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The Forward View in Rheumatology
by Kimberly J. Retzlaff
Presentations at the 4th annual ACR/Arthritis Foundation (AF) Rheumatology Research Workshop—held May 4–5, 2012, in Denver—juxtaposed overarching themes of emerging science and career development. The research workshop is intended to support budding rheumatologists and scientific investigators, said Bruce Cronstein, MD, Paul R. Esserman professor of medicine, director of NYU-HHC Clinical and Translational Science Institute in New York City. The workshop “is oriented to science, but more so to career development,” he explained. “This is a unique group—many are recipients of early career development assistance. They are our future leaders and will be leading rheumatology in 15 to 20 years.”
“The workshop is especially relevant to research fellows and junior faculty members,” said Elana J. Bernstein, MD, a rheumatology fellow at the Hospital for Special Surgery and New York Presbyterian Hospital, New York, N.Y. “[The workshop] teaches you about starting a career in academic rheumatology and gives an overview of grant funding and exposure to research in different areas of rheumatology.”
Scientific presentations at the workshop covered hot topics such as stem cell research, ultrasound technology, and how the changing shape of the healthcare system affects patients with rheumatic disease. Career-focused presentations included grant funding—what’s out there and how to get it—landing a job, and time management.
Possibilities for Mesenchymal Stem Cells in OA
The work being done with adult mesenchymal stem cells (MSCs) has exciting therapeutic possibilities for osteoarthritis (OA), said Rocky Tuan, PhD, director of the Center for Cellular and Molecular Engineering and professor at the departments of orthopaedic surgery and bioengineering at the University of Pittsburgh. MSCs possess both tissue-building and tissue-regenerating properties. It is, therefore, theoretically possible to remake the entire joint structure—cartilage, ligament/tendon, bone, muscle, nerves, etc.—using MSCs, which are multipotent, Dr. Tuan said. “They can become, with some coaxing, all of these things.”
Dr. Tuan and his team are using MSCs to create cartilage and help regrow it in an animal model of posttraumatic OA. Using a bioreactor consisting of a vessel that spins on a central axis, they were able to grow cartilage with medium change and growth-factor supplementation. “At the end of the day, we got this 1.5-cm version 1.0 cartilage piece,” he said.
To test its clinical application, they used a mini-pig model and drilled out an 8-mm defect in the knee cartilage. After implanting a xenograft with human MSCs seeded within a nanofibrous scaffold, they saw significant cartilage repair at six months postimplantation. The team has since developed a supraphysiological impact-mediated cartilage-degeneration model to induce posttraumatic OA, and is in the process of testing the therapeutic value of the MSC constructs to repair this type of cartilage defect.
Using Ultrasound for Diagnosis
Advances in ultrasound technology now allow for an assessment of joint effusion, the extent of synovial proliferation, and cartilage changes in knee OA, said Anthony Reginato, PhD, MD, assistant professor of medicine in the division of rheumatology at The Alpert School of Medicine at Brown University in Providence, R.I. Ultrasound gives rheumatologists real-time information about tissue structure and damage, including joint inflammation, which can assist in developing treatment options, he said. A trend of the future is fusion imaging, in which ultrasound images are superimposed on CT and MRI images, and more recently, the application of elastography, for example.
Current uses of ultrasound in rheumatology include differentiating between synovitis or tenosynovitis and gout versus pseudo gout, more easily placing needles for fluid removal with bursae around the knee, helping with a final diagnosis of Achilles enthesis, or showing changes such as thickening of the tendon in subclinical entheseal involvement in psoriasis or other spondylarthropathies.
Pathogenesis of Spondylarthritis
Genetic research has uncovered clues to the pathogenesis of spondylarthritis (SA), said Robert Inman, MD, professor of medicine/immunology at Toronto Western Hospital in Ontario. Specifically, in genome-wide association studies (GWAS), there have been “a number of hits that pop up across the human genome, which is encouraging,” Dr. Inman said.
B27, which has dozens of subtypes, not all of which are associated with SA, is thought to affect disease expression and susceptibility in terms of earlier onset of disease, back pain, and increased inflammation. Research suggests that two additional genes, endoplasmic reticulum aminopeptidase (ERAP) 1 and ERAP-2, seem to be involved.
