More than 18 million people worldwide suffer from rheumatoid arthritis, including nearly 1.5 million Americans.

Rheumatoid arthritis is an autoimmune, inflammatory form of arthritis, meaning a person’s immune system attacks their joints, causing substantial inflammation. This inflammation can cause pain, stiffness and swelling in the joints, and in many cases, patients report fatigue and a flu-like feeling.

If left untreated, rheumatoid arthritis can lead to damage of the joints. But even when treated, this condition can lead to significant disability. In highly active disease or advanced stages, patient may have difficulty performing daily tasks, such as preparing food, caring for children and getting dressed.

Up to now, this condition has been treated once patients have already developed symptoms. But a growing body of evidence suggests this disease can be identified earlier – and maybe even ultimately prevented.

I’m a physician specializing in rheumatoid arthritis and a researcher who has conducted a clinical trial on treatments for this condition. I believe this research is moving us toward being able to identify people who are at risk for rheumatoid arthritis before the disease fully develops, and to finding treatments that will delay or prevent it altogether. My hope is that this could lead to changes in how we manage rheumatoid arthritis in the next several years.

Finding the disease before it causes harm

Currently, when someone visits their health care provider because they are experiencing joint pain or other symptoms of an immune attack, health care providers can make a diagnosis by examining the joints for swelling. The health care provider will also run tests to find blood markers called autoantibodies, which help in confirming the diagnosis. While not all people with rheumatoid arthritis will have abnormal blood markers, the two autoantibodies that are seen in up to 80% of people with rheumatoid arthritis are rheumatoid factor and anti-cyclic citrullinated peptide.

But multiple studies have now confirmed that rheumatoid arthritis has a preclinical stage of development. This is a time about three to five years or longer, prior to the onset of swollen joints when markers like rheumatoid factor and anti-cyclic citrullinated peptide are detectable in the blood. The presence of these markers indicates that autoimmunity is occurring, yet the body and organs are still functioning well, and a person who is at risk of getting rheumatoid arthritis may not feel sick yet.

Now that researchers have identified this preclinical stage, health care providers can use markers such as autoantibodies and symptoms like prolonged early morning joint stiffness to identify people who are at risk for rheumatoid arthritis but do not yet have joint inflammation.

At this point, predicting future rheumatoid arthritis is still in the research stage, although the field is working toward established ways to test for risk for rheumatoid arthritis as a routine part of health care. This is akin to how cardiovascular disease risk is assessed through measuring cholesterol levels.

Ongoing research

Because of advances in the ability to predict who may get rheumatoid arthritis in the future, researchers are now working on identifying treatments that can delay or prevent the full-blown condition from developing.

In particular, trials have been performed in people who tested positive for anti-cyclic citrullinated peptide, or who have other risk factors for rheumatoid arthritis. These risk factors include joint pain and subclinical joint inflammation, which is when an imaging study, like magnetic resonance imaging, sees joint inflammation that can’t be seen by a clinician examining the joints.

To date, almost all of these trials have used immune drugs that are commonly used to treat full-blown rheumatoid arthritis, such as methotrexate, hydroxychloroquine and rituximab. Researchers have been testing whether a short course of any of these drugs could lead to a lasting reset of the immune system and prevent rheumatoid arthritis from developing.

While there is not yet an approved drug for rheumatoid arthritis prevention, these studies offer hope that researchers are on track to find the right drug – as well as the right dosage and duration of that drug.

Researching the preclinical stage of rheumatoid arthritis

Some challenges remain to be addressed before preventive treatments become the norm in clinical care.

First, researchers need to better understand the biology of the preclinical stage of disease. Until recently, most studies have focused on patients with full-blown arthritis and generally ignored people at risk for developing the disease.

But now, researchers can use blood markers like anti-cyclic citrullinated peptide antibodies to identify those who are at risk much more easily. And a growing number of studies of people with this marker are informing how scientists understand the biology of rheumatoid arthritis development.

In particular, it is now apparent that the preclinical stage is marked by multiple circulating immune system abnormalities in cells, autoantibodies and inflammation. The hope is that researchers will find interventions that effectively target the immune system abnormalities driving the development of rheumatoid arthritis before the patient’s joints begin to swell.

Researchers are also finding that the abnormalities in the immune system during the preclinical stage may be coming from sites in the body other than the joints. An emerging idea called the mucosal origins hypothesis posits that the early autoimmunity of rheumatoid arthritis is caused by inflammation at mucosal surfaces of the body, such as the gums, the lungs and the gut. According to this theory, the joints are involved only later as the disease progresses.

More research is needed, but the mucosal origins hypothesis may help explain why periodontal disease, emphysema or other forms of lung disease and exposure to tobacco or forest fire smoke are risk factors for rheumatoid arthritis. It would also explain why certain bacteria have been associated with the disease. Future trials targeting interventions to a mucosal process could help researchers better understand the nature of this disease.

Making predictions

But while biomarkers like the anti-cyclic citrullinated peptide antibodies are strongly predictive for future rheumatoid arthritis, one difficulty remains: Some people who test positive for them never develop the full-blown disease.

Studies have shown that about 20% to 30% of people who are positive for anti-cyclic citrullinated peptide antibodies develop rheumatoid arthritis within two to five years, although the presence of combinations of risk factors can identify people who have a greater than 50% risk for developing the condition within one year.

This makes it difficult to find participants for clinical trials for rheumatoid arthritis prevention. If you can’t predict who will get the disease, it’s hard to know whether you’re preventing it.

So far, researchers have tried to recruit people who have already come to their health care provider with early joint symptoms of rheumatoid arthritis but still no swollen joints. That has worked well, but there are likely far more people at risk for rheumatoid arthritis who have not yet sought care. Since health care providers are not yet testing everyone for blood markers for rheumatoid arthritis, researchers will need larger, international networks that can test for risk factors like autoantibodies to identify candidates for participation in prevention trials.

More needs to be done, but it’s exciting to see the field advancing toward the point where prevention may be part of routine clinical care for rheumatoid arthritis.

Dr. Deane has received grant funding from the Arthritis Foundation, the National Institutes of Health, Boehringer Ingelheim, Gilead and ThermoFisher, and has had consulting/advisory board participation with Werfen, Boehringer Ingelheim, AllInBio, and Lilly. Dr. Deane also part of task forces for prediction of rheumatoid arthritis that are sponsored by the American College of Rheumatology and the European Alliance of Associations for Rheumatology.