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Where are we with treating Pre-Rheumatoid Arthritis?

The ability to prevent rheumatoid arthritis (RA) in individuals at risk of developing this condition is a holy grail in rheumatology.

There is a long-history of interest in this area dating back to the PROMPT trial of methotrexate and PRAIRIE trial of rituximab. Both of these trials showed an effect, but it seemed more likely to be a delaying of RA than prevention or modulation. Framing it another way, there were better outcomes in pre-RA because we were actually treating RA as it emerged with a proven effective treatment. It is in this setting that three trials of ongoing studies in RA preventative therapy are presented at ACR.

The ARIAA study evaluated abatacept in pre-RA. This was presented as an oral abstract (0530) at Saturday's abstract session on “RA – Diagnosis, Manifestations, and Outcomes I: Pre- and Early Disease”. ARIAA enrolled patients with ACPA positive arthralgia and subclinical joint inflammation demonstrated on MRI. Of course, many would argue that patients with MRI demonstrated synovitis, really do have RA and we are just not good enough at detecting it clinically. This was a randomised double blind controlled trial with a 6-month treatment period of abatacept vs placebo and a 12-month follow-up. The 6-month results were presented at last ACR showing a significant benefit, not surprising given that patients were receiving abatacept to that timepoint. We now have the 18-month results presented, with patients off abatacept for 12 months. These demonstrate a persistent benefit with progression to RA in 35% of the abatacept group vs 57% of the placebo group (p=0.008). 18-month MRI findings demonstrated improvement in 57% of abatacept patients and 29% of placebo patients. To me this 18-month data is much more convincing of the potential benefits than the 6-month data was.

The TREAT-EARLIER study evaluated methotrexate in pre-RA. This was presented as an oral abstract (1603) at Sunday’s abstract session “Abstracts: RA – Treatment II: Pre- and Early Disease”. This was a similar design to ARIAA with patients at high clinical suspicion of progression to RA and subclinical joint inflammation on MRI. This was also a randomised double blind controlled trial with 12 months of methotrexate vs placebo treatment followed by 12 months follow up. 236 patients were recruited. 24-month arthritis free survival was similar, 81% vs 82%. High risk participants less frequently developed arthritis during treatment, but by 24-months 67% in both groups had developed RA. Function (HAQ), pain, presenteeism and MRI-detected inflammation showed sustained treatment induced improvements in the methotrexate group up to 24 months however. This suggests that while methotrexate does not prevent arthritis development, it does seem to modulate disease course, with early initiation having sustained long-term benefits.

Finally, the StopRA trial of hydroxychloroquine was presented as an oral abstract (1604) at Sunday’s abstract session “Abstracts: RA – Treatment II: Pre- and Early Disease”. This double-blind randomised controlled trial included ACPA positive patients who did not have arthritis. Participants received hydroxychloroquine or placebo for 1 year followed by 2 years of follow-up. 142 patients were included. The interim analysis is now presented, which has resulted in the study being stopped for futility as per pre-specified criteria. Probabilities of RA were 34% in the hydroxychloroquine arm and 36% in the placebo arm (p=0.844)

Overall these studies suggest to my mind that we are not there yet in preventing RA.

It seems that hydroxychloroquine does nothing. Methotrexate ultimately does not prevent RA (once treatment stops) but does seem to modulate future disease activity. This argues that early methotrexate initiation in pre-RA may ultimately reduce the severity of the ensuing RA. The abatacept data is very interesting and shows a sustained benefit up to 12 months following cessation of treatment. I would like to see longer term data before my reticence is overcome, but it is encouraging.



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