Dr. Inman and his team used gene silencing to suppress ERAP-1 in B-cell lines and found altered peptide presentation. “If you shut down ERAP, there is an accumulation of intracellular free heavy chains [in the cell] as well as at the cell surface,” Dr. Inman explained. Furthermore, the altered free heavy chain profile on the cell surface is associated with presentation of unusual long peptides, but only in cells expressing subtypes of B27 associated with ankylosing spondylitis (AS).
This is an important area to study at the moment, Dr. Inman said, “because this analysis is beginning to shed light on one of the oldest questions in clinical genetics research: How does HLA-B27 confer susceptibility to AS? Insights into altered peptide presentation that is associated with B27 and ERAP polymorphisms could actually define the molecular basis of AS in particular and immune response in general.”
New Therapeutic Targets in Scleroderma Research
In systemic sclerosis, treatment options focus on symptoms, such as calcium channel blockers or angiotensin-converting enzyme inhibitors for Raynaud’s phenomenon, methotrexate for skin problems, and glucocorticoids plus cyclophosphamide for interstitial lung disease. “We need to get from this current organ targeted approach and get toward a molecular targeted treatment, and to do that we have to understand more how the disease is happening,” according to Sandeep K. Agarwal, MD, PhD, assistant professor of medicine at Baylor College of Medicine in Houston.
A popular pathway that is being studied in scleroderma is the WNT and beta-catenin pathway. The WNT signaling pathway is disregulated in scleroderma patients, and WNT activation in the skin can increase dermal thickness. In an animal model, increasing nuclear beta-catenin leads to an increase in dermal fibrosis. These findings make WNT and beta-catenin “intriguing candidates for therapies down the road,” Dr. Agarwal said.
Cadherins, a family of adhesion molecules, may be another way to regulate these pathways, Dr. Agarwal said. Cad-11 plays a role in synovial inflammation, and in scleroderma, recent findings show that cad-11 expression is higher in scleroderma skin relative to controls. In addition, cad-11–deficient mice develop less lung and skin fibrosis than wild type mice in mouse models of tissue fibrosis.
“Cad-11 regulates TGF beta production and the epithelial to mesenchymal transition,” Dr. Agarwal said. “I think, and indeed we’re hoping, it’s another therapeutic target in scleroderma.”
Using Pharmacogenetics to Treat RA
There are no reliable genetic predictors of response to therapy in rheumatoid arthritis (RA), but there are some promising and interesting predictors according to Robert Plenge, MD, PhD, director of genetics and genomics in the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital in Boston. Dr. Plenge and his team found a statistically significant association between the response to anti–tumor necrosis factor (TNF) therapy and an RA risk allele at the PTPRC gene locus (rs10919563) based on qualitative endpoints of response to treatment using the European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score in 28 joints (delta-DAS28). An opportunity for future research is to define disease activity more quantitatively and to use novel approaches for gathering larger patient samples.
GWAS genotyping is helping researchers make strides in this arena because it allows the sample size to be greatly increased—up to 8 million single-nucleotide polymorphisms (SNPs). The disadvantage is that the sample becomes more heterogeneous. The future likely will include incorporating polygenic models and using electronic medical record (EMR) data to create virtual cohorts, Dr. Plenge said.
“One major limitation [of current research models] is we don’t use the human as a model organism enough,” Dr. Plenge said. “We don’t have integrated clinics that involve investigation across disciplines. We need to think about ways to integrate and bring these silos together. As we begin to do this, we can actually find better biomarker predictors.”
Health System as a Risk Factor in RA and SLE
At hospitals with a clinic specific for vulnerable populations (e.g., with translators, physicians experienced with other cultures), there is less disparity in the outcome of RA, according to Edward Yelin, PhD, professor in residence of medicine and health policy in the division of rheumatology and Institute for Health Policy Studies at the University of California, San Francisco. For the future, Dr. Yelin said, “We need to figure out what it is about clinics devoted to the vulnerable that reduces the disparities in outcomes.”
Current trends toward increased cost sharing in health insurance are affecting patients with rheumatic diseases disproportionately, Dr. Yelin said. There is increasing prevalence of uninsured and underinsured people across the nation, and the way the U.S. healthcare system is organized has direct effects on people who have RA or systemic lupus erythematosus (SLE). Because RA and SLE are not “mortal” diseases, patients are more likely to go without care because of the costs.
Other trends indicate that Medicaid patients travel more than twice as far to get care for SLE, patients who live in areas of poverty or who have lower levels of education see their physicians 20% less, and uninsured patients have a substantially lower pass rate for quality indicators. Poverty variables are correlated to a higher incidence of clinical depression in patients with SLE. Those with lower education levels, who are immigrants, or who are Asian or Hispanic are more likely to report communication issues with their physicians, which is correlated with worse outcomes in RA.
