Novel Initiatives Address Complexities in Treating Rheumatic Diseases

Source: Brigham and Women's Hospital - On a Mission
Date: 12/04/2019
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There are many challenges to treating autoimmune diseases such as rheumatoid arthritis and lupus. Brigham and Women’s Hospital has recently undertaken a number of new initiatives to address some of these challenges and improve patient care.

“One of the biggest problems we see is lack of access, especially for more specialized rheumatology services,” said Susan Ritter, MD, PhD, associate medical director of the Brigham and Women’s Arthritis Center. “This is a larger issue in other parts of the country, where there are not enough providers to meet the needs of the population. However, it’s a problem even in Boston. We have a large number of providers, but there is so much demand.”

One project that the Brigham has undertaken to address this concern involves optimizing best practices for recurring functions in patient care. Through a pilot program, members of the rheumatology team—including physicians, nurses and medical assistants—took a closer look at common questions and requests from patients and identified ways to establish and enhance processes for meeting these needs.

“We focused on ways to improve best practices for 20 of the most common things that we do on a regular basis,” Dr. Ritter said. “For example: What do we do when a patient calls and has a question about medication? How do we optimize referrals for lab tests? We’ve created documentation to streamline all of these frequently occurring processes.”

Meeting Demands Through Education and Prioritization

Continuing medical education programs for primary care providers that focus on rheumatic diseases, offered through Harvard Medical School, are another important way the Brigham is meeting increasing demands in patient care. Patients stand to benefit significantly when primary care providers are educated on the initial steps needed for evaluation and management of these diseases as well as on the signs and symptoms that should prompt more urgent referrals to rheumatology specialists.

In diseases for which it’s vital for patients to see a specialist right away, the team at the Brigham has put systems in place to ensure those with more urgent needs are prioritized. “One example of this is giant cell arteritis, where it’s important that we get a biopsy within two weeks,” Dr. Ritter explained. “We’ve created a button right in our computer system that flags these patients in our system. It allows us to fast-track their care.”

Another recurring challenge is getting buy-in from insurance companies to approve some of the newer small molecule and biologic therapies. This is a particular concern in the treatment of rheumatoid arthritis because a number of medications are now available, but these drugs are expensive. When patients can benefit, however, it’s important that they start taking these medications as soon as possible to prevent the permanent damage to joints that can result from unresolved inflammation.

“When patients check in for their appointments, we give them iPads and they’re asked a series of questions about their medications and symptoms,” Dr. Ritter said. “We can use that data to show over time how well somebody is responding to a particular therapy. These data allow us to identify when the therapy isn’t working, so we know that we should try something different. All of this goes right into our electronic medical records and is also available within the clinic documentation.”

Dr. Ritter noted that this system has the added benefit of helping patients become more active in their own care by allowing them to see trends in their data. “We will be moving toward doing this for other rheumatic diseases,” she said. “It helps us to better care for our patients and to justify to the insurance companies the therapies that they need.”

High Volume Leads to Specialized Expertise

Because of the high volume of patients seen at the Brigham, individual rheumatologists can develop special areas of expertise in conditions that are not commonly seen at other centers. One emerging specialization is in immune-related adverse events caused by checkpoint inhibitors for cancer.

“We have several doctors who are specifically interested in seeing these patients,” Dr. Ritter said. “We work with the oncologists at the Dana-Farber Cancer Institute to make sure patients are seen quickly.” The goal of this collaboration is to optimize cancer care while managing the many immune-related adverse events from these drugs.

Another example of a team approach is in the treatment of Raynaud’s disease. A specialized clinic allows patients to see experts in rheumatology and cardiovascular disease on the same day. In addition, it enables physicians to collaborate and communicate with each other on treatment methods.

The Brigham also has experts with an interest in working with people who have lupus. “As part of our Lupus Center, we provide additional information to patients in the form of regular newsletters as well as other services,” Dr. Ritter said. “The health care system can be a challenge for people with lupus, many of whom come from disadvantaged backgrounds. We want to help them get the care they need.”

Research Adds to Arsenal of Treatments for Rheumatoid Arthritis

Source: Brigham and Women's Hospital - On a Mission
Date: 12/04/2019
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Beginning with methotrexate in the mid-1980s, clinical investigators at Brigham and Women’s Hospital have led the development of a number of drugs for treating rheumatoid arthritis (RA). Thanks to methotrexate and additional progress in the decades since it was approved, the majority of people with RA now experience effective disease management.

“I can confidently say that treatments for RA today are very effective and will continue to improve going forward,” said Elena M. Massarotti, MD, of the Brigham’s Division of Rheumatology, Inflammation and Immunity. “But there are still challenges to overcome.”

