Preclinical RA and RA Prevention: Part 2

There is an increasing focus on efforts aimed at RA prevention, which would involve a combination of public health and “personalized prevention” measures.¹ We recently checked in with 2 experts for an in-depth discussion about the concept of preclinical RA and needed steps toward a widespread RA prevention framework.

In Part 2 of this 2-part series, we interviewed Kevin Deane, MD, PhD, associate professor of medicine in the division of rheumatology and the William P. Arend Endowed Chair in Rheumatology Research at the University of Colorado Anschutz Medical Campus in Aurora. Dr Keane co-authored several recent reviews on RA prevention.^2-4

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

Dr Deane: Multiple studies have now shown that in RA there is a period called “preclinical RA” or “pre-RA,” during which there are immune system abnormalities and, in particular, autoantibodies that are detectable through blood tests which can be used to predict with fair accuracy who will get “full-blown” arthritis from RA within several years.

The most predictive blood test is for antibodies to citrullinated protein antigens (ACPA), measured via anti-cyclic citrullinated peptide (anti-CCP) assay. As rheumatoid factor (RF) is much less specific for RA, prediction models for future RA now generally focus on anti-CCP positivity. However, if a patient has abnormal anti-CCP and RF tests, then they are even more likely to progress to RA.

In general, an individual who is positive for anti-CCP has a 20% to 70% chance of developing full-blown RA within 2 to 5 years.² The accuracy of prediction can be improved if other factors are present, such as certain genetic factors and more “symptoms” of arthritis even if there are not any clearly inflamed joints upon physical examination.

That prediction isn’t perfect, but it is pretty reliable and importantly has supported the development of several prevention trials in RA in which anti-CCP positive individuals are given an intervention to see if the onset of RA can be delayed or prevented. A high-profile study called PRAIRI has been completed in which the drug rituximab vs placebo was given to ACPA- and RF-positive individuals. Those who received rituximab had a delay in the onset of arthritis by about 12 months.⁵

There are now several other studies being conducted to understand exactly how to treat someone who is in the “pre-RA” period to conclusively prevent or delay future RA. These studies are testing drugs such as hydroxychloroquine, methotrexate, and abatacept to prevent or delay the full-blown arthritis of RA.

I’m the principal investigator for one of these studies (StopRA), which is currently underway in the US.⁶You can learn more about the study and preclinical/pre-RA in general at the study’s website: www.stop-ra.org. However, we don’t yet know the right way to intervene on pre-RA, and as such the current standard of care is to wait until clearly inflamed joints are present before giving a diagnosis of RA and starting treatment.

How well accepted is the concept of preclinical RA currently?

Dr Deane: Even if they have not been formally referring to such patients as being in “pre-clinical/pre-RA,” I think many health care providers are aware of patients who have symptoms of RA such as joint pain, stiffness, and swelling but don’t have any clearly inflamed joints on examination but then also have blood test abnormalities for ACPA/anti-CCP and/or RF.

Notably, it is tempting if someone has joint symptoms that seem like RA and abnormal ACPA and/or RF to go ahead and call it RA even if there are no clearly inflamed joints on examination, and to treat them. However, while such individuals may progress to full-blown RA, they may not, so we need to be careful not to overtreat. As such, it is recommended that those patients undergo evaluation by a rheumatologist to help fully identify if they have RA or if they are in a “preclinical/pre-RA” period.

Importantly, it is unusual to find someone without any joint symptoms who has RA-related autoantibodies like ACPA and RF because these individuals are not generally seen in primary care. Some of the current clinical trials in RA prevention are actually testing individuals who don’t have any joint symptoms, and those findings should help us know in the near future who we should be testing for ACPA and RF and who would most likely benefit from preventive interventions.

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

Dr Deane: We need to wait for formal screening recommendations for RA to be developed, as well as for more research studies to be completed that will provide us guidance on how to intervene in preclinical/pre-RA to prevent or delay full-blown disease. However, one of the best things we know right now that we can do for people who have RA is to make a diagnosis early and get them on the right therapy to prevent joint damage.