The Truth about Study Sections
Many grant applicants may envision the study section panel as an angry mob, replete with torches and pitchforks. This is not actually the case, Dr. Cronstein said. Rather, the panels are composed of members who make “a very honest effort to get to the essence of what you’re trying to do … and decide whether it makes any sense.”
When the study section convenes, discussions include an overview of the proposal and rationale, the potential impact on the field, and the researchers’ approach and qualifications. “As junior investigators, we give you a lot of slack because there is an appreciation that we need another generation of people doing this,” Dr. Cronstein said.
Although the process is primarily fair overall, there are some nonfinancial conflicts of interest in grant evaluation. Some examples include disciplinary conflicts (i.e., bias against other disciplines), as well as personal rivalries and cronyism, which are fairly uncommon.
When the reviewers reach their consensus, the group votes to assign a score. Those who disagree can voice their dissent, but they have to do so publicly and with explanation. When the applicant gets the review back—online access to scores is available within about a week of when the study section meets and the “pink sheets” are sent about six to eight weeks later—the discussion characterizes the main points that ultimately came out in the review.
Launching an Academic Career
The ability to obtain grant funding is an important part of landing a faculty position. Institutions are more likely to provide matching funds for researchers who already have grants, said S. Louis Bridges, Jr., MD, PhD, Harbert-Ball Professor of Medicine and director of the division of clinical immunology and rheumatology at the University of Alabama at Birmingham. Although the dollar amounts of salary or start-up funds are important, he said, other factors weigh heavily.
“At one place, the start-up package may have more dollars but not infrastructure or personnel to support career development, where another offer may be better because of collaborators and core facilities,” Dr. Bridges explained. “It’s not the monetary amount so much as what the monetary amount will provide you with.”
To help land a faculty position, it is important to publish—a signature paper and at least one additional paper—said William Robinson, MD, VA Palo Alto Health Care System, Palo Alto, Calif., and associate professor at Stanford University School of Medicine in Stanford, Calif. He stresses the need to create a research niche, which establishes visibility and leadership, and to foster collaboration because “translational research takes a village.”
Jason Jungsik Song, MD, associate professor at Yonsei University, Korea (South), collaborated with other researchers on protein in coagulation and inflammation and to translate the mouse data on the mechanism of autoimmune disease into human disease. Dr. Song believes obtaining K08 funding is a team process. He obtained National Institutes of Health (NIH) K08 funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) after a second submission. “It was a very painful process, but I learned a lot about research grant applications,” he said.
Veena Ranganath, MD, MS, assistant clinical professor at UCLA Rheumatology at the University of California, Los Angeles, who obtained NIH K23 funding from NIAMS, believes that working with a statistician early in the process can help determine whether a study proposal is feasible. Dr. Ranganath also believes having the support of a strong mentorship team is a necessity for success.
Fostering a synergistic relationship with a mentor (or mentors) is an essential ingredient for optimizing a research environment and launching an academic career, Dr. Robinson said. Another key ingredient is persistence. Rejection in academics is a near-daily occurrence, Dr. Robinson said. “You have to brush it off and soldier on. … Savor the successes when they come.”
In addition to learning from colleagues about research and academics, it can be helpful to learn time-management skills from those who do well at prioritizing. M. Elaine Husni, MD, MPH, department vice chair and director of the arthritis and musculoskeletal center at the orthopedic and rheumatologic institute at the Cleveland Clinic, suggests speaking with colleagues who are good time managers—not the ones who are at work until 8 p.m. every night, but those who leave at a reasonable hour, have kids, and are doing productive research—to learn tips for organization and prioritization. Establishing effective time-management skills can improve productivity and ultimately reduce (or eliminate) stress, she said.
To improve prioritization skills, Dr. Husni recommends a variety of methods, such as Stephen Covey’s four-quadrant model or developing a conditioned response model. By setting goals and sharing them with family members, for example, everyone can celebrate when the goals are met with a special reward, such as dinner out at a favorite restaurant. To help stymie procrastination, Dr. Husni suggests the 10-minute rule: spend 10 minutes every day focused solely on the most “onerous task.”
“There are all these creative ways [to manage time effectively],” Dr. Husni said. “So just go out there and find the one that works best for you.”
Kimberly Retzlaff is a medical journalist based in Denver.