Dr. Ellen M. Gravallese In the Spotlight

Dr. Gravallese and Yukiko Maeda, PhD, instructor in medicine in the Gravallese laboratory, review data.

Robert Finberg, MD, chair of medicine at the University of Massachusetts (UMass) in Worcester, describes Ellen M. Gravallese, MD, as one of a dying breed: a quadruple-threat physician who excels in basic science research, clinical care, teaching and administration. Dr. Gravallese holds the Myles J. McDonough Chair in Rheuma­tology, is professor of medicine and serves as chief of the Division of Rheumatology at UMass Medical School. She began her exemplary career as an undergraduate in biochemistry at Harvard College, at which time she planned to concentrate on basic science research. An interest in understanding the mechanisms underlying disease and a desire to do work “that was clinically relevant and that, with luck, would help change the course of a disease” led her to medicine.

Below, Dr. Gravallese, who will serve as ACR president beginning in 2019, reflects on some of the important mentors and junctures in her career as a preeminent researcher in rheumatology and immunology.

Dr. Gravallese’s research opportunities included working as an undergraduate with mentor Guido Guidotti, PhD, Higgins Professor of Biochemistry, with whom she investigated red cell membrane proteins. She identified a red cell membrane anion channel during work on her senior honors thesis, work that caught the attention of H. Franklin Bunn, MD, the researcher at Brigham & Women’s Hospital who identified hemoglobin A1c as a glycosylated protein in diabetes. Dr. Bunn hired Dr. Gravallese to explore red cell membrane proteins to determine whether they, too, were glycosylated in diabetic patients. In collaboration with a hematology fellow, John Miller, MD, she published her first article in the Journal of Clinical Investigation as a medical student at Columbia University College of Physicians and Surgeons. Other important mentors would follow.

Routes to Rheumatology

As a medical student at Columbia, Dr. Gravallese developed a fascination with rheumatic diseases. Much of that fascination was thanks to Gary Hoffman, MD, her mentor during a rotation at Mary Imogene Bassett Hospital. Dr. Hoffman made major contributions to the field of vasculitis after joining the Vasculitis and Related Diseases Section at the National Institutes of Health, and is currently professor emeritus at the Center for Vasculitis Care and Research at the Cleveland Clinic.

Dr. Gravallese then began her internship in internal medicine at Brigham & Women’s Hospital in Boston. She had thought ultimately to combine anatomic pathology with basic science research, but patient contact in medicine, she realized, supplied a critical missing link. Her Pathology Department chair, the late Ramzi S. Cotran, PhD, the F.B. Mallory Professor of Pathology at Harvard, suggested a solution for combining her dual career interests. Renowned not just as a molecular scientist but also as an intuitive mentor, Dr. Cotran developed a joint residency in pathology and medicine for her, and at the end of that residency she became a diplomate in both specialties.

Interestingly, her course of study in path­ology linked her with Chief of Surgical Pathology Joseph Corson, MD, who for 30 years had collected autopsy specimens from patients with rheumatoid arthritis (RA). “In my spare time I went through all those autopsy slides,” she recalls. This resulted in her identification of rheumatoid aortitis as a clinically significant entity. This work was done in collaboration with another important mentor and close colleague in rheumatology, former ACR President Michael Weinblatt, MD.¹

Career Focus

Dr. Gravallese joined the Harvard Medical School faculty as an instructor, and by 2003 she was an associate professor of medicine. The work in her laboratory continued apace. Seminal work published in 1998 was the first milestone in understanding the structural damage that occurs in RA. Her initial observation, in collaboration with Steven Goldring, showed definitively the presence of osteoclasts at the pannus-bone interface in joints of RA patients.² A follow-on study from her group showed the critical link between receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoclastogenesis and bone erosion by inducing inflammatory arthritis in RANKL knockout mice, and demonstrating the mice were protected from articular bone loss.³

Since 2006 Dr. Gravallese has been a professor of medicine at UMass, attaining tenure in 2012. The following year she was named the Myles J. McDonough Chair in Rheumatology. In her laboratory, she has continued to focus on mechanisms of bone erosion and inhibition of bone repair.⁴ Her recently published clinical trial in RA, done in collaboration with Dan Solomon and Jonathan Kay, assessed the efficacy of intermittent parathyroid hormone therapy to promote healing of articular erosions.⁵ Current work in her laboratory seeks to understand the innate immune mechanisms that contribute to the onset, progression, persistence and regulation of sys­temic auto­immune disease.⁶

Dr. Gravallese’s myriad accomplishments include national and international visiting professorships, service on the Boards of Directors of the ACR and the Bone and Joint Decade, among other organizations, and an active role in administration and training of fellows at Harvard and UMass. She was elected to the Henry Kunkel Society, and in 2017, the American Society for Bone and Mineral Research honored her with the Stephen Krane Award for her research. The Arthritis Foundation has also honored Dr. Gravallese with the Marian Ropes Physician Achievement Award.

From 2012–13, Dr. Gravallese completed a fellowship with the Hedwig van Ameringen Executive Leadership in Academic Medicine (ELAM), a national program designed to prepare senior women faculty to move into positions of institutional leadership. She says that experience was invaluable in providing a better understanding of organizational structure and finance.

In addition to her full research, clinical and administrative calendar, Dr. Gravallese is now an associate editor of the New England Journal of Medicine, a post she is enjoying because of the exposure to cutting-edge work being done in clinical medicine. She keeps clinical duties in the mix, she says, “because I’ve always felt that was a major influence in all of my work.”

As discoveries about osteoclastogenesis and other pathways of inflammatory joint damage have led to new targets for intervention, Dr. Gravallese has been a major contributor to the paradigm shift in the treatment of rheumatic diseases. She reflects on the immense changes in the field, recalling that when she was a fellow, RA patients in clinic waiting rooms were often wheelchair bound. “When I show pictures of those patients to our fellows now, they are shocked,” she says. “We can pretty much avoid the crippling effects of RA now due to the research that’s been done by many investigators in the field over the past 15 years. It’s been very rewarding to be a part of the journey.”

Gretchen Henkel is a health and medical journalist based in California.

References

1. Gravallese EM, Corson JM, Coblyn JS, et al. Rheumatoid aortitis: A rarely recognized but clinically significant entity. Medicine (Baltimore). 1989 Mar;68(2):95–106.
2. Gravallese EM, Harada Y, Wang JT, et al. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1998 Apr;152(4):943–951.
3. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001 Nov;159(5):1689–1699.
4. Walsh NC, Reinwald S, Manning CA, et al. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res. 2009 Sep;24(9):1572–1585.
5. Solomon DH, Kay J, Duryea J, et al. Effects of teriparatide on joint erosions in rheumatoid arthritis: A randomized controlled trial. Arthritis Rheumatol. 2017 Sep;69(9):1741–1750.
6. Baum R, Sharma S, Carpenter S, et al. Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II deficient mice. J Immunol. 2015 Feb 1;194(3):873–877.