Why aren’t we preventing RA yet? Save

 Who wouldn’t want to prevent RA?  

Ever since the seminal studies demonstrating a prolonged preclinical period for seropositive RA, which have been replicated in multiple cohorts around the world using both retrospective and prospective study designs, the rheumatology community has been tantalized by the prospect of preventing the onset of inflammatory joint disease in seropositive individuals exhibiting no clinically detectable synovitis.

The general approach is to identify high risk individuals with detectable circulating RA autoantibodies, with or without suggestive symptoms that are often referred to as clinically suspect arthralgia. These individuals are enrolled in RA prevention studies. Despite several well-rationalized clinical trials, primarily using repurposed RA drugs such as methotrexate, hydroxychloroquine, rituximab, and abatacept, the best that has been achieved to date is either delayed onset, and/or possibly a milder disease phenotype.

So why can’t we prevent RA yet?

Here are some potential factors to consider:

• Finding appropriate study subjects takes a heroic effort. Different strategies for identifying suitable participants for RA prevention clinical trials yields different study populations. For example, if study recruitment targets individuals with “clinically suspect arthralgia” who are typically seen in primary care offices, most experts would agree this population is perilously close to RA onset…is RA prevention even possible in such a study population? In contrast, if the recruitment strategy focuses on recruiting anti-CCP positive individuals from the general population, many of these individuals may never develop RA. Indeed, we have shown that a substantial proportion of these individuals revert to a seronegative state over time. Moreover, this screening strategy requires a coordinated effort between many centres, such as what was undertaken in the context of the SERA studies based at the University of Colorado. A particularly compelling question is whether an anti-CCP positive individual without a family history has the same RA risk as an anti-CCP positive individual with a family history, such as a first -degree relative (FDR)…likely not. International efforts are underway to appropriately stratify individuals deemed to be in the “preclinical” RA stage and place them into risk categories that can help inform clinical trial design.  
• It takes a long time to find out if RA has been prevented. Most clinical trials cannot accommodate the years of structured followup that are needed to unequivocally demonstrate RA prevention, irrespective of what therapeutic approach is being tested. As such, while waiting for RA to “start”, how do we know we are accomplishing anything? Reliable surrogate biomarkers have not been reproducibly identified. Promising biomarkers indicative of maturation of the autoimmune response, such as epitope spreading of the anti-citrullinated protein antibody (ACPA) response, and the ACPA glycosylation patterns, need to be validated before they can serve as surrogates in prevention trials. In this regard, there is a compelling need for preclinical studies of immune cell subsets. Other less specific approaches using proteomics, lipidomics, and metabolomics, although easier to undertake in clinical trials, need to be validated before they are ready for “prime time”. 
• The risk/benefit ratio of our current interventions remains unclear. We have shown in focus groups comprised of RA patients, their FDR, and clinicians, that the perspective of the unaffected individuals is vastly different from that of the RA patients and the clinicians, particularly as it relates to how they weigh risk/benefit. This is compounded by the fact that the rheumatology community has yet to develop validated models of risk, such as in cardiovascular diseases. Low risk strategies such as dietary manipulations are more readily accepted than pharmacologic approaches, but the efficacy of the former is far from clear. 

Is it time to rethink how RA prevention trials are undertaken?

The warp speed with which the most effective COVID-19 therapies were selected was based on a compelling need for new clinical trials designs, particularly adaptive trial designs. Perhaps we need to take some lessons from that playbook in designing RA prevention studies. This will require large international collaborations, several of which have already been established. 

I am reminded of what one of our community study facilitators said when I asked him why he thought participant recruitment had dropped off recently…he said “because you haven’t cured anyone yet”. Hard to argue with that.