By the time the pain appears, is it "too late"? The shocking revelation that rheumatoid arthritis "started several years ago"

Even without pain, has the disease already started?

"I feel a bit stiff when I wake up in the morning, but maybe it's just my age."
This slight discomfort, which many might overlook, could actually be a sign that a silent immune war has been brewing inside the body for a long time.

A recent study reported on November 26, 2025, indicates that rheumatoid arthritis (RA) is not a disease that begins "the moment the joints become swollen and painful," but rather, the immune system starts to undergo significant changes several years prior.ScienceDaily

In other words, by the time pain appears, inflammation has already surfaced as a result of a long "preliminary skirmish."

What is rheumatoid arthritis?

Rheumatoid arthritis is a representative autoimmune disease where the immune system mistakenly attacks its own joints. Chronic inflammation causes swelling in small joints such as fingers, wrists, and ankles, eventually leading to the destruction of bones and cartilage.

Thanks to advances in medication, starting treatment early can significantly prevent joint destruction. However, there are still many cases where "by the time it was noticed, joint damage had progressed," leading to voices from both patients and healthcare providers wishing they had known sooner.

This study focuses precisely on that "much earlier" stage.

Tracking individuals before onset for seven years

The research team, as part of a collaborative project involving multiple institutions such as the Allen Institute, University of Colorado Anschutz Medical Campus, University of California San Diego, and Benaroya Research Institute, tracked individuals in the pre-stage of rheumatoid arthritis over a long period.ScienceDaily

Participants were those considered at high risk for RA, known as "ACPA (anti-citrullinated protein antibody) positive" individuals. ACPA is an autoantibody that tends to appear in people likely to develop RA in the future and is already used in clinical settings as a "sign of onset risk." The study followed these ACPA-positive individuals for up to seven years, analyzing immune cells and inflammation markers in their blood in detail during that time.ScienceDaily

The key point is that data was continuously collected "from the stage before rheumatoid arthritis had developed." Many studies target patients after symptoms appear, but this time, the entire "pre-onset period" was captured and examined.

The body already in "rheumatoid-like" inflammation mode

The analysis revealed that the immune systems of ACPA-positive individuals who would eventually develop RA had already switched to "rheumatoid mode."ScienceDaily

• Systemic inflammation at the whole-body level
  The inflammation was not just occurring in the joints but showed a "systemic inflammation pattern" spreading throughout the body via the bloodstream. This pattern was said to closely resemble the systemic inflammation seen in patients who have already developed RA.ScienceDaily

• B cells switching to "attack mode"
  Normally, B cells are responsible for producing antibodies to protect the body from pathogens. However, in high-risk individuals, B cells were skewed towards a more aggressive inflammatory type, preparing a "belligerent antibody repertoire" that includes autoantibodies.ScienceDaily

• Expansion of T helper cells (Tfh17-like)
  Among T helper cells, which orchestrate immune responses, there was an increase in the type that particularly induces B cells to produce antibodies (a group similar to Tfh17 cells). This can be interpreted as further strengthening the groundwork for producing autoantibodies.ScienceDaily

• Even "naive" T cells had their programming rewritten
  Amazingly, even "naive T cells," which had never encountered pathogens, showed changes at the epigenetic level (the mechanism of turning genes on and off, rather than the DNA sequence itself).ScienceDaily
  The genes themselves hadn't changed, but the expression patterns had been pre-tuned to a "state prone to autoimmune reactions."

• Monocytes in the blood already resembling macrophages in the joints
  Monocytes in the blood of individuals before onset already showed characteristics similar to macrophages, which play a crucial role in inflamed joints of RA patients. These monocytes were releasing large amounts of inflammatory substances and were reported to be in a "ready state to cause inflammation as soon as they gather in the joints."ScienceDaily

Looking at it this way, even during the period when a person feels "there are no symptoms yet," the entire immune system is gradually being restructured into a "self-attack mode."

