Focus Area: Inflammatory Arthritis (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis)
Building on advancements in the treatment of inflammatory arthritis such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, the Northwestern University Feinberg School of Medicine Division of Rheumatology continues its leadership role in this area by providing one-of-a-kind clinical practices, administering cutting-edge clinical trials, and conducting promising clinical and translational research and laboratory-based translational studies.
No other medical center in the Midwest can match the multitude of options that the Division of Rheumatology provides to patients with these conditions or the opportunities for scientific collaboration that translate into tangible results. Feinberg clinicians have been pioneers in creating unique clinical programs such as the first joint rheumatology-dermatology psoriatic arthritis clinic in the country. Eric M. Ruderman, MD, associate professor in rheumatology, established the clinic in 2002 to ensure that patients didn’t fall through the cracks between the two medical specialties best equipped to deal with the skin and joint manifestations of psoriatic arthritis.
“We recognized that by offering a coordinated approach to patient care with a rheumatologist and dermatologist working side by side, we could tailor therapy to address all aspects of psoriasis and psoriatic arthritis. No one else was offering this approach when we launched the clinical service,” says Ruderman, who partners with Feinberg dermatologist Prashant Singri, MD. “The clinic has since been replicated by at least two of the top 10 rheumatology programs nationwide.”
Working closely with the world-class Rehabilitation Institute of Chicago (RIC)—voted “No. 1 Rehabilitation Hospital in America” by U.S. News & World Report every year since 1991— Feinberg also provides synergistic services with RIC’s physiatry and physical and occupational therapy for patients with limited function or disability resulting from arthritis. Drs. Ruderman and Rowland W. Chang, a rehabilitative rheumatology specialist, direct the rheumatologic services of the RIC Arthritis Center, where Dr. Chang serves as principal investigator for the program’s arthritis research registry.
During the past decade, novel biologic therapies have revolutionized the management of rheumatoid arthritis for as many as 50 percent of patients. In large part due to Feinberg’s vast experience as a clinical trial site for all the major new biologics from etanercept (Enbrel®) to abatacept (Orencia®), the medical school’s rheumatology clinicians can not only more quickly offer patients choices not yet widely available, but also contribute to the development of breakthrough drugs based on hands-on experience in the clinical trial setting. Further expanding that knowledge to improve patient outcomes, Dr. Ruderman spearheads Feinberg’s participation in the Consortium of Rheumatology Researchers of North America, Inc. (CORRONA) registry, one of the largest clinical registries in the country that collects data from both physicians and patients. Formerly a board member, Dr. Ruderman now serves on CORRONA’s scientific advisory board.
From the Bird’s Eye View to the Molecular Level
Chronic inflammation and its role in arthritis presents several avenues for study, from the bird’s eye view of the epidemiologist to the microscopic perspective of the basic scientist. The varied interests of clinical and laboratory-based investigators in the Division of Rheumatology cover the gamut when it comes to improving care for patients with rheumatic conditions linked to inflammation.
Complementing the physical activity promotion research of Dr. Chang (see section on Physical Activity and Arthritis), Darcy S. Majka, MD, assistant professor of medicine, is investigating the relationship between physical activity and markers of inflammation such as high-sensitivity C-reactive protein (hs-CRP). One of Dr. Majka’s recently published studies looked at the potential influence of race and gender on this relationship; it yielded findings that suggest the association between moderate/vigorous physical activity and hs-CRP differs by race and gender. In addition, in ancillary studies sponsored by the National Institutes of Health’s National Heart, Lung, and Blood Institute and the Arthritis Foundation, Dr. Majka examines the relationship between autoimmunity and cardiovascular outcomes in two general population cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) Study and the Multi- Ethnic Study of Atherosclerosis (MESA).
Several Division of Rheumatology investigators are focusing on the mechanisms, such as chronically inflamed cells or macrophages, that fuel the development of rheumatoid arthritis. These cells resist apoptosis and don’t die as they should. By better understanding the biology of inflammation, researchers hope to translate their laboratory findings into improved clinical therapies. Exciting discoveries are coming from research groups led by Richard M. Pope, MD, Mabel Greene Myers Professor and chief of rheumatology; Harris R. Perlman, PhD, associate professor of medicine; Arthur M. Mandelin, MD, PhD, instructor of medicine; and Christian Stehlik, PhD, John P. Gallagher Research Professor of Rheumatology, to name a few.
In the basic science laboratory of Dr. Pope, researchers have identified the upregulation of the anti-apoptotic protein Flice Like Inhibitory Protein (Flip) during monocyte to macrophage differentiation that protects macrophages from programmed cell death. “Flip is a molecule that prevents cell suicide,” says Pope. “In animal studies we’ve found that if we knock out the gene in macrophages, this modification may offer some protection against an experimental model of rheumatoid arthritis and provides us with an important molecule to target.”
Additional studies being conducted by this group, led by Qi-Quan Huang, MD, research assistant professor of medicine, examine the mechanisms by which components of the inflamed joint lead to chronic, persistent inflammation. These studies focus on the role of Toll-like receptors, which under normal circumstances help defend against bacteria and viruses, but in rheumatoid arthritis these receptors recognize structures within the inflamed joint as danger signals resulting in exacerbation of the inflammatory process.
Looking for a novel way to halt and even reverse rheumatoid arthritis, Dr. Perlman has developed an imitation of a suicide molecule that floats undetected into overactive immune cells. The stealthy molecule mimics a critical molecule, Bim, which is low in rheumatoid arthritis immune cells. When injected in mice, the BH3 mimetic causes the cells to self-destruct, reducing joint swelling and bone destruction. These results offer the potential for a new, less toxic drug that could prevent disease progression.
Other investigator-initiated basic science translational studies include that of inflammatory arthritis specialist Dr. Mandelin. Joining Drs. Pope and Perlman in studying apoptosis and rheumatoid arthritis, his research focuses on the control of programmed cell death in rheumatoid arthritis fibroblasts.
Research assistant professor Shiva Shahrara, PhD, is exploring the role of the cytokine interleukin (IL)-17 in the pathogenesis of rheumatoid arthritis. Supported by an American College of Rheumatology Research and Education foundation grant, Dr. Shahrara’s work has already revealed the key role IL-17 plays in the chemotaxis of monocytes into the rheumatoid joint, which eventually leads to inflammation and joint destruction. She has also identified the cytokine’s effect in mediating angiogenesis in the rheumatoid arthritis joint, which has important implications for the development of new therapeutic targets.
Studying inflammation in general, Dr. Stehlik and his research team are working to delineate the molecular mechanisms of the inflammatory host defense and of chronic inflammatory disease. In particular, the Stehlik lab is studying the regulation of inflammasomes—protein platforms responsible for the secretion of bioactive IL-1 beta and IL-18 cytokines by macrophages. When appropriately activated, these inflammatory mediators can help ward off infection and promote wound repair. However, inappropriate activation and dysregulation an result in uncontrolled production of these two cytokines, which has been linked to inflammatory diseases, including inflammatory arthritis.
“Identifying how these inflammatory responses are regulated on the molecular level will help us understand the events leading to chronic inflammatory disease such as rheumatoid arthritis,” says Stehlik. “This knowledge is the first step in eventually providing us with the basis for developing novel and improved strategies to interfere with and ameliorate chronic inflammation.”