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  1. D. Krijbolder1,
  2. M. Verstappen1,
  3. B. van Dijk1,
  4. Y. Dakkak1,
  5. L. Burgers1,
  6. A. Boer1,
  7. Y. Jung Park1,
  8. M. De Witt2,
  9. K. Visser3,
  10. M. R. Kok4,
  11. E. Molenaar5,
  12. P. de Jong6,
  13. S. Böhringer7,
  14. T. Huizinga1,
  15. C. Allaart1,
  16. E. Niemantsverdriet1,
  17. A. van der Helm-van Mil1,6
  1. 1Leiden University Medical Center (LUMC), Rheumatology, Leiden, Netherlands
  2. 2Reinier de Graaf Gasthuis, Rheumatology, Delft, Netherlands
  3. 3Haga Hospital (Leyweg), Rheumatology, Den Haag, Netherlands
  4. 4Maasstad Hospital, Rheumatology, Rotterdam, Netherlands
  5. 5Groene Hart Hospital, Rheumatology, Gouda, Netherlands
  6. 6Erasmus MC, Rheumatology, Rotterdam, Netherlands
  7. 7Leiden University Medical Center (LUMC), Biomedical Data Sciences, Leiden, Netherlands


Background Rheumatoid arthritis (RA) is the most common autoimmune disease, and requires long-term treatment to suppress inflammation. Currently, methotrexate is initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling. However, disease processes begin long before and become clinically recognizable when patients develop symptoms. We hypothesized that the ‘at risk phase’ of symptoms and subclinical joint-inflammation is a therapeutic window to permanently modify the disease course.

Objectives We studied if intervention in the pre-arthritis phase of arthralgia and subclinical joint inflammation prevents the development of clinical arthritis or reduces the burden of disease.

Methods In this randomised, double-blind, 2-year proof-of-concept trial, adults with arthralgia clinically suspected of progressing to RA and MRI-detected subclinical joint-inflammation, recruited from all rheumatology outpatient-clinics in the southwest-Netherlands, were randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a one-year course of oral methotrexate (up to 25 mg/week), or placebo injection and placebo tablets. Subsequently, participants were followed for another year without study medication. The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥2 joints) that persisted for at least 2 weeks. Patient reported physical functioning, along with symptoms and workability, were key secondary endpoints and measured 4-monthly. Additionally, the course of MRI-detected inflammation was studied (the sum of tenosynovitis, synovitis, osteitis, scored with the RA-MRI Scoring (RAMRIS) method). All participants entered the intention-to-treat analysis. We performed two prespecified subgroup analyses. Firstly, analyses were restricted in participants with high risk of clinical arthritis development (PPV ≥70%). Secondly, analyses were stratified for ACPA-status. The trial is registered with the Netherlands Trials Registry (NTR4853 trial NL4599).

Results From April 16th, 2015 to September 11th, 2019, we randomly assigned 236 participants to treatment (n=119) or placebo (n=117). After 24 months, arthritis free survival was similar in both groups (80% versus 82%, HR 0.81 (95%CI 0.45, 1.48)). Physical functioning improved more in the treatment-group during the first months and remained better (mean between-group difference over two-years HAQ -0·1(-0·2,-0·03;p=0·004). Similarly, pain (-9 on scale 0-100: (95%CI -12,-4; p<0·001), morning stiffness (-12 (95%CI -16,-8;p<0·001), presenteeism (-8% (95%CI -13%,-3%;p=0·001) showed sustained improvement compared to placebo. MRI-detected joint-inflammation was also persistently improved (mean difference over 2 years -1·4 points (95%CI -2·0,-0.9;p<0·001). High-risk participants in the treatment group showed a delay in clinical arthritis development: they developed the endpoint less often during treatment, but frequencies became similar at 24 months (67% in both groups). A similar delaying effect was observed in ACPA-positive participants, where 48% and 52% had developed persistent clinical arthritis at 24 months. The number of serious adverse events was equal between the groups; adverse events were as expected from methotrexate.

Conclusion Methotrexate, the cornerstone treatment of RA, initiated at the pre-arthritis stage of joint symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as measured by sustained improvement in MRI-detected inflammation, related symptoms and impairments. These findings of sustained disease modification may open up a new treatment landscape in a pre-arthritis phase of RA, where limitations can be just as severe as at the onset of clinical arthritis.

Acknowledgements We thank Prof. dr. R. ten Cate, prof. dr. S. le Cessie and dr. A.M.J. Langers for their role in the Data Safety and Monitoring Board. We thank all participants, and all rheumatologist of the following hospitals: Albert Schweitzer Hospital, Alrijne Hospital, Erasmus Medical Center, Haven-policlinic Rotterdam, IJselland Hospital, Ikazia Hospital, Franciscus Gasthuis & Vlietland Hospital, Groene Hart Hospital, Haaglanden Medical Center (all locations), Haga Hospital, Langeland Hospital, Meander Medical Center, Maasstad, Hospital, Reinier de Graaf Gasthuis, Reumazorg Zuid-West Nederland and Spaarne Gasthuis. We acknowledge the team of treating rheumatologists and research nurses of the LUMC, in particular Dr F.J. van der Giesen. Our gratitude also goes to the PhD students who scored MRIs for trial screening, in particular dr. H.W. van Steenbergen, dr. W. Nieuwenhuis, dr. R.M. ten Brink, dr. D.M. Boeters, dr. L. Mangnus, X.M.E. Matthijssen and F. Wouters. We thank dr. M. Reijnierse, prof. dr. S.C. Cannegieter and prof. dr. D. van der Heijde for their advice, and dr. J. Schoones for his help with the systematic literature search. We acknowledge the funder of the study: NWO ZonMW grant (program ‘translationeel onderzoek’, project number 95104004).

Disclosure of Interests None declared.

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