A new study by scientists at the University of Colorado Anschutz Medical Campus reveals that joint tissue from patients with early-stage rheumatoid arthritis often have high levels of a protein called granzyme used by the immune system to attack pathogens.
The study also detected remnants of a bacteria that causes gum disease – gingivitis – in the tissue samples. While a connection between gingivitis and rheumatoid arthritis has long been suspected, this is the first time physical evidence of the bacteria in the joint tissue has been detected.
‘Findings, could lead to earlier diagnosis and treatment ‘
Researchers said the findings strongly support the hypothesis that these bacteria, initially colonizing gum tissue, somehow drive the development of rheumatoid arthritis, at least in some patients. How the bacteria get into the joints remains unknown. These findings, they said, could lead to earlier diagnosis and treatment of this chronic disease.
The study, published online in Immune Network, also revealed a correlation between the severity of the disease and the amount of granzyme present.
Rheumatoid arthritis or RA is chronic life-long autoimmune disease affecting the joints, characterized by inflammation and degradation of bone and cartilage. Drugs can temporarily reduce symptoms, but the disease usually returns. Research indicates that treating RA early contributes to better outcomes.
In this study, scientists looked at joint tissue biopsies from patients in the early stages of RA. They found a suite of proteins used by the immune system to attack pathogens. The process is often called the granzyme-perforin pathway. Immune cells such as killer T cells or natural killer cells secrete these proteins. They then work together to perforate the pathogen, enter, and kill it from within.
‘We discovered that higher levels of these immune proteins are linked to worse disease’
“We discovered that higher levels of these immune proteins are linked to worse disease,” said the study’s senior author Nirmal K. Banda, PhD, professor in the division of rheumatology at the Barbara Davis Center for Diabetes at CU Anschutz.
According to the clinical trial, treatments like Rituximab which targets B cells and Tocilizumab which blocks inflammation, reduced the protein levels in the joints. That suggests granzymes and their proteins are partially driving the inflammation in the early stages of RA.
‘Discovery of remnants of Porphyromonas gingivalis in joint biopsies’
Perhaps the biggest surprise was the discovery of remnants of Porphyromonas gingivalis in these joint biopsies. P. gingivalis is a bacterium that causes gingivitis. No live bacteria were found, only traces of bacterially-derived material.
“There’s long been a theory that a bacterial infection might start rheumatoid arthritis,” Banda said. “We found tiny traces of it in the joint tissue, especially in areas where those immune proteins were highly active – supporting the idea that a past infection might help trigger RA.”
Researchers also found that the amount of granzyme protein present in joint tissue correlated with the severity of the disease, often measured as joint inflammation. This correlation was independent of whether patients tested positive or negative for other common RA markers. This suggests that testing for these proteins may have predictive value.
“They could be biomarkers that identify the presence of inflammation, track its severity and help guide future treatment,” Banda said.
The study’s first author is Francisco G. La Rosa, MD, associate professor of pathology at the CU School of Medicine.
Co-authors include a team of national and international collaborators: Larry W. Moreland, Luigi Nibali, Mike Curtis, Kevin D. Deane, Colin Strickland, Jennifer Seifert, Accelerating Medicines Partnership (AMP) RA/SLE Network, Carson Keeter, Dmitri Simberg, Robert I. Scheinman, Rachel Lau, Costantino Pitzalis, Myles J. Lewis and V. Michael Holers.