One of the biggest of these challenges is that despite effective therapies, 30 percent of patients are unable to achieve complete disease control. This reality drives the continued focus on research into the causes and drivers of RA and the search for additional drugs.

“About one-third of patients with RA go into remission with methotrexate alone,” said Michael E. Weinblatt, MD, co-director of clinical rheumatology and associate director of the Center for Arthritis and Joint Diseases at the Brigham. “Many more can achieve remission with the addition of other drugs. But we still have about 10 percent of patients with high disease activity, and another 20 percent with disease activity in the moderate range. Their disease has improved, but they’re not where we want them to be.”

Encouraging Signs

Other types of drugs that have greatly improved the treatment of RA by targeting the chronic inflammation that leads to the disease include inhibitors of tumor necrosis factor, inhibitors of IL-6, T cell costimulatory blocking agents, B cell depleting agents and new oral agents that block inflammation.

Controlling RA in a timely fashion is vital because structural damage caused by the inflammation progresses over time. “Fortunately, the need for surgery in people with RA is much less common than it was 15 or 20 years ago,” Dr. Massarotti said. “I’m sending fewer and fewer people for joint replacements. This is because the medical treatments have gotten so much better.”

The Brigham sees about 4,500 people with RA every year. This high volume gives its rheumatologists insights into what works as well as where further research is needed. A patient registry called the Brigham and Women’s Hospital RA Sequential Study (BRASS) also contributes to advances in clinical research for RA.

“We’ve enrolled about 1,500 patients in this registry,” Dr. Weinblatt said. “Some of them have been followed for more than 18 years. It’s greatly increased our understanding of the pathogenesis of the disease and of which factors are active in RA. It also allows us to study the side effects of these drugs.”

The registry serves as a clinical database and a sample repository. According to Dr. Weinblatt, more than 80 papers have come out of the BRASS dataset. In addition, the clinical data and samples are made available to investigators from all over the world who are studying RA.

The Search for Genetic Markers

One important goal of the Brigham’s RA team, along with RA investigators more broadly, is developing biomarkers to predict which people will respond to which therapies. “When a patient walks into the exam room, we have no idea which drug or drugs will be best for them,” Dr. Weinblatt said. “We would like to develop programs that can identify for each individual which treatments will work. This includes the search for genetic markers.”

“The Brigham has a long history of treating people with RA, even before methotrexate,” Dr. Massarotti said, referencing the institution’s status as the country’s first teaching hospital devoted to arthritis and other rheumatic diseases. “And we will continue to lead the way into the future.”

Genomic Research Connects Juvenile and Adult Forms of Arthritis

Source: Brigham and Women's Hospital - On a Mission
Date: 12/23/2019
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Traditionally, juvenile idiopathic arthritis (JIA) has been considered a distinct condition from the types of arthritis seen in adults. But increasingly, research is showing that juvenile and adult forms of arthritis represent a continuum.

“One of the central themes of my recent work has been pointing out the similarities between juvenile and adult forms of arthritis,” said Peter A. Nigrovic, MD, director of the Center for Adults with Pediatric Rheumatic Illness (CAPRI) at Brigham and Women’s Hospital. “The big picture is that these diseases are much more similar than they are different. I think the differences in nomenclature between the two types have been a hindrance rather than a help in understanding disease biology.”

Studying the Genetics of Arthritis

JIA is a blanket term that covers several different subtypes of arthritis. Like adult forms of the disease, it is characterized by symptoms that include pain and swelling of the joints, stiffness and, in systemic JIA, also rashes and fever. In some cases, it can also affect the eyes or internal organs. A case of arthritis is defined as “juvenile” if it appears before the age of 16. Once it develops, however, JIA can continue into adulthood.

At the Brigham, Dr. Nigrovic cares for adults who have JIA. He also sees children with the disease as an attending physician in the Boston Children’s Hospital rheumatology program. Some of his recent research has looked at the genetics of arthritis.

“One of the strongest pieces of evidence that these diseases are similar has to do in particular with the HLA locus on chromosome 6,” said Dr. Nigrovic, who also directs a lab that uses both human specimens and mouse models to study the basic immune mechanisms of arthritis and other rheumatic diseases. “Proteins encoded at this locus control how peptides are presented to T cells, including autoantigens that can trigger arthritis.”

He noted that the particular HLA genes that carry arthritis risk change with the type of arthritis, but are largely shared between adult-onset and childhood-onset forms of the disease. Risk genes outside of the HLA locus are also shared.

In a paper published in Nature Genetics in July 2018, Dr. Nigrovic and his team used a new technique termed SNP-seq to test thousands of candidate genetic variants linked to JIA risk by genome-wide association studies (GWAS). Through this work, they identified 148 candidate functional single nucleotide polymorphisms (fSNPs) that may modulate the binding of regulatory proteins. For fSNPs near the CD40 and STAT4 genes, they were able to confirm the fSNPs and identify specific transcription factors that likely modulate these genes differentially in individuals who carry protective gene variants compared with those who carry variants associated with enhanced disease risk.

