The immune system produces anti-citrullinated protein antibodies (ACPAs) to target citrullinated proteins. ACPAs can help doctors diagnose early rheumatoid arthritis (RA) and predict how likely it is to erode bone.

RA is an autoimmune condition, meaning that the immune system attacks the body’s own tissues in error, causing pain, stiffness, and swelling in the joints. While the causes of RA are still unclear, the immune system affects the body by releasing certain chemicals called antibodies to target tissues.

The ACPA is one of these chemicals. It disrupts specific cell processes and can drive a cycle of cell damage and autoimmune activity that may contribute to RA.

Read on to learn more about the link between RA and ACPAs, why ACPAs develop, and how they factor into RA diagnosis.

According to a 2021 review of literature, doctors consider ACPAs a specific biological sign in the blood, or biomarker, of RA.

However, the authors of the article advise that a positive test for ACPA may not always mean that a person has RA. Levels of rheumatoid factor (RF), another antibody, could also indicate RA.

Doctors may consider levels of the two antibodies when diagnosing RA, which can show different elements of disease progression or outlook.

For example, if a person tests positive for ACPA and RF, an individual likely has RA and may have more aggressive symptoms. A person who receives a positive ACPA test but not one for RF might have early RA or a risk of developing RA in the future.

However, if both ACPA and RF tests are negative, the individual may still have RA based on other criteria or symptoms, and they may still develop ACPAs over time.

If tests are positive for ACPAs and RA, the individual might have a different autoimmune condition, such as systemic lupus erythematosus (SLE) and Sjögren disease. However, this is rare.

ACPA-positive RA occurs when a person with RA has ACPAs. If they do not have ACPAs, or are ACPA-negative, this may lead to different disease progression.

A 2022 study involving 198 people with RA found that those who had ACPA-positive RA had continuously low levels of joint inflammation during periods of remission, but those with ACPA-negative RA responded more to treatment with disease-modifying antirheumatic drugs (DMARDs) in the first year of therapy.

The study also suggests that people with ACPA-negative RA who are in remission have similar inflammation levels to those who do not. However, those with ACPA-positive RA who move into remission have much lower inflammation levels from the point of diagnosis onward.

Some 2020 research involving 108 individuals with RA concluded that those with ACPA-positive RA showed more severe bone damage than people with ACPA-negative RA. In fact, the scores tracking bone erosion were 3.7 to 4.4 times higher in the group with ACPA-positive RA. This erosion often happens in the fifth metatarsophalangeal joint, or little toe joint.

Having ACPA-positive or ACPA-negative RA might also impact the effect of environmental risk factors on RA development. For example, a 2018 study in Sweden found that smoking increased a person’s risk of RA for both ACPA-positive and ACPA-negative individuals, but it had more of an influence on ACPA-positive RA.

The immune system produces ACPA in response to a process called citrullination. Citrullination occurs when an enzyme called peptidyl-arginine deiminase (PAD) converts arginine, a protein building block called an amino acid, into a different amino acid, citrulline.

It is a normal process that supports brain development, skin health, and cells dying at the natural point in their life cycle. However, this process happens too much in people with RA. One of the proteins that citrullination affects is collagen, an essential part of connective tissue, tendons, and ligaments that RA may affect.

Cell damage can mean that PAD works too hard, which causes excess citrullination. In response, the immune system produces ACPAs that attack the citrullinated proteins. However, PAD occurs in immune cells such as neutrophils and monocytes, and ACPAs can reactivate neutrophils, leading to more citrullination.

This feedback loop can increase inflammation and tissue damage in people with RA. Smoking or air pollution may worsen this.

Doctors can identify ACPAs using a blood test for CCP antibodies, a type of ACPA. This blood test usually takes no more than 5 minutes.

As these are a type of ACPA, they can help a physician diagnose or rule out RA.

However, other conditions can also lead to raised CCP antibodies. These include:

A doctor will consider other factors when diagnosing RA, including:

  • an individual’s medical history
  • a physical exam
  • the results of other tests

RA is complex, and doctors often test for other antibodies to confirm a diagnosis. These include:

A doctor may also request X-rays of the joints to assess damage.

According to a 2022 review, anti-cyclic citrullinated peptides (anti-CCP) antibodies are a type of ACPA. Anti-CCP antibodies react to CCPs such as fibrinogen or myelin basic protein but respond differently to each, whereas ACPAs can react to more than CCPs.

Anti-citrullinated protein antibodies (ACPAs) target proteins that have undergone a process called citrullination. Doctors consider this a sign for diagnosing rheumatoid arthritis (RA). A blood test can detect anti-cyclic citrullinated peptides (anti-CCP) antibodies, which are a type of ACPA.

A person’s RA symptoms may be different depending on whether they have ACPA-positive RA or ACPA-negative RA. Doctors may consider ACPA levels alongside rheumatoid factor (RF) levels when trying to predict the course of RA progression and recommending treatment.