Early diagnosis largely depends on primary care, where people generally present with their first joint symptoms. While RA is fairly rare, first-line providers need to be aware of its possibility and carefully evaluate joints and consider testing for ACPA/anti-CCP and RF. They should refer to a rheumatologist as quickly as possible if inflammatory arthritis is found on examination and/or if ACPA/anti-CCP and/or RF are abnormal.

That said, I believe that the clinical trials that are currently underway for prevention of RA will soon give us more information and, based on those results we may soon be screening for RA through approaches that we take for diseases like cardiovascular disease prevention today – like checking blood pressure, testing cholesterol, and then intervening to prevent or delay a cardiovascular event in the future. Envision an individual going to their health care provider for a routine annual visit and getting tested for ACPA/anti-CCP and RF, or perhaps other markers, and then being offered strategies to prevent future RA based on their test results.

An emerging issue in RA is using imaging studies like ultrasound or MRI to identify inflamed joints that are not otherwise apparent on a physical examination.⁷ In the near future, such tests may become standard of care to identify arthritis even earlier than we can on joint examination. For now, while somewhat controversial, most rheumatologists don’t recommend treating for RA based solely on an imaging finding.

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

Dr Deane: We need to see the results of the current clinical trials. Also, we still need to learn more about how RA develops and how to find individuals who are at risk for future RA and work with them to participate in research studies. Given RA affects about 1% of the population, the infrastructure to find those at future risk will need to be large.⁸

Once we learn what works to prevent or delay future disease, we’ll see a big public health push for RA screening and prevention. That will be a very exciting change in the field, since what we largely do now is wait for someone to develop full-blown RA before we treat. We will likely need some new diagnostic labels to include in systems such as ICD codes, as a diagnosis of RA for someone in a pre-RA period likely won’t be appropriate. Groups are working on such coding systems changes now.

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

Dr Deane: One question I get asked a lot is, “What can I do now if I see a patient who is in ‘pre-clinical/pre-RA’ but doesn’t have clear inflammatory arthritis?” Certainly, if one can work with that person to participate in research that would be terrific. However, other advice that, while not well proven, makes sense based on what is known as well in terms of general health benefits includes stopping use of tobacco products, exercising regularly, maintaining a healthy weight, and considering an anti-inflammatory diet such as the Mediterranean diet.

In particular, such an individual should be counseled about what RA is and the signs and symptoms of arthritis. I also believe they should see a rheumatologist perhaps annually for an in-person joint examination and seek help if they have worsening joint symptoms so that if they do transition to RA, they can get a diagnosis and treatment right away.

References

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
Greenblatt HK, Kim HA, Bettner LF, Deane KD. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr Opin Rheumatol. 2020;32(3):289-296. doi:10.1097/BOR.0000000000000708
Deane KD, Holers VM. Rheumatoid arthritis pathogenesis, prediction, and prevention: an emerging paradigm shift. Arthritis Rheumatol. 2021;73(2):181-193. doi:10.1002/art.41417
Mahler M, Martinez-Prat L, Sparks JA, Deane KD. Precision medicine in the care of rheumatoid arthritis: Focus on prediction and prevention of future clinically-apparent disease. Autoimmun Rev. 2020;19(5):102506. doi:10.1016/j.autrev.2020.102506
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
ClinicalTrials.gov. Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis. NCT02603146. Accessed online October 15, 2021.
Xu Y, Wu Q. Prevalence trend and disparities in rheumatoid arthritis among US adults, 2005-2018. J Clin Med. 2021;10(15):3289. doi:10.3390/jcm10153289
Kgoebane K, Ally MMTM, Duim-Beytell MC, Suleman FE. The role of imaging in rheumatoid arthritis. SA J Radiol. 2018;22(1):1316. doi:10.4102/sajr.v22i1.1316

Preclinical RA and RA Prevention: Part 2

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