysis were done per protocol (PP) according to a non-inferiority hypothesis (non-inferiority margin at 0.25 for DAS44 and 0.07 for relapse rates). Results: 117 patients were randomized in Spacing arm and 116 in Maintenance arm (90 and 112 respectively for PP analysis). 165 (72.4%) patients were treated with TCZ and 63 (27.6%) with ABA. At the end of the follow-up in the Spacing arm, 12.4% of patients were able to discontinue their bDMARD (step 4), 38.9% had tapered them (step 1 to 3) and 23.9% needed to go back to initial step (step 0). In terms of disease activity, the non-inferiority of the Spacing strategy in terms of disease activity (DAS44) was not demonstrated for the whole population and the ABA subgroups: slope difference of 11% (95% CI: -9%, 32%) and 37% (95% CI: -4%, 77%) respectively. However, it was satisfied for the TCZ subgroup: slope difference 3% (95% CI: -21%, 27%) (Figure 1). Relapses (Figure 2) were more frequent in the Spacing arm: +45% (95% CI: 32%, 57%), +48% (95% CI: 24%, 71%) and +43% (95%CI: 29%, 58%) in the whole population, ABA and TCZ subgroups respectively. Durable relapses were more frequent in the Spacing arm: +10% (95%CI: 0%, 19%), 16% (95%CI: -5%, 37%) and 7% (95%CI: -3%, 16%) in the whole population, ABA and TCZ subgroups respectively, compared with Maintenance arm. Conclusion: The TOLEDO trial generally failed to demonstrate the non-inferiority of the proposed tapering strategy in comparison to maintenance at full dose. However, the non-inferiority was satisfied in terms of disease activity for the TCZ subgroup.
