Moving Forward on RA Prevention Trials Save

Now that multiple prevention clinical trials for rheumatoid arthritis (RA) have been completed, a group of investigators have reviewed the results and published their recommendations for future trial designs and drug development to assess interventions that may alter disease development.

Important is the identification of individuals at risk for RA - these can be identified by population screening, referrals of arthralgia suspicious for RA and serologies.  Thus far, it appears that patients with pre-clinical RA do not respond to limited courses of corticosteroids, atorvastatin and hydroxychloroquine,  While it appears rituximab delays clinical RA onset, methotrexate has transient effects in ACPA+ individuals with subclinical joint inflammation identified by imaging. 

Based on published data, abatacept delays clinical RA onset but does not fully prevent onset of RA (Editors note: the recently presented AMPLIFY trial showed no effect of ABA in seropositive or shared-epitope positive early RA patients).

The authors recommend future trials of interventions may focus on 1) preventing clinical RA onset; 2) treating existing symptoms and 3) improving imaging-defined subclinical inflammation.  The challenges however will be in Identifying, defining and risk-stratifying those at risk for RA.  The authors also recommend that enrollment should rely on networks and methods used in cardiovascular or type 1 diabetes prevention trials and that patients need to be risk stratified based on types of risk factors (symptoms, inflammatory markers, genetics or environmental or immunologic perturbations).

The authors prefer the terms ‘at risk of RA’ or an ‘at-risk state’, rather than pre-RA for those at stage of RA that precedes the first swollen joint (where risk factors for RA may be present).  While all of these early intervention trials precluded inclusion of those with clinically swollen joints, more recent trials have enrolled patients with "subclinical synovitis" identified by imaging (eg, MRI or ultrasound). 

Interesting "points" from this report:

• ACPA positivity is associated with PPVs of developing RA between 20%–50%, over time
• ‘palindromic rheumatism’ should be included in this group; as some of these may not develop persistent arthritis
• We need to be clear about whether to include patients with imaging subclinical synovitis and what the predictive value this designation carries
• We need to study and clarify the role of lifestyle modifications in at-risk persons (diet, smoking, weight loss, etc)
• We need to consider the rold and targeting of the "mucosal hypothesis of RA" that "posits that the initial systemic break in immune tolerance to self-antigens occurs in association with chronic inflammation and/or dysbiosis at mucosal sites, such as the lungs, the periodontium and the gut"  

The authors conclude, "In much the same way that CVD prevention has transformed healthcare, the same approach to autoimmune disease can provide substantial population benefits".