“We believe that this approach will allow us to identify particular pathways that drive disease biology,” he said. “And we expect to find the same sets of pathways in children and adults.” He added that once these pathways are fully characterized, it could eventually enable the development of better targeted treatments for disease subtypes in both children and adults.

Developing a ‘Fingerprint’ Would Be Key

One of Dr. Nigrovic’s long-term goals is to identify drugs that would target pathways engaged by the new protein-DNA interactions identified in his lab. By understanding which variants each individual carries, it may be possible to develop a “fingerprint” that will help determine what treatments will be best for each individual with arthritis, irrespective of age of onset.

“We hope to use GWAS data to identify these common pathogenic pathways,” he said. “We’re not there yet, and we’ll need many patient samples to achieve this goal. But between the large volume of patients that we see—as well as our expertise in other related areas of research at both the Brigham and its related institutions—we are well-positioned to make important contributions in this field.”

Clinical and Basic Research from the Brigham Highlighted at Annual ACR Meeting

Source: Brigham and Women's Hospital - On a Mission
Date: 01/17/2020
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This November, members of Brigham and Women’s Hospital’s Division of Rheumatology, Inflammation and Immunity presented several groundbreaking studies at the American College of Rheumatology’s (ACR’s) annual meeting in Atlanta.

Among the work presented was clinical research examining avoidable health problems in Medicaid recipients with lupus and basic research focusing on single-cell analysis of immune cells from various autoimmune disease tissues.

Preventive Care in Low-Income Lupus Patients

The lupus study was led by investigator and clinician Candace H. Feldman, MD, MPH, ScD. She and her colleagues used billing claims data for Medicaid beneficiaries to look at vaccine-preventable illnesses for which lupus patients end up in the emergency room or hospital. They found a significant burden of acute care use for these conditions that could be prevented with vaccines.

Many lupus patients have difficulty accessing outpatient care, where most preventive services are provided. Obstacles include transportation problems, an inability to miss work due to financial constraints and a lack of childcare. Dr. Feldman noted that she and colleagues focused on conditions that would be potentially avoidable or whose harm or adverse events would be lessened through sustained access to high-quality outpatient care.

According to Dr. Feldman, studies have shown that lupus patients tend to have low rates for several vaccines, including human papillomavirus (HPV), influenza and pneumococcal disease. “Also, compared with the general population, people with lupus are more susceptible to infections both from the disease itself and from the medications that suppress their immune system and are more likely to have severe complications if they develop these infections,” she added.

One reason vaccines may be overlooked, Dr. Feldman explained, is that patients with complicated illnesses usually have a number of other things to discuss during clinic visits. She pointed out that a few studies, mostly case reports, have suggested that vaccines may be unsafe for people with autoimmune diseases like lupus, but stressed that larger studies have refuted these findings and confirmed that these non-live vaccines are both safe and efficacious for most patients with lupus.

“Another issue is that many people with lupus, especially younger patients, tend to get much of their primary care from rheumatologists. Yet rheumatologists may not be thinking about whether their patients need these vaccines or stock them in their clinics or be equipped to provide preventive care like pap tests,” Dr. Feldman said. “It’s important that rheumatologists be aware of these issues and talk to their patients about vaccinations and other forms of preventive care.”

Immune Cell Subtypes Across Many Inflammatory Diseases

The single-cell analysis study included an in-depth examination of immune cells from people with immune dysfunction, such as rheumatoid arthritis, lupus nephritis, ulcerative colitis, Crohn’s disease and interstitial lung disease. All samples were from human tissues and compared to tissues of the same type taken from noninflammatory or health samples.

“Traditional bulk RNA sequencing provides average quantifications of gene expression across different populations of cells. Recent advances of single-cell technologies have provided single-cell transcriptomics to unbiasedly uncover diverse immune cell populations from disease tissues,” said Fan Zhang, PhD, a computational biologist at the Brigham, Harvard Medical School and the Broad Institute of Harvard and MIT, who presented the work at ACR. “Single-cell analysis gives us a much higher resolution and allows us to quantify many finer immune subtypes and their contributions to disease pathogenesis in each individual sample.”

The data used in this study came from several publicly available datasets, including the single-cell data generated by the Accelerating Medicines Partnership RA/SLE consortium, which is funded by the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases and several pharmaceutical companies.

“Many researchers have done immunogenomics research with a focus on only a preselected cell type and one immune dysfunction disease,” Dr. Zhang said. “Something that was unique about our study was that we compared multiple immune cells from similar inflammatory diseases from different tissues and organs. Thus, there was obviously a computational challenge that required a lot of multidata integration as well as an understanding of immunology and rheumatology.”

