Rheumatoid arthritis begins years before symptoms, study finds

• Rheumatoid arthritis is a chronic autoimmune condition that cannot be cured but can be treated to prevent its progression.
• Individuals at risk of developing rheumatoid arthritis can be identified 3-5 years prior to symptom onset based on autoantibody levels, but only 30-60% of individuals expressing these autoantibodies develop this condition.
• A recent study has identified changes in the immune profile or signature of individuals at risk for developing rheumatoid arthritis as they progress in the disease.
• These findings could help with detecting rheumatoid arthritis early and developing more effective preemptive therapies.

Rheumatoid arthritis (RA) is an autoimmune condition that currently has no cure; however, researchers are trying to find ways to detect it early in hopes of preventing its progression. One area scientists have focused on is biomarkers in the blood.

Individuals with rheumatoid arthritis exhibit elevated levels of autoantibodies several years prior to the onset of the disease and its characteristic symptoms — such as pain and swelling in the joints. While these antibodies are useful in predicting whether a person will develop RA, a significant portion of individuals with these antibodies do not develop this condition.

A recent study published in the journal Science Translational Medicine characterized the changes in individuals’ immune systems as they progressed from being at risk of developing rheumatoid arthritis to actually showing clinical symptoms.

Characterizing this immune profile in at-risk individuals who progress to clinical rheumatoid arthritis could allow the early detection of this condition and the development of preemptive therapies for this at-risk population.

The study’s author, Gary Friestein, MD, senior associate vice chancellor for health sciences at the University of California, San Diego School of Medicine, said, “Most people who are at-risk for RA never develop the disease. That makes prevention studies difficult because some individuals who do not need therapy will be treated with medicines with potential side effects.”

“We hope that the findings from this study will directly support new ways to predict RA as well as potentially identify targets for prevention trials,” added the study’s co-author, Kevin Deane, MD, Professor of Medicine at the University of Colorado Anschutz.

Rheumatoid arthritis is an autoimmune condition in which the body mistakenly produces an immune response to healthy tissue, specifically the lining that covers the joints.

The disease-modifying drugs used for the treatment of RA cannot reverse the damage, but can prevent the progression of the disease and help manage the condition. However, studies suggest that 5 to 27% of individuals with rheumatoid arthritis do not respond to these treatments, and relapse is also common after remission in individuals who respond to treatments.

Early detection of individuals at risk of developing rheumatoid arthritis can help prevent the condition from progressing.

“Currently, once someone develops the swollen joints of RA, the disease is usually ‘forever,’ meaning that they will need to be on treatments for life. Furthermore, worldwide, RA affects millions of people’s lives and costs billions of dollars to manage,” said Deane.

“If we find ways to prevent the first swollen joints in RA, or even ‘reset’ the immune system in an at-risk stage, this could lead to people never getting full-blown RA — or having a much milder form of disease. That could have huge benefits for individuals’ well-being, as well as for public health.”
— Kevin Deane, MD

Individuals with rheumatoid arthritis exhibit elevated levels of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) 3-5 years prior to the onset of clinical symptoms. Approximately 30-60% of individuals with elevated ACPA and RF levels go on to develop rheumatoid arthritis. In other words, ACPA and RF levels are not accurate predictors of progression to RA.

Attempts are currently underway to develop preemptive treatments to prevent the development of rheumatoid arthritis in the at-risk population expressing ACPA and RF. For instance, studies have shown that the drug abatacept can reduce the risk of rheumatoid arthritis development in this at-risk population.

The characterization of the changes in the immune profile of at-risk individuals who develop RA could help understand the mechanism of the disease and more effectively target the subset of at-risk individuals who progress to develop RA symptoms.

The study’s author, Mark Gillespie, Ph.D., Assistant Investigator at the Allen Institute, explained, “Prior to this study, the field lacked an understanding of the biology of the ‘at-risk’ period and the changes that occur when individuals who are at-risk for RA go on to develop clinical disease.”

In the present study, the researchers examined the changes in the immune profiles of at-risk individuals who later developed rheumatoid arthritis, referred to as converters.

The immune profiles of converters were compared with the profiles of at-risk individuals who did not develop RA, referred to as non-converters, and healthy individuals who showed absence or very low levels of ACPA.

The study consisted of 45 at-risk individuals, with 16 of them developing rheumatoid arthritis during the follow-up period, and a group of 11 individuals with early clinical rheumatoid arthritis. The control group consisted of 38 healthy individuals.

The researchers found that at-risk individuals exhibited increased levels of inflammatory proteins in their circulation compared with healthy controls at the start of the study. This sign of systemic inflammation was present in at-risk individuals, regardless of whether they developed rheumatoid arthritis during the follow-up duration.

Similarly, there was an increase in the number of immune cells, such as monocytes, that are involved in inflammation in both converters and non-converters. Moreover, these immune cells showed increased expression of inflammatory genes and proteins.

The researchers were unable to detect any differences in gene or protein expression in immune cells between converters and non-converters at the start of the study.

The researchers then characterized changes within the group of converters from the time of their last visit without clinical symptoms to their next visit when they were first diagnosed with clinical RA. These changes in the immune profile of converters were compared with those in healthy controls over a similar time frame.

Autoimmune conditions are caused by the immune system’s failure to distinguish between the body’s own proteins and foreign proteins or antigens from germs. Autoimmune conditions are characterized by a dysfunction of T and B lymphocytes, which are crucial components of the immune system involved in producing a coordinated response in an antigen-specific manner.

In the present study, the researchers found changes in gene expression of B and T cells in converters, suggesting the activation or stimulation of these cells. Naive lymphocytes become activated upon their exposure to antigens, leading to their proliferation and differentiation into effector cells or memory cells. The short-lived effector cells are involved in the immediate immune response, whereas long-lived memory cells facilitate a faster response to future infections.

Naive or memory B cells are activated upon binding to an antigen, leading to their proliferation and differentiation into antibody-producing effector cells. In rheumatoid arthritis, subsets of B cells produce autoantibodies against the lining of joints.

In the present study, naive and memory B cells in converters exhibited changes in their gene expression profiles that suggested their activation. In other words, the B cells showed a shift towards a pro-inflammatory state. Moreover, the researchers identified a subset of activated memory B cells in converters with a profile similar to those found in clinical rheumatoid arthritis patients.

Helper T cells, which express the CD4 protein on their surface, interact with B cells and are essential for the activation of B cells. Consistent with the increase in activated B cells in converters, the researchers also found an increase in the population of effector CD4 T cells in this group of individuals. Moreover, these CD4 T cells showed increased expression of genes that are involved in B cell activation.

The activation of B cells and the increase in the number of helper T cells in converters suggest a shift toward increased autoantibody production, which could contribute to disease progression. In addition, naive CD4 T cells also showed changes in gene regulation mechanisms, priming them to differentiate into effector cells capable of promoting B cell activation.

Looking and feeling ‘healthy’

“Our team discovered that during this ‘at-risk’ period, where individuals look and feel healthy, their immune systems are dramatically different. Individuals at risk for RA exhibit widespread inflammation and signs of immune activity, including in B cells that produce the autoreactive antibodies characteristic of RA, as well as in T cells that interface with and instruct the B cells to produce these antibodies.”
— Mark Gillespie, Ph.D.

“We also discovered immune changes in ‘naïve’ T cells, which are significant because these cells have not encountered any threats previously and may suggest that immune cells in individuals at-risk for RA are already wired to respond in a determinantal manner,” Gillespie added.