Patients who develop psoriatic arthritis usually have some warning. Psoriasis, a skin condition characterized by splotchy patches of redness, typically precedes the arthritis by about 10 years.
Chris Ritchlin, M.D., M.P.H.
But even with all that lead time, addressing the disease — which occurs in 30 percent of psoriasis patients — has proved challenging. So in the hopes of advancing treatments or even preventing the condition, researchers at UR Medicine are now studying a specific molecule on the surface of the cells that lead to the crippling form of arthritis, which results in joint inflammation in 50 percent of patients within two years of diagnosis.
The research, led by Chris Ritchlin, M.D., M.P.H., chief of the Department of Allergy, Immunology, and Rheumatology at UR Medicine, is supported by a 2-year, $250,000 incubator grant from the CTSI, which began on July 1.
“If we can identify targets that we can inhibit, we can block the formation of these bone-resorbing cells,” said Ritchlin. “We can develop new medications to stop bone-resorbing diseases like arthritis, osteoporosis, metastatic cancer.”
The molecule being studied, DC-STAMP, is responsible for cell fusion, and winds itself through the cell membrane on osteoclast precursors. Minsoo Kim, Ph.D., associate professor of microbiology and immunology at UR Medicine and co-principal investigator for the project, devised a sequence of rhodopsin molecules that would fuse to DC-STAMP. This allows researchers to activate the molecule and study its properties, a critical advance, since the molecule that binds to DC-STAMP remains unknown.
Minsoo Kim, Ph.D.
But advancing the basic science behind DC-STAMP is merely one of the three goals of Ritchlin’s research.
The second aim is to determine whether DC-STAMP-expressing cells can drive inflammation as well as bone damage. To accomplish this, Ritchlin is taking mice that don’t possess any DC-STAMP molecules and placing two different kinds of cells — DC-STAMP- and DC-STAMP+ — from healthy mice into the bone marrows of irradiated mice prone to arthritis.
If his hypothesis is accurate — that DC-STAMP-expressing cells trigger arthritis — then the would-be arthritic mice won’t develop the disease after transplant when given DC-STAMP- cells but would show joint inflammation when given DC-STAMP+ cells.
Ritchlin is also working alongside Brendon Boyce, M.B.Ch.B, vice chair for anatomic pathology and co-principal investigator in the project, for the third prong of the research, which studies patients who already have aggressive psoriatic arthritis.
Brendan Boyce, M.B.Ch.B.
Patients with psoriatic arthritis don’t always respond to certain medications, so Ritchlin and Boyce are studying another important cell molecule called TRAF3. By measuring the level of TRAF3 in a patient’s blood cells, the researchers believe they can determine whether anti-Tumor Necrosis Factors (TNF) agents, costly but effective drugs in about 60% of psoriatic arthritis patients, are likely to relieve joint inflammation and damage before starting the drug.
They are also following the level of DC-STAMP+ cells in the blood after starting anti-TNF agents since this marker drops rapidly in patients who respond clinically.
“There are a lot of drugs we can treat patients with,” said Ritchlin. “By identifying those early response markers, we can say ‘This drug is working, we should keep them on it,’ or we can switch them to another drug.”
Eddie Schwarz, who was on the committee that selected Ritchlin’s work from an array of proposals, said that the project exemplified what the CTSI was looking for it was seeking a match for its incubator grant.
“It starts with a highly-significant problem with unmet clinical needs, as well as several remarkable discoveries,” said Schwarz, associate director for funding programs at the CTSI. “What we’re looking for in the incubator as much as anything, is integrated projects by two or more PIs that really have the potential to synergize and accelerate the pace of basic science, clinical research, and translation to human health.”
The CTSI recently released requests for applications for both the CTSI Incubator Program and the CTSI Pilot Awards Program.