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Berlin – People with CCP antibodies (cyclic citrullinated peptides, ACPA), rheumatoid factor and symptoms such as inflammatory joint pain have a high risk of developing rheumatoid arthritis (RA). Preventive treatment strategies for high-risk patients have yet to be developed.

The extent to which the immunosuppressant abatacept, which is already used as a basic therapy for RA, can intercept RA in the early stages was investigated in two double-blind, multicenter, placebo-controlled clinical studies that were published in March 2024 (ARIAA study: The Lancet2024; DOI: 10.1016/S0140-6736(23)02650-8; APIPPRA study: The Lancet2024, DOI: 10.1016/S0140-6736(23)02649-1).

In the ARIAA study, 50 individuals without palpable joint swelling but with joint pain, with ACPA antibodies, and evidence of inflammatory changes such as synovitis, tenosynovitis or osteitis on MRI were treated with either abatacept or placebo for 6 months and then observed for 12 months. An improvement in inflammation on MRI was observed in 57% of participants on abatacept and 31% on placebo.

8% of participants on abatacept and 35% on placebo developed manifest arthritis. After 12 months without treatment (i.e. a total of 18 months), an improvement in MRI inflammation parameters was observed in 51% of patients on abatacept and 24% on placebo; progression to RA was observed in 35% of participants in the abatacept group and in 57% in the placebo group.

In the APIPPRA study with over 200 participants (positive for ACPA and rheumatoid factor, inflammatory joint pain), the researchers also came to the conclusion that abatacept over 12 months reduces the progression to RA, with sustained effectiveness also being demonstrated beyond the treatment period. After 24 months, 27 (25%) in the abatacept group had developed RA, compared with 38 (37%) in the placebo group.

Matthias Schneider: With the new preventive therapy, 80% of those affected do not get the disease in the first place.

Matthias Schneider, head of the Hiller research group, Heinrich Heine University Düsseldorf. / University Hospital Düsseldorf

Yes, preventive treatment should be recommended for people at high risk for rheumatoid arthritis. Two RCTs have shown that abatacept can reduce the development of clinical RA in a high-risk group by 80% (from 35 to 8% and from 29 to 6% respectively) (The Lancet2024; DOI: 10.1016/S0140-6736(23)02650-8, The Lancet2024; (DOI: 10.1016/S0140-6736(23)02649-1).

Even if the 6- or 12-month use of this therapy could not prevent the development of joint disease in the high-risk populations beyond that, which would be ideal, the effectiveness was still clear 12 months after the end of therapy. Previous studies with glucocorticoids or methotrexate could not show such an effect, which supports the hypothesis that activated T cells play a crucial role in the development of RA. Abatacept is a fusion protein of the Fc region of IgG 1 with the extracellular domain of CTLA-4 that is approved for RA and is therefore a co-stimulation blocker.

Since the discovery of antibodies against citrullinated peptides (ACPA), we have known that RA develops continuously over the years and that ACPA allows risk detection, which was used in both studies. In both studies, a 40 percent probability of developing clinical RA was assumed, and in the Erlangen study, this was actually 57% (ARIAA study).

If such preventive therapy is recommended, then 2-3 out of 5 patients will be treated unnecessarily; this will need to be explained. Taking into account the slightly increased risk of infection and the fact that a few developed clinical RA during treatment, the number needed to treat (NNT) for the use of abatacept in this preventive indication is around 10. This is a great result compared to, for example, the NNTs of statins in cardiovascular prevention.

The risk of overtreatment increases the further you advance therapy and is reflected in higher response rates. We are also in this risk area in the so-called “window of opportunity”, the target window of early RA (Journal of Rheumatology2020; DOI: 10.1007/s00393-020-00775-6). We are very satisfied if we can bring 60% of the patients into remission. With the new preventive therapy, 80% of those affected do not even notice the disease.

This presents us with a new challenge: how do we identify people at high risk for RA at the population level?

Markus Gaubitz: Preventive treatment could only be recommended in the future once the group at high risk of progression is better characterized.

Markus Gaubitz, Interdisciplinary Diagnostics and Therapy, University of Münster /private

The two studies in Lancet 2024 expand the data on the question of preventive RA treatment, but are not sufficient to recommend preventive treatment.

Firstly, in my opinion, the two studies, especially ARIAA, are not studies in the preliminary phase, but in an early phase of the disease: Most rheumatologists would describe a patient with joint pain, ACPA antibodies, an average of 4 tender joints and signs of inflammation in the MRI as a patient with early arthritis, not as an individual “at risk”. The still valid classification criteria for RA from 2010 (which require at least one palpably swollen joint) should be revised (Annals of the Rheumatic Diseases2010; DOI: 10.1136/ard.2010.138461): The detection of arthritis by ultrasound or MRI should be introduced as equivalent to the palpation findings.

Another argument against the general recommendation is the threat of overtreatment. Lancet-Studies show that 63% and 43% of those who do not show any progression to clinically detectable (palpable) disease during the observation period are treated.

In addition, treatment before the clinical symptom of joint swelling develops cannot be justified with a moderate benefit for the patient, when consistent and early treatment after the first swelling appears (i.e. the current procedure according to the guideline) results in remission rates of over 70%, and in individual studies up to 90% (The Lancet2016; (DOI: 10.1016/S0140-6736(16)30363-4).

The effect of early treatment should also be the possibility of terminating this therapy (Nature Reviews Rheumatology2023; DOI: 10.1038/s41584-023-01035-y). However, this was only achieved in a small proportion of the studies with a short observation period. Under these conditions, it seems doubtful that people can be convinced of the usefulness of very early treatment.

In summary, the new studies discussed here are certainly important, but they are more likely to be studies of early arthritis. Preventive treatment could only be recommended in the future when the group at high risk of progression is better characterized (for example, by several antibodies or imaging findings). Earlier treatment should also more often enable remission without therapy.

In 2024, better and more consistent treatment of those manifestly suffering from RA, making more frequent use of excellent drug options, is a goal that is far from being achieved and more urgent. © gie/aerzteblatt.de