Preclinical RA and RA Prevention: Part 1

Rheumatoid arthritis. General practitioner examining a patient’s hand for signs of rheumatoid arthritis. This condition is caused by the immune system attacking the body’s own tissues, causing progressive joint and cartilage destruction. As the cartilage is worn away, new bone grows as part of the repair process. This causes stiffness and deformity of the fingers. Treatment is with anti-inflammatory drugs and physiotherapy.
We spoke with an expert about preclinical RA and steps needed toward a widespread rheumatoid arthritis prevention framework: Vivian P. Bykerk, BSc, MD, FRCPC.

The treatment landscape for rheumatoid arthritis (RA) has vastly improved since the introduction of biologic agent therapies. However, given the range of potential adverse events associated with these agents and the lack of curative therapies for RA, there is an increasing focus on efforts aimed at RA prevention.

In a paper published in August 2021 in the European Journal of Immunology, Hensvold and Klareskog proposed that RA may represent a potential protype for the prevention of autoimmune diseases, to include both public health and “personalized prevention” measures. This approach would require further elucidation of the nature of preclinical RA to inform the development of appropriate prevention strategies.1

They point to the success of similar efforts that have led to reductions in morbidity and mortality in cardiovascular disease through public health measures such as smoking cessation campaigns, along with targeted therapies for high-risk patients, including strategies to reduce blood pressure and lipid levels. “We now need similar strategies for autoimmune diseases addressing modifiable environmental and lifestyle risk factors with public health measures and with immunology and immunotherapy at the center for personalized prevention,” they wrote.1

We checked in with 2 experts for an in-depth discussion about preclinical RA and needed steps toward a widespread RA prevention framework. In Part 1 of this 2-part series, we interviewed Vivian P. Bykerk, BSc, MD, FRCPC, rheumatologist and director of the Inflammatory Arthritis Center of Excellence at Hospital for Special Surgery and professor of medicine at Weill Cornell Medical College in New York.

What are the most notable findings thus far regarding preclinical RA?

Dr Bykerk: We know there is a period of preclinical autoimmunity, which ultimately will evolve to clinically apparent RA over time as more and more antibodies are produced that target citrullinated peptides, mostly on mucosal areas of the body. [The potential for RA prevention] is actually a very complex question and involves the issue of primary and secondary screening. It presumes that a very early pre-disease intervention could stop it and a person could become drug-free for life.

This has never been shown because it is so difficult to find people with preclinical autoimmunity (ie, with immune findings without any symptoms) or even to find people with symptomatic pre-RA (fleeting arthralgias, no swelling, positive immune findings – usually a meaning a positive anti-CCP and/or RF), screened for in arthralgia clinics or through a concerted community effort (secondary screening).

By the time a rheumatologist sees these people, symptoms have usually escalated to the point that a diagnosis of RA can be established. In the first 2 scenarios, a minimum treatment can delay the development to established disease for up to a year, but no studies have looked at repetitive prevention treatments.

How well accepted is the concept of preclinical RA currently?

Dr Bykerk: The concept of preclinical RA is generally well accepted. The challenge is identifying those at risk, ie, high risk for developing clinically apparent disease that is persistent, as they may have intermittent symptoms without obvious findings, rarely are seen by rheumatologists, or don’t get tested for RA-related antibodies.

It can take a patient up to 3 months to even seek medical help and depending on who they see, it can take another 3 months before the progression to RA is recognized. They may or may not see a rheumatologist, as many see other specialists or surgeons. The average symptom duration of a patient who has very early incident RA as seen by a rheumatologist is 3 to 6 months, and this has not changed in many years.2,3 I hear from clinicians this has even become worse since the pandemic started.

Health care centers that have screening clinics to rapidly assess people with very early-onset joint pain can identify these patients much sooner. Others identify patients at risk by canvassing people through health fairs. The challenge is the secondary screening that is needed and recognizing those who are at risk. 

What are the implications for clinicians in terms of screening and preventive efforts in RA?

Dr Bykerk: In addition to the points above, primary care clinicians should know how to screen for very early RA. Such simple maneuvers as performing a MTP squeeze test and MCP squeeze test and testing for RF and anti-CCP would likely identify people earlier. RA also occurs more often in people who have first-degree relatives with RA, and having first-degree relatives with autoimmune disease is also related to RA risk.

What are the most important remaining research needs in this area?

Dr Bykerk: We need a way to identify those at risk and screen for them. We need trials of agents that can downregulate the progression to RA. We need a better understanding of the pathogenesis from being asymptomatic with few autoantibodies to the development of clinical autoimmunity. This means we will need further research to understand the triggers and mediators of this progression including involved genes, genetic predisposition, relevant exposures such as infection, smoking, or other environmental factors or stressors, and how these factors initiate and propagate RA-related autoimmunity both in the preclinical phase and the period of evolution to RA.

We need to understand how ACPAs that likely originate in other locations end up becoming integral in the pathogenesis of RA in the joint. And how do we prevent the onset of disease in the long term in a way that is safe and effective?

In closing, what additional points would you like to mention about this topic?

Dr Bykerk: We need to reproduce and extend the findings of studies that have shown that one can prolong the onset of disease using certain agents. The PrAIRI study showed a 40% reduction in clinically apparent and persistent rheumatoid disease with a 1,000 mg dose of rituximab.4

The greatest barrier in making progress in this area is finding patients who are at high risk for RA (with joint pains and ACPA levels well above normal) and who are interested in participating in these kinds of trials, as they do not yet have a disease and there are risks to the treatments. We are also waiting on results of clinical trials currently investigating how to prevent RA.


  1. Hensvold A, Klareskog L. Towards prevention of autoimmune diseases: The example of rheumatoid arthritis. Eur J Immunol. 2021;51(8):1921-1933. doi:10.1002/eji.202048952
  2. Rosa JE, García MV, Luissi A, et al. Rheumatoid arthritis patient’s journey: delay in diagnosis and treatment. J Clin Rheumatol. 2020;26(7S Suppl 2):S148-S152. doi:10.1097/RHU.0000000000001196
  3. Riad M, Dunham DP, Chua JR, et al. Health disparities among Hispanics with rheumatoid arthritis: delay in presentation to rheumatologists contributes to later diagnosis and treatment. J Clin Rheumatol. 2020;26(7):279-284. doi:10.1097/RHU.0000000000001085
  4. Gerlag DM, Safy M, Maijer KI, et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann Rheum Dis. 2019;78(2):179-185. doi:10.1136/annrheumdis-2017-212763