Treating Rheumatoid Arthritis – A Roll of the Dice

Treating Rheumatoid Arthritis – A Roll of the Dice

Dr. Noss is an assistant professor, division of rheumatology, Roosevelt Clinic, University Washington Medical Center. Dr. Noss received her MD as well as her PhD in 2002 from Case Western Reserve University. She completed her residency in internal medicine in 2004 and her fellowship in rheumatology in 2008, both at Brigham and Women’s hospital, Boston.

Trial and Error

Despite the improvements in rheumatoid arthritis (RA) treatment that have been made in the last two decades there are still sizeable challenges facing rheumatologists today, particularly relating to selection of the correct treatment option for their patients. In striving to treat patients, these difficulties come to the forefront for Dr. Noss. “The hardest part about being a rheumatologist is starting patients on the right drug,” she says. “With RA, all you can do is give it your best shot. You’re simply rolling the dice.”

In her career, Dr. Noss has seen her patients face many hardships. One such patient underwent years of swollen joints, stiff knees and debilitating pain; She was particularly impacted by her symptoms as her career as a social worker required regular travel for home visits and other appointments. This patient returned to the clinic time and again, looking for some form of relief. Each time a patient is put onto a new drug regime it takes three to four months to establish an effect. It’s a waiting game that, in this case, took six attempts and many months to find a drug that offered relief from RA symptoms.

So how do treating physicians choose the best drug for their patients? Unfortunately, there is no easy answer to this question. Physicians must decide whether to target the immune-system cells: T-cells or B-cells, or one of the body’s inflammatory chemicals. One cannot simply keep changing or adding new drugs. There’s a limit to how many drugs people can take to suppress the immune system before chronic infections become a serious side effect. Even with numerous new treatments, remission is not achievable for all patients. Around 80% of patients do find some level of relief after trying a number of different treatments. It is Dr. Noss’ ambition to improve this percentage and offer relief to a greater number of patients.

The Role of Fibroblasts

Funding as an ANRF fellow and grant recipient has allowed Dr. Noss to rigorously pursue this goal. This research is directed towards activated fibroblasts. Fibroblasts are biological cells key in the synthesis of the extracellular matrix and collagen necessary in the structural framework of tissues and wound healing (tissue damage induces the production of fibroblasts).

In patients with RA, this system of cells is sent into overdrive. Fibroblasts are pumped out at an accelerated rate, clogging the joints, intensifying inflammation and destroying the cartilage that normally cushions the joints. As RA begins in the immune system, it made sense to Dr. Noss to search for potential new drugs that work at a cellular level. This led to a number of research questions – Is it possible to block these rogue fibroblasts? How do you reduce the associated risk of infection? Is there a way to combine drug therapies to target fibroblasts with current biologicals that block the immune system? “Maybe a cell that’s not traditionally a drug target, like a fibroblast, will someday put people completely into remission.”

Recent Observations

Dr. Noss’ research has focused on the role of cadherins in fibroblasts. Cadherins are cell adhesion molecules that are important in the formation of adherens junctions and protein complexes, which allow cells to bind to one another. Cadherin 11 is a protein expressed in the cell lines responsible for bone formation (osteoblasts), it is stimulated during the differentiation of these cells, suggesting a specific function in bone development and maintenance. In studies published in the prestigious journals – Science and PNAS, Dr. Noss showed that deficiency, or blockade, of cadherin 11 resulted in protection, in mouse models, from arthritis and demonstrated that binding of this adhesion molecule leads to induction of pro-inflammatory cytokines (inflammation-inducing chemical). Cadherin 11 is a marker and regulator of synovial fibroblast function – responsible for cartilage integrity and joint lubrication – in inflammatory arthritis. Unpacking the mechanisms behind this relationship may lead to new therapeutic targets that prevent long-term joint destruction resulting from RA.

Despite the difficulties of 2020, Dr. Noss and her team have made substantial progress in this area of research. The data generated has not only seen them achieve a number of their original objectives but has in fact, allowed them to expand on them. Dr. Noss also proposed that the platelet-derived growth factor-alpha (PDGFRA), a molecule highly present on[CA1]  the joint fibroblasts, as a potential treatment target. Data generated during her time as an ANRF scholar has shown, using a mouse model, that silencing PDGFRA reduced the severity of arthritis. This supports the notion that this molecule may provide a new way to target fibroblast responses in RA. Recently the team published that PDGFRA interacts with cadherin-11, to promote joint fibroblast proliferation, thereby amplifying local inflammation and destruction of joint cartilage. This result is potentially significant as expansion of the number of fibroblasts is a key feature of RA pathology. The ANRF grant allowed an expanded understanding of PDGFR biology in the joint more generally, which Dr. Noss believes led to recent NIH support to more extensively study the roles of PDGFRs and their binding properties in arthritis biology.

With this continued support from the NIH, Dr. Noss hopes to test the expanded PDGFR model, striving to clearly separate normal and pathologic activities, a step that is critical to effectively targeting this growth factor receptor family in arthritis treatment. Reflecting on this past year and the Covid-19 pandemic, Dr. Noss had these optimistic concluding remarks “In terms of our research, we were impacted initially, like everyone else, by the first stay-home orders. I feel fortunate that the university I work for implemented an early and comprehensive approach to workplace safety, letting us continue our research in these challenging times. More generally, I am really proud of how the scientific community has responded to the Covid-19 pandemic. Despite how it might seem, the advancement in development of tests, therapeutics, and potential vaccines has been light years faster than anything that might have been predicted even 10 or 20 years ago. To go from a new virus to large vaccine trials in less than 9 months is frankly amazing.”

Article Author
Arthritis National Research Foundation
arthritisresearch@curearthritis.org

The Arthritis National Research Foundation's mission is to provide initial research funding to brilliant, investigative scientists with new ideas to cure arthritis and related autoimmune diseases. There are several ways to support research through the ANRF. Find out more and donate today.

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