Blood Tests for Rheumatic Diseases

By Linda Rath | March 10, 2024

Autoimmune and rheumatic diseases are diagnosed based mainly on a thorough medical history and physical exam, with some input from imaging and lab tests. Blood tests may provide clues, but they don’t confirm or rule out a particular type of arthritis, and tests sometimes have false results. 

Blood tests should only be performed and interpreted in the context of a thorough medical history and physical exam, cautions John Davis, III, MD, a professor, rheumatologist and researcher at Mayo Clinic in Rochester, Minn. He says the unreliability of lab tests is “part of the challenge and frustration of rheumatology.” 

It’s important to know what blood tests can and can’t do. If you don’t understand why you’re having a certain test or what the findings mean, be sure to ask your health care provider.

Autoimmune Arthritis

If you have symptoms such as painful, swollen joints, fatigue and rash, you may have one or more of these tests as part of a complete evaluation:

• What it is: This test can detect an autoimmune response, which occurs when the immune system mistakenly attacks a person’s own cells, damaging tissue and causing widespread inflammation.
• Who it’s for: Patients whose symptoms suggest an autoimmune disease like lupus, rheumatoid arthritis (RA) or scleroderma. A positive ANA is among the criteria for a lupus diagnosis according to 2019 European Alliance of Associations for Arthritis (EULAR)/ American College of Rheumatology (ACR) guidelines. However, this has raised some questions because, while most people with lupus are positive for ANA, less than 15% of people with a positive ANA have lupus, according to the ACR.
• Pros: A negative ANA test may rule out lupus for most people, but it doesn’t rule out other disorders.
• Cons: Many completely healthy adults – up to 30% of the population – have anti-nuclear antibodies, leading to a false positive test. The chance of false positives increases with age, viral infections, other autoimmune diseases and certain medications. Findings should be interpreted with care, Dr. Davis says. “An ANA test can’t diagnose an autoimmune disorder on its own and should never be ordered for someone with no symptoms.”

• What it is: Measures the amount of rheumatoid factor in your blood. Rheumatoid factors are autoantibodies – proteins that can attack healthy cells and tissue. High blood concentrations of RF are usually associated with RA or Sjogren’s but may not be obvious until later stages of disease.
• Who it’s for: Often ordered to help diagnose rheumatoid arthritis, it should be reserved for patients whose symptoms and physical exam suggest RA once other possibilities have been ruled out, Dr. Davis says. It’s not meant for people with suspected fibromyalgia or osteoarthritis (OA).
• Pros: Although RF often produces false positives, a very high positive RF – three times above the normal range – may be more accurate than a low positive RF.
• Cons: RF can return false positive results in healthy older adults and in people with other autoimmune diseases and infections, especially hepatitis C. According to Dr. Davis, it’s not uncommon for some RF-positive patients to have hepatitis C-related arthritis, which closely mimics RA. Conversely, people who actually have RA can test negative for RF. Some of these patients may be diagnosed with what’s known as seronegative RA.

• What it is: Citrullination is a normal process where one amino acid, arginine, is converted into another amino acid called citrulline. It’s involved in many body processes, including brain and nervous system function and regulation of the immune response.  But improper citrullination can cause widespread inflammation and the production of antibodies against healthy tissue. Although citrullination is strongly associated with rheumatoid arthritis, it now appears to play a part in other autoimmune and inflammatory diseases, including type 1 diabetes, lupus and cancer.
• Who it’s for: People who experience six to 12 weeks of pain and stiffness, particularly in the small joints of the hands and feet, have a family history of RA or have a personal history of asthma or thyroid disease (both of which are more common with RA).
• Pros: “Anti-CCP has around 95% specificity, so most positive tests are true positives,” Dr. Davis says. A positive test may also be associated with an increased risk of RA. Because anti-CCP is more accurate than RF factor, your doctor may order both.
• Cons: A positive anti-CCP test can rule out certain types of arthritis, but it's not conclusive for RA. People with other conditions, including lupus, psoriatic arthritis (PsA) and active tuberculosis can also test positive. And a negative test doesn’t rule out RA.

