Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial

Tanja Stamm ,Farideh Alasti,Gerd R Burmester ,Emilio Martı́n-Mola ,Peter E Lipsky ,Winfried Graninger,Wolfgang Ebner,Georg Schett,Alexandre Sepriano,D T Boumpas ,Maurizio Cutolo,Désirée Van Der Heijde ,Daniel Aletaha,Ferdinand C Breedveld ,David S Pisetsky ,Tom W J Huizinga ,Martin Aringer,Robert Landewé ,Paul‐Peter Tak ,Hendrik Schulze‐Koops ,Klaus Machold ,Josef S Smolen

doi:10.1186/s13075-018-1667-z

Abstract

BackgroundIn the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis.MethodsIn an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0–2 tender joints, and an acute-phase reactant within the normal range.ResultsNinety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients.ConclusionsThese results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution.Trial registrationThe trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.

Highlights

In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis
Data are shown as mean ± standard deviation or n (%) as appropriate The parameters showed no significant differences between the three groups at baseline Tables with additional data on baseline characteristics as well as 1-year data for the patients who were in remission at 1 year are provided in Additional file 2 (Tables SC and SD) ACR American College of Rheumatology, ARA American Rheumatism Association, EULAR European League Against Rheumatism, IFX infliximab, MTX methotrexate, PL placebo, Rheumatoid arthritis (RA) rheumatoid arthritis aSymptom duration refers to the first visit when the patients presented themselves at the centres
These findings suggest that once joint inflammation is clinically manifest, symptomatic therapy does not impact on the course of disease, that initiation of Disease-modifying anti-rheumatic drug (DMARD) therapy is warranted to improve outcomes, and that early intensive treatment with anti-TNF + MTX leads to drug-free remission in 1 of 4 patients

Summary

Introduction

We explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. In the course of RA, a unique stage called the “window of opportunity” may exist During this stage, key steps in pathogenesis may be reversible, with DMARD therapy blocking progression to full disease manifestations and potentially leading to sustained remission [13, 14]. Several findings provide support for the window of opportunity hypothesis: an increase in the risk of persistent disease after several months of arthritis symptoms [15, 16]; differences in immunological abnormalities in very early compared with established disease [17, 18]; and the ability of early treatment with a tumour necrosis factor (TNF) inhibitor plus methotrexate (MTX) to allow some patients with RA to achieve a drug-free remission [19, 20]. Recent data obtained in patients with early disease suggest that, in those fulfilling the classification criteria of RA, drug-free remission after such induction therapy may be uncommon [12, 21]

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Results

Discussion

Conclusion