New Biomarker for RA Discovered

Rheumatoid arthritis (RA) affects the lining of joints, causing painful swelling and ultimately leading to joint deformity. There are many biomarkers related to RA, however, the levels of these marks found in blood work do not always reflect the severity of symptoms experienced by an individual, which can leave people feeling invalidated and confused. This disconnect can be distressing to patients who have significant subjective symptoms of RA but have low, or even absent, levels of these currently-used biomarkers. Finding novel ways to objectively assess the symptoms and progression of RA will create greater cohesiveness between the experience of the individual and the interventions of the treatment team.

Antibodies and antigens

Researchers have been expanding their research into antibodies and antigens related to RA, looking for novel biomarkers to increase their understanding of RA. Antibodies are proteins produced by the immune system that attach to target antigens, such as foreign proteins and sugars in the body. This attachment identifies the invader for the immune system to target and attack. In autoimmune disorders the body attacks its own tissue, causing inflammation and pain. Because the body is attacking itself, it can be difficult to identify meaningful markers that occur in individuals with RA but not in healthy individuals.

Antibodies are useful markers because they are dispersed throughout the blood and easily accessed through venipuncture, unlike their antigen (or target), which is usually fixed in one location in the body and difficult to access without directly sampling the affected area, such as taking a sample directly from the joint.

Antibodies in Rheumatoid Arthritis

In RA, citrullinated proteins are proteins which are highly-specific to this diagnosis because they are not one of the 20 amino acids encoded into DNA. This makes the antibodies unique to RA because they are not found in healthy individuals. Citrullinated proteins occur when arginine, an amino acid, is converted into citrulline. Examples of these are fibrinogen, vimentin, and glucose-6-phosphate isomerase. Anticitrullinated protein antibodies (ACPA) target these citrullinated proteins and autoreactivity to the citrullinated protein is associated with increased risk of developing RA.

These proteins are commonly found in joints affected by RA, and a team of researchers at the University of Tsukuba recently investigated the presence of these citrullinated proteins in the blood. They compared the serum protein of patients with RA as well as peptide glucose-6-phosphate isomerase-induced arthritis (pGIA), Sjogren’s syndrome, systemic lupus erythematosus, and osteoarthritis. A control group of healthy individuals was also studied.

Within these groups, researchers found that the protein inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) was present and highly specific to the RA group compared to the other groups. This suggests that citrullinated ITIH4 may be involved in the development of RA. Additionally, the levels of ITIH4 were higher before, and lower after, effective RA treatment.


Citrullinated ITIH4 may be an important and new biomarker to identify RA from other rheumatic diseases, and also provide a more accurate assessment of the disease activity than currently-used biomarkers. It is known to occur in the joints affected by RA, and is found in blood, making it both useful and accessible in the diagnosis and assessment of rheumatoid arthritis. By having meaningful and easy to access biomarkers, which occur in predictable levels which mirror symptom severity, health care providers will have measurable ways to better understand their patient’s subjective symptoms.

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