Disease is not "on/off" but a gradient

Traditionally, we tend to perceive health as a binary choice between "healthy" and "sick." However, this study suggests that RA progresses as a continuum.

1. Completely healthy state

2. RA-related antibodies (ACPA) begin to appear, but there are no symptoms

3. The function and genetic control of immune cells gradually change, forming a "pre-RA" immune pattern

4. Inflammation begins to concentrate in the joints, manifesting as pain and swelling (clinical onset)

The team has particularly clarified the reality of the "invisible zone" between stages ② and ③.ScienceDaily

This suggests an image closer to "RA doesn't happen suddenly one day," but rather, "preparations have been underway for years in unseen areas, and symptoms erupt all at once after crossing a certain threshold."

What changes? New goals of early detection and prevention

So, what does this discovery bring to our healthcare and lives?

The research team points out the possibility of combining various immune patterns (biomarkers) discovered in this study to more accurately predict "who among ACPA-positive individuals is particularly likely to develop RA."ScienceDaily

If this becomes a reality, scenarios such as the following may come into view.

• Select high-risk groups from among ACPA-positive individuals and conduct more frequent monitoring and lifestyle guidance

• Attempt interventions to suppress inflammation and immune overactivity before symptoms appear

• Even for those who have already developed RA, it will become easier to consider personalized treatment tailored to their immune profile

Of course, clinical applications such as "measuring everyone's immune profile in screenings" will not start immediately. It is still in the research stage, and further verification is needed on how to combine which indicators to predict risk accurately.

Nevertheless, the goal of "catching the disease before the joints hurt" and "preventing the onset itself," which was once close to a dream, has become somewhat more realistic.

How is it perceived on social media?

This news has spread through overseas media and research institution announcements, eliciting various reactions on X (formerly Twitter) and patient communities. Here, we present typical voices as anonymized images.

Voices from patients and families

"If we had known a little earlier, maybe my mother's joints wouldn't have been so damaged. If a system to detect it before onset is developed, it could truly change many lives" (40s, family of a patient)

"It's scary to hear that 'the disease starts before symptoms appear,' but conversely, it means 'we might be able to take action during that time.' I want to take it as hope" (30s, RA patient)

"As someone who is ACPA positive but has no symptoms yet, I've always been uncertain about 'how much to worry' and 'when to consider treatment.' I would be happy if this research could serve as a decision-making tool" (nuanced from an SNS post)

Reactions from healthcare providers and researchers

"The immune map of 'pre-onset rheumatoid arthritis' has become quite specific. If this leads to full-scale prevention trials, it could change the paradigm of RA treatment" (rheumatology specialist)

"On the other hand, we must also consider societal issues, such as the anxiety of those labeled as 'pre-RA' and problems with insurance and employment" (public health researcher)

Simple questions from general users

"At what point would you want to know if you might develop RA in the future? Some people might prefer not to know..."
"If preventive medication becomes common, how will the balance with side effects be considered?"

On social media, there are many mixed reactions of "hope" and "anxiety." Knowing about a disease early is not always a good thing—therefore, future discussions will need to consider not only medicine but also ethics and social systems.

What can we do now?

So, what should we be aware of as we read this article?

1. Do not over-rely on self-judgment
   Hearing that "the immune system changes years in advance" might make every small discomfort seem like "pre-RA." However, the probability and conditions under which people progress to rheumatoid arthritis are still under research. If you have concerning symptoms, it is important to consult a specialist rather than relying on self-judgment.

2. Organize family history and test results
   Having family members with rheumatoid arthritis or having been pointed out RA-related antibodies in past tests may become increasingly significant. Keeping test results at hand and being prepared to consult a rheumatology specialist if necessary provides peace of mind.

3. View the "pre-onset period" as an opportunity
   The study highlights the harsh reality that "immune abnormalities progress well before symptoms appear," but it also offers hope that "this period is an opportunity for intervention."
   For those identified as high risk for onset, multifaceted preventive approaches, including lifestyle changes and treatment, are expected to be considered in the future.
   
   
   

How will rheumatology care change in the future?