The investigators identified 21 diverse cell-type populations across multiple tissue sources, including distinct subpopulations of myeloid cells, T cells, B cells and plasma cells.

“Our research showed what these diseases have in common and also what’s different about them,” Dr. Zhang said. “They suggested new approaches for common therapeutic drugs based on the shared inflammatory immune cells, which may be effective for a number of different autoimmune diseases. I think integration of computational biology and immunogenomics with the field of rheumatic diseases is promising and will generate new insights for drug discovery.”

Brigham and Women’s Hospital Rheumatologists Shine at ACR’S Annual Meeting

Source: Brigham and Women's Hospital - On a Mission
Date: 01/22/2020
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The Division of Rheumatology, Inflammation and Immunity at Brigham and Women’s Hospital was well-represented among the presenters, moderators and award recipients at the American College of Rheumatology’s (ACR’s) annual meeting, held in November in Atlanta.

The division had 117 accepted research abstracts, 39 oral presentations, 78 posters and 24 invited presenters and moderators.

“This is a meeting where rheumatologists and scientists from all over the globe come together to share ideas and make connections,” said Daniel Solomon, MD, MPH, chief of the Section of Clinical Sciences in the Division of Rheumatology, Inflammation and Immunity. “For a single institution to contribute such a considerable proportion of research at a single meeting is noteworthy.”

Experts from the Brigham presented significant research in disease areas such as lupus, vasculitis, psoriatic arthritis and ankylosing spondylitis, according to Dr. Solomon. Another important topic at the meeting was immunophenotyping for patients with rheumatic diseases. This effort aims to guide treatment decision-making and eventually develop more personalized therapies for different subsets of patients based on the subtypes of immune cells driving their disease.

A Number of Honors

Recently, two members of the division have taken on major leadership roles within the ACR. Ellen M. Gravallese, MD, who became chief of the Brigham’s Division of Rheumatology, Inflammation and Immunity in November, officially took up the mantle as the 83rd president of the ACR. Her term will run from November 2019 to November 2020. Meanwhile, Dr. Solomon was named editor-in-chief of Arthritis & Rheumatology, the major journal in American rheumatology.

At this year’s ACR annual meeting, members of the division were presented with several awards and appointed to leadership positions during the annual meeting, including:

Sarah Kim Chen, MD, MPH, received a Distinguished Fellow Award. Dr. Chen’s research focuses on the use of prescription opioids among patients with rheumatic diseases compared to people with other diseases, including hypertension.

Jonathan Scott Coblyn, MD, and Simon M. Helfgott, MD, were appointed ACR Masters. This prestigious designation honors members who have made outstanding contributions to the field of rheumatology through scholarly achievement and/or service to their patients, students and profession. Dr. Coblyn, whose research focuses primarily on rheumatoid arthritis, is director of clinical rheumatology and director of the Center for Arthritis and Joint Diseases. Dr. Helfgott’s research focuses on the medical treatment of rheumatoid arthritis and other inflammatory disorders.

Candace H. Feldman, MD, MPH, ScD, received the Mary Betty Stevens, MD, Young Investigator Prize for her research on systemic lupus erythematosus (SLE). Dr. Feldman is a clinician and epidemiologist who studies health care disparities, particularly in people with SLE. Read about her work here.

Maura Daly Iversen, MPH, DPT, ScD, received a Lifetime Achievement Award from the Association of Rheumatology Professionals, a division of the ACR. Dr. Iversen is a behavioral scientist and epidemiologist whose research focuses on clinical and translational trials of exercise to manage arthritis symptoms and reduce cardiovascular risk.

Katherine P. Liao, MD, MPH, received the Henry Kunkel Young Investigator Award, which recognizes physician-scientists aged 45 or younger who have made outstanding contributions to basic or clinical research in the field of rheumatology. Her lab is developing bioinformatics methods to study rheumatoid arthritis and the clinical and genetic factors that lead to outcomes such as cardiovascular disease and severe joint damage.

Beyond the awards given out at the ACR meeting, Sonali Parekh Desai, MD, MPH, also of the Division of Rheumatology, Inflammation and Immunity, was given the Donabedian Award in Quality and Safety from the American Public Health Association on November 5. Dr. Desai, medical director for ambulatory patient safety at the Brigham, is leading work to reduce diagnostic errors through an ambulatory safety net program focused on missed and delayed diagnosis of cancer.

“The Division of Rheumatology, Inflammation and Immunity continues to be one of the top-ranked programs in the United States,” Dr. Solomon said. “The members of the division demonstrate outstanding leadership throughout all aspects of the field, including clinical care, research, publishing and teaching.”