Inflammatory marker tests

“There are many challenges with inflammatory marker tests,” Dr. Davis says. “They’re not diagnostic and are best used to monitor disease activity.” The two most common are:

• What it is: This test, developed at the end of the 19^th century, measures the amount of inflammation in the body. It checks the rate at which whole red blood cells fall to the bottom of a vial in an hour. The faster they fall, the more inflammation.
• Who it’s for: To monitor disease activity in people with an inflammatory condition.
• Pros: Some healthy people naturally have sed rates higher or lower than the normal range. But most often, a high sed rate indicates inflammation somewhere in the body.
• Cons: ESR can’t tell you or your doctor what’s causing inflammation. “A high sed rate does not mean you have an autoimmune disease,” Dr. Davis says. “It’s inherently nonspecific.” He notes that many health conditions, from an active infection to sickle cell disease, can cause inflammation. A high sed rate “may be evidence of an inflammatory disease or it may be misleading,” he says.

• What it is: C-reactive protein measures proteins produced by the liver in response to the pro-inflammatory cytokine, interleukin-6 (IL-6). CRP starts to rise soon after there’s an infection or inflammation in the body.
• Who it’s for: One of several tests that may used to help diagnose an inflammatory disease like RA or monitor response to treatment. When inflammation goes down, CRP should go down, too.
• Pros: CRP is measured in milligrams per liter (mg/L). Depending on the lab, results of 8 mg/L or 10 mg/L are considered high. “Normal values are reassuring; it means you don’t have RA,” Dr. Davis says.
• Cons: Like sed rate, CRP can’t pinpoint the cause of inflammation. Lots of conditions can cause a high CRP, including obesity, diabetes and chronic kidney disease as well as a long run or tough workout. And although high CRP often correlates with more severe disease activity, some people with RA have normal CRP levels, even during flares. CRP tests are often used along with other disease activity measures.

• What it is: MBDA uses a validated algorithm composed of blood concentrations of 12 protein biomarkers, including CRP, to measure disease activity. It’s scored from 1 to 100, with any score above 45 considered high.
• Who it’s for: Adults who have RA or possibly a chronic pain state like fibromyalgia.
• Pros: Dr. Davis says he has used MBDA carefully and selectively when disease activity is hard to monitor.
• Cons: “This test has some of the limitations of CRP,” Dr Davis notes. “For example, obesity and older age can cause a higher score. It’s also being ordered as part of diagnosis, but it’s not a diagnostic test. It’s a disease activity assessment. Sometimes it’s helpful, but often it’s not.”

Genetic tests

• What it is: This test can confirm the presence of a genetic marker called HLA-B27. It provides instructions for making a protein on the surface of white cells that helps the immune system distinguish the body’s cells from harmful pathogens like viruses and bacteria. When HLA genes are faulty, the immune system may not perform this critical function the way it should.
• Who it’s for: HLA-B27 is closely associated with a big family of rheumatic diseases called spondyloarthropathies. It includes ankylosing spondylitis (AS)  psoriatic arthritis, reactive arthritis and autoimmune-related uveitis, an inflammatory eye disease. The test may be used for someone who has symptoms that suggest one of these diseases or other autoimmune conditions.
• Pros: Like other arthritis blood tests, HLA-B27 can’t diagnose any disease. It adds one more piece of information that may help support or rule out a particular diagnosis. About 80% to 90% of people with AS have this gene.
• Cons: Many perfectly healthy people have HLA -B27 and never develop an autoimmune disease. It’s also possible to develop a condition like AS without having the gene. Prevalence of HLA-B27 varies with race and ethnicity.  About 60% of African Americans with AS have it compared to 85% of whites and Hispanics. But because fewer than 1% of African Americans overall carry HLA-B27, a positive test means they have a disproportionately greater chance of developing AS.

Wanted: Better Tests

“Clinicians need the tools to make a diagnosis with better certainty, especially when there are negative test results,” Dr. Davis says. “The hope is that we can develop better blood-based tests, and we [at Mayo Clinic] and others around the world are working on this.”

Better tests could not only help people get a diagnosis and treatment more quickly, but they may help guide health care providers to more customized treatment choices. “We need more predictive biomarkers that actually improve outcomes. I have to believe we will find them,” he adds.