Self-Destruction: Understanding Rheumatoid Arthritis
It often starts subtly, with stiff, sore, and swollen joints that could be chalked up to overuse or exhaustion. However, for many people, these symptoms signify a greater underlying problem, rheumatoid arthritis (RA).
RA is an autoimmune disease in which the immune system attacks the body's own joints. Over time, this can lead to inflammation, pain, and irreversible damage to the body. But how do we go about treating RA or halting the progression of the body’s internal attack? To answer this, I reached out to Dr. Gary Firestein at UC San Diego, who is a leading expert in the molecular mechanisms driving rheumatoid arthritis and other autoimmune diseases.
RA Early Discoveries
When Dr. Firestein began his research career, RA was still poorly understood and often devastating. Around that time, individuals with RA had a reduced life expectancy of 5 to 10 years less than healthy individuals.
To combat this life-altering outcome and discover the underlying mechanisms of RA, Dr. Firestein first worked to measure joint proteins, more specifically cytokines, which are small signaling molecules that help regulate an immune response. What he found through his research changed the RA field. He was one of the first to map the profile of cytokines, which essentially measures and visualizes multiple cytokines and how they behave together. Through these studies, he discovered not only which cytokines were present in RA, but that cytokines are a driving factor in the disease itself. Dr. Firestein then hypothesized that treatments targeting the cytokines responsible for inflammation would improve the signs and symptoms of rheumatoid arthritis.
Today, this idea forms the foundation for many existing RA treatments like TNF inhibitors. TNF is a cytokine that drives inflammation, joint swelling, and cartilage damage. Blocking TNF could directly target these inflammatory pathways and improve patient outcomes. RA was once a debilitating disease, but now it can be controlled in most patients. “In fact, 85 to 95 percent of patients can achieve remission or low disease activity with the right treatment,” he notes.
New Discoveries
After the cytokine profiling, Dr. Firestein and his team discovered the role of fibroblasts, which are a type of cell that contributes to the formation of connective tissue, in RA. “They become aggressive, almost tumor-like,” he explains. And they are responsible for much of the joint damage.” This finding is significant as it shows that RA, an autoimmune-driven disease, actually involves multiple cell types that contribute to the inflammation and destruction.
His work also predominantly contributed to the idea of targeting intracellular signaling pathways, such as kinases. Previously, these approaches were thought of just as last-line cancer treatments due to the concerns of toxicity. However, this approach is effective in RA as well. “People thought blocking kinase could only be done in cancer,” he explains.
His latest work consists of observing the epigenetics associated with RA. Epigenetics is the study of how gene expression is regulated without actually altering the underlying DNA sequence itself. Furthermore, Dr. Firestein is working towards identifying the individual risk of developing RA even before symptoms arise.
Challenges of Drug Development
While Dr. Firestein played a critical role in identifying drug targets, he emphasized that translating those discoveries into a treatment can be a very complex process.
“The dream is to find a target, develop the drug, and test it. In real life, that integrated approach is difficult in the academic world where there is a conflict of interest and a need to separate yourself from commercialism,” he explains.
Academic researchers are best at coming up with ideas, hypothesizing, testing, and validating biological mechanisms. However, when it comes to drug development, the many resources and infrastructure required are typically outside of what universities can provide. As a result, many breakthroughs rely on partnerships with pharmaceutical companies. Dr. Frirestein has collaborated with industry and even co-founded a company to help bring therapies closer to patients.
Future of Medicine: Precision and Prevention
Despite all the progress and therapies developed, there still is an overarching challenge when it comes to treatment: Not all patients respond to the same treatments, even if their symptoms appear similar. “For example, Drug A with mechanism A, some might respond to; but Drug B with mechanism B, they might not respond,” Dr. Firestein explains. “Rheumatoid arthritis’ clinical phenotypes are the same, but the mechanisms can be different.”
He believes that the future is heading towards precision medicine, being able to tailor treatments based on a specific individual's body and specific disease. In addition to this, he also sees efforts in early diagnostics and prevention becoming a focus. If we can intervene early, we may be able to stop the disease before it starts.
What RA Patients Should Know
While scientific advancements continue, Dr. Firestein emphasizes the effectiveness of treatments that already exist and believes that patients should start taking advantage of them. “Taking advantage of biological evolution, TNF blockers, B-cell depleters, T cell blocking therapy, and other agents is important, and these can be very effective,” he suggests.
On top of therapies, lifestyle factors also play a role. Smoking, in particular, is a well-established risk factor that should be avoided, especially for those with higher risk or with active disease.
For patients already diagnosed, general health practices like maintaining a balanced diet, getting ample sleep, and managing stress can all be additional support. Mindfulness practices like meditation can also help with symptom management, although they are not substitutes for medical treatment.
Dr. Firestein also warns against over-reliance on certain mediation. “Steroids can help in the short term, but can have significant long-term risks.” Instead, he highlights methotrexate, which is a drug that has been used since the 1960’s and has been a prominent RA treatment, but the problem still stands. It is not effective for everyone, and about ⅔ of patients need to add a second medication.
Closing Thoughts
Seemingly minor symptoms, such as a stiff joint or small ache, can be easily overlooked. But as Dr. Firestein’s work has shown, RA is not just a disease in the joints, but a more complex disease involving immune signals, cells, and pathways that scientists are still working to fully understand. Yet, what was once a life-shortening illness has become a manageable disease through targeted therapies. Remission has become a real possibility.
Still, some challenges come with therapies, notably understanding which medicine to use in each patient. What the future holds is a rise of precision medicine to address unmet needs, as well as early prevention to stop the disease before it begins. Until then, the progress made serves as a reminder that even when the body might turn against itself, science can help fight back.†
Written by Staff Writer Lana Chuang (lachuang@ucsd.edu)
Work Cited
Firestein, Gary S. “Mechanisms of Disease N Engl J Med, Vol. 344, No. 12 · March 22, 2001 ·.” Nature Publishing Group, May 2003, www.columbia.edu/itc/hs/medical/pathophys/immunology/2004/misc/articles/NEJM_Rheum_arth-cytok.pdf.
Firestein, Gary S., and Beatrix Bartok. “Fibroblast-like Synoviocytes: Key Effector Cells in Rheumatoid Arthritis.” National Library of Medicine (NIH), Jan. 2010, pmc.ncbi.nlm.nih.gov/.
Ma, Xixi, and Shengqian Xu. “TNF Inhibitor Therapy for Rheumatoid Arthritis - PMC - NIH.” National Library of Medicine (NIH), 29 Nov. 2012, pmc.ncbi.nlm.nih.gov/articles/PMC3956207/.
Sidransky, Ellen. “Fibroblast.” National Human Genome Research Institute, 21 June 2026, www.genome.gov/genetics-glossary/Fibroblast.
Staff, CDC. “Epigenetics, Health, and Disease | Genomics and Your Health | CDC.” Epigenetics, Health, and Disease, 31 Jan. 2025, www.cdc.gov/genomics-and-health/epigenetics/index.html.
Staff, Mayo Clinic. “Rheumatoid Arthritis - Symptoms and Causes - Mayo Clinic.” Mayo Clinic, 9 Apr. 2025, www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648.
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