Not too many years ago, a diagnosis of rheumatoid arthritis (RA) was just that — a diagnosis of rheumatoid arthritis. And if you received that diagnosis, your treatment was pretty much the same as anyone else who received it — large doses of aspirin followed by a corticosteroid and/or disease-modifying drugs such as gold or sulfasalazine.

Just as treatment has changed through the years, so has the thinking about RA in some cases. Rather than a single disease with a one-size-fits-all treatment strategy, some researchers believe that rheumatoid arthritis may actually be a collection of diseases. Genetic differences in individuals, they say, could affect the various features of the disease, the factors that trigger its development and the best treatments. Their hope is that a better understanding of the differences between the diseases we call RA may provide insights that could eventually lead to new ways to treat and, perhaps in some cases, even prevent it. 

Seropositive and Seronegative RA

The most recognized differences in RA cases is between anti-CCP positive and anti-CCP negative (also referred to as seropositive and seronegative) disease, according to David S. Pisetsky, MD, PhD, professor of medicine and immunology at Duke University School of Medicine in Durham, N.C. 

Anti-citrullinated protein antibodies (Anti-CCPs) are antibodies produced against proteins in the body undergoing a process called citrullination (a molecular change in structure). They are present in approximately 60 to 80 percent of people diagnosed with RA. Studies have found that, for many people, the antibodies precede the development of clinical symptoms by 5 to 10 years. If you have symptoms consistent with RA and a positive test for the antibody, an RA diagnosis is almost a certainty.

“You can have RA without being seropositive, but it is easier to meet the criteria if you are positive,” says Dr. Pisetsky. “In the seronegative group, people need to have more care in the physical exam and maybe more radiographic evidence,” he says. 

Aside from the presence of the antibodies there are a few differences in people with anti-CCP positive and negative disease. “They are somewhat different genetically,” he says. “The anti-CCP positives are so-called shared epitope positives.” The shared epitope is an amino acid sequence within the human leukocyte antigen (HLA) genetic site, or locus, that controls immune responses. It is not known how the amino acid sequence contributes to RA, but it has been proposed that it attaches to parts of proteins called citrullinated peptides, and therefore contributes to the production of anti-CCP antibodies. Other differences have to do with the risk factors associated with seropositive and seronegative disease. For example, smoking has been shown to be associated with RA in people with the shared epitope and positive anti-CCP but has not shown the same association with anti-CCP negative disease.

Alcohol and coffee consumption are also associated with the development of seropositive disease, while obesity and breastfeeding are associated with the development of seronegative disease. While one might predict that anti-CCP negative would be milder disease, that isn’t always the case. And although it is unlikely that a person with seronegative RA will ever turn positive, it is possible for people with seronegative disease to eventually be diagnosed with a different disease altogether, he says. 

Dr. Pisetsky gives these examples:

  • A person diagnosed with seronegative may eventually develop a skin rash that would cause the doctor to change the diagnosis of psoriatic arthritis.
  • Joint fluid tests in what appears to be RA could lead to a diagnosis of chronic gout.
  • Osteoarthritis can sometimes be confused with seronegative RA. 

A Common Clinical Endpoint

Some researchers contend that RA is not a separate and distinct disease, but rather represents a common clinical endpoint for various starting points, each of which is guided by as yet poorly understood aspects of the genetic background of the affected individual, says John D. Carter, MD, associate professor, chief of the division of rheumatology and director of clinical research at the University of South Florida in Tampa.

“Depending on the trigger and the individual’s genetic makeup you get different manifestations of what we call RA, and these different presentations are lumped into one diagnosis,” he says. 

In addition to share epitope associated with seropositive disease, genetic makeup may account for other differences such as extraarticular manifestations (beyond the joints) including lung or eye involvement or rheumatoid nodules, Dr. Carter says. Researchers are looking for genetic differences in individuals with RA that may explain variances as disease severity, manifestations, triggers and treatment responses that may have significant consequences for future research and the development of new therapeutic interventions. 

“This obviously could be tremendously important when it comes to treatment, as a predictor of response,” says Dr. Carter. “Many are now looking for biomarkers to predict response. I believe this feeds into the same theory. A different biomarker ‘signature’ probably exists for each different type of what we now call RA.”