Dr. Firestein is director of the Clinical and Translational Research Institute and the dean and associate vice chancellor of translational medicine at UC San Diego. Dr. Firestein joined the faculty at UC San Diego School of Medicine as assistant professor of medicine in 1988. Four years later, he was recruited by Gensia, Inc. to be director of Immunology where he supervised drug discovery efforts focusing on the potential role of purines in inflammation. In 1996, he returned to UC San Diego where he served as chief of the Division of Rheumatology, Allergy and Immunology from 1998 until 2010.
Dr. Firestein's research interest focuses on the pathogenesis and treatment of rheumatoid arthritis. He was among the first to map the cytokine profile of RA and demonstrate the dominance of macrophage and fibroblast products. These studies played a pivotal role in the development of highly effective anti-TNF and other anti-cytokine therapies for RA. In 1998, Dr. Firestein received the Carol-Nachman Prize, which is an international award given for outstanding contributions to rheumatology research. In 2006 and 2009, he received the Arthritis Foundation Lee C. Howley Sr. Prize for Arthritis Research and the American College of Rheumatology Distinguished Investigator Award, respectively. Dr. Firestein received the Arthritis Foundation's Jane Wyman Humanitarian Award in 2010 for contributions to rheumatology. He has been elected to the American Society for Clinical Investigation and the Association of American Physicians.
Firestein has written more than 300 articles and chapters and has edited or written several books. He served as the Deputy Editor of Arthritis & Rheumatism and is currently the Editor-in-Chief of the Kelley and Firestein’s Textbook of Rheumatology. He was chairperson of the FDA Arthritis Advisory Committee and has served on the Board of Directors of the ACR Research and Education Foundation, the ACR Committee on Research, the Arthritis Foundation Research Committee, the board of directors of the Veteran's Medical Research Foundation and NIAMS Advisory Council. He currently serves on the American College of Rheumatology board of directors.
Areas of Expertise (7)
Metalloproteinase and Cytokine Gene Regulation
Lee C. Howley Sr. Prize for Arthritis Research
2016 Arthritis Foundation
Distinguished Alumnus Award
2012 Johns Hopkins Alumni Association
John Hokins University: M.D., School of Medicine
Harvard College: A.B.
- Clinical and Translational Research Institute (CTRI)
- FDA Arthritis Advisory Committee
Media Appearances (3)
Rheumatoid Arthritis and Huntington’s Disease May Share a Common Link
“We did not expect to find an overlap between rheumatoid arthritis and Huntington’s disease, but discovering the unexpected was the reason that we developed this technology,” Dr. Gary Firestein, a senior study investigator and dean and associate vice chancellor of translational medicine at the UCSD School of Medicine, said in a statement. “Now that we have uncovered this connection, we hope that it opens a door for treatment options for people living with either disease.”...
Joint resolution: A link between Huntington's disease and rheumatoid arthritis
The research team, led by senior author Gary S. Firestein, MD, dean and associate vice chancellor of translational medicine at UC San Diego School of Medicine, said the unexpected connection between RA and Huntington's disease opens up the possibility of new therapeutic targets and drugs for both conditions....
Disjointed: Cell differences may explain why rheumatoid arthritis varies by location
Not only are there distinct differences in key cellular processes and molecular signatures between rheumatoid arthritis (RA) and osteoarthritis (OA) but, more surprisingly, there are joint-specific differences in RA, report researchers. The findings help explain why drugs treating RA vary in effect and provide a potential new template for precisely targeting treatment for each and every ailing joint...
Firestein GS, McInnes IB
2017 Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics.
Ai R, Hammaker D, Boyle DL, Morgan R, Walsh AM, Fan S, Firestein GS, Wang W
2016 Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients.
Maeshima K, Stanford SM, Hammaker D, Sacchetti C, Zeng LF, Ai R, Zhang V, Boyle DL, Aleman Muench GR, Feng GS, Whitaker JW, Zhang ZY, Wang W, Bottini N, Firestein GS.
2016 The PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for PTPN11 overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in PTPN11 intron 1, which contained a glucocorticoid receptor–binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS. RA FLS stimulation with the glucocorticoid dexamethasone induced GR binding to the enhancer and PTPN11 expression. Glucocorticoid responsiveness of PTPN11 was significantly higher in RA FLS than OA FLS and required the differentially methylated CpGs for full enhancer function. SHP-2 expression was enriched in the RA synovial lining, and heterozygous Ptpn11 deletion in radioresistant or innate immune cells attenuated K/BxN serum transfer arthritis in mice. Treatment with SHP-2 inhibitor 11a-1 reduced RA FLS migration and responsiveness to TNF and IL-1β stimulation and reduced arthritis severity in mice. Our findings demonstrate how abnormal epigenetic regulation of a pathogenic gene determines FLS behavior and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for RA.
Ai R, Whitaker JW, Boyle DL, Tak PP, Gerlag DM, Wang W, Firestein GS