For months, mornings have been difficult for Natalia, a 44-year-old high school teacher. She has no severe pain, but stiffness in her hands makes her open and close her fingers before starting the day. She initially blamed chalk and computer use, but her primary care physician raised the possibility of arthritis, despite no visible joint deformities or damage on x-rays. Although a diagnosis has not been confirmed, there may be an opportunity to intervene early.

There are other details in Natalia’s medical history that become significant when considered as a whole. She has been smoking since she was 19, has had inflamed gums for some time, and her mother was diagnosed with arthritis at age 50. None of these factors alone can predict that she will develop the disease; however, together with other symptoms and markers, they can help identify people at higher risk.

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which the immune system attacks the body’s own tissues, particularly those in the joints. Its development can begin long before the first swollen joint appears. During this phase, some people exhibit immune abnormalities and autoantibodies that may precede the clinical onset of the disease, although not everyone with these markers will eventually develop it.

Research aims to identify this early phase and determine whether it is possible to intervene to reduce the risk or delay the onset of arthritis. Several clinical trials have yielded promising results in selected groups of high-risk individuals, although definitive prevention remains a goal.

When Risk Has a Name

One of the main risk indicators for arthritis is anti-citrullinated peptide/protein antibodies (ACPA), along with rheumatoid factor. Both can be detected years before clinical joint inflammation appears, but their presence alone does not mean that a person will develop RA.

Risk depends on a combination of clinical, serologic, genetic, and imaging factors. Researchers are also studying the immune changes that occur during this early phase. A recent longitudinal study (2025) has identified systemic inflammation and signs of T- and B-cell activation in individuals at risk for arthritis. In those who progressed to clinical disease, the study identified changes in atypical B cells and an expansion of memory CD4 T cells with profiles associated with activation and B-cell help, without necessarily increased circulating levels of ACPA.

Taken together, these findings support the existence of biological alterations prior to the onset of clinical arthritis, but they do not allow for a definitive prediction of each individual’s course of the disease. The review by Hitchon and El-Gabalawy, published in Nature Reviews Rheumatology (2026), provides a framework for understanding these advances and the possibilities for prevention.

Who Is at High Risk?

To better distinguish between individuals with symptoms that may progress to arthritis and those at lower risk, a joint working group from the European Alliance of Rheumatology Associations and the American College of Rheumatology developed risk stratification criteria. The analysis included 2293 individuals from 10 cohorts with arthralgia considered suspicious for progression to inflammatory arthritis. The model incorporated clinical and serologic variables, such as the duration of morning stiffness, perceived swelling, difficulty clenching a fist, C-reactive protein, rheumatoid factor, and ACPA.

When subclinical inflammation detected by MRI was also incorporated, the model’s predictive ability improved. For progression to RA, the model combining clinical, serologic, and imaging variables achieved an area under the curve of 0.93. These criteria may help stratify risk and better identify candidates for specific follow-up or future preventive trials; however, they do not, on their own, constitute a diagnostic test.

MRI provides particularly valuable information here: it can reveal inflammation before a rheumatologist detects a swollen joint during a physical examination. However, not all subclinical inflammation necessarily means the disease will develop. The challenge lies in distinguishing a transient signal from a progressive disease.

Intervening to Prevent

The next step has been to study whether treatments can alter the course of the disease during this high-risk phase. One of the key trials in this field is the APIPPRA trial, published in The Lancet Rheumatology in 2024 and 2026. It included 213 people with RA-associated autoantibodies and inflammatory joint symptoms, but without clinical arthritis. Participants received abatacept, a biologic drug that modulates T-cell activation, or a placebo for 1 year and were followed for an additional 12 months.

During the first year, 6% of those who received the treatment went on to develop arthritis, compared with 29% in the placebo group. At 24 months, the proportions were 25% and 37%, respectively. The results suggest that the treatment may reduce or delay progression in selected high-risk individuals, but they do not demonstrate that the disease has been definitively prevented.

Follow-up data published in 2026 provide additional information on the duration of the benefit. To accurately describe these results, it is necessary to distinguish between the time elapsed without arthritis and the proportion of participants who eventually develop the disease. The effect appears to be particularly relevant in individuals with autoantibody profiles associated with a higher baseline risk.

For its part, the ARIAA trial studied a group selected using additional criteria: individuals with ACPA, joint pain, and signs of subclinical inflammation detected by MRI, but without clinical arthritis. After 6 months of treatment with abatacept, 8% developed RA compared with 35% in the placebo group. This trial also explored the changes observed on MRI and the subsequent course of the participants.

Taken together, APIPPRA and ARIAA trials suggest that intervening before the onset of RA may alter its course in certain high-risk groups. However, reducing progression or delaying the onset of the disease does not equate to demonstrating permanent prevention. Patient selection, the duration of benefit, and the course of the disease after treatment is discontinued remain key issues.

Palindromic Rheumatism: A Window of Opportunity

The Spanish PALABA study, published in Nature Medicine in 2026, enrolled patients at 14 hospitals and evaluated whether RA could be prevented in people with palindromic rheumatism. The condition causes recurrent episodes of joint pain and inflammation that resolve between attacks and generally do not lead to permanent joint damage. Published studies suggest that 30%-60% of affected patients eventually develop RA, particularly those who test positive for rheumatoid factor or ACPA.

The trial compared abatacept with hydroxychloroquine over 24 months in people with palindromic rheumatism who were positive for rheumatoid factor or ACPA. In the primary analysis, 20.6% of treated participants developed the disease compared with 50% of those who received the antirheumatic drug. The risk for progression over time was also lower with the biologic.

Among participants with available data, the corresponding proportions were 10% in the biologic-treatment group and 35.7% in the comparator group. Symptom remission occurred in 55.9% of patients receiving the biologic and 22.9% of those in the comparator group. Joint flares were less severe with treatment, although their frequency did not differ significantly between groups.

About 70 adults participated in the main analysis. Although the results are promising, the trial is small and open-label, and it studies a specific group of patients; therefore, its conclusions cannot be generalized to all people at risk for RA.

According to Raimon Sanmartí, head of the Inflammatory Arthropathies research group at August Pi i Sunyer Biomedical Research Institute and a rheumatologist at Hospital Clínic of Barcelona in Barcelona, Spain, the results show that “early intervention is possible to alter the natural course of the disease and reduce the risk of patients developing more severe and irreversible conditions.” The specialist believes that the study opens the door to a paradigm shift in the treatment of these patients.

From Biomarkers to Personalized Treatment

The next challenge is identifying which patients may benefit from treatment before arthritis develops. Treating everyone who tests positive for ACPA or rheumatoid factor with immunomodulatory drugs may not be appropriate, because many will never develop the disease. Any preventive treatment strategy must carefully balance potential benefits against risks.

That is why researchers are investigating models that combine different sources of information: autoantibodies, symptoms, C-reactive protein, genetics, imaging, and, increasingly, molecular biomarkers. A study published in Nature Communications (2025) analyzed the plasma proteome of 278 patients with RA, 60 at-risk individuals, and 99 healthy control individuals. The researchers identified distinct proteomic signatures across the different stages of the disease and developed machine-learning models to predict the response to specific combinations of disease-modifying antirheumatic drugs.

These results point to the potential of molecular biomarkers to improve disease characterization and study treatment response, but they remain in the realm of research. There is no routine laboratory test capable of determining with certainty whether a specific person will develop RA or which preventive treatment would be appropriate. The goal is to move from a general risk estimate to a more precise individual assessment, which would make it possible to identify who should be closely monitored and who might benefit from early intervention.

This story was translated from El Médico Interactivo on Univadis, part of the Medscape Professional Network.