U.S. News evaluated nearly 4,500 hospitals in 14 specialties. Hospital performance was assessed based on various measures, including patient outcomes, level of nursing care, patient-reported experience, and available technology such as computer-assisted orthopedic surgery. The methodology factored in data from the Centers for Medicare & Medicaid Services, professional organizations, and medical specialists.

“We are proud to once again be recognized as a leader in orthopedics and rheumatology,” said HSS President and CEO Bryan T. Kelly, MD, MBA. “This distinction reflects the extraordinary expertise, dedication, and collaboration of the entire HSS team. For patients across the New York metropolitan region, it is also a powerful validation that the best orthopedic care in the country is available right here in their community. Through comprehensive musculoskeletal care, we help patients preserve mobility, enhance their quality of life, and extend their healthspan so they can continue doing what they need and love to do.”

“This recognition from U.S. News reflects HSS’s unwavering commitment to advancing musculoskeletal health through clinical excellence, innovation, and patient-centered care,” said Douglas E. Padgett, MD, surgeon-in-chief and medical director of HSS. “Perhaps the greatest measure of our impact is the trust of patients who travel to HSS from across the country and around the world seeking care have placed in us. This distinction reflects our dedication to achieving exceptional outcomes and our belief that preserving movement is the foundation of longevity and quality of life.”

Patients come to HSS from all 50 states and more than 100 countries, often for both common and complex medical conditions or challenging surgeries requiring highly specialized care. As a global destination for orthopedic and rheumatologic care, HSS brings together world-renowned physicians, advanced treatment approaches, and multidisciplinary teams dedicated to delivering personalized, evidence-based care for patients of all ages and activity levels.

“Our rankings reflect the extraordinary expertise, dedication, and innovation of the physicians, scientists, researchers, and care teams who make HSS a leader in rheumatology,” said Anca D. Askanase, MD, MPH, Chair of the Department of Medicine and Chief of the Division of Rheumatology at HSS. “Through groundbreaking research, advanced therapies, and highly personalized care, we are helping to transform the lives of patients living with complex autoimmune and inflammatory diseases.”

“The pace of discovery in musculoskeletal medicine is accelerating at an unprecedented rate,” said Joel Press, MD, Physiatrist-in-Chief at HSS. “Advances in artificial intelligence, data science, and precision medicine are helping researchers uncover new insights faster and translate those discoveries into more effective, personalized care. With HSS’s singular focus on musculoskeletal health and unmatched depth of clinical expertise, we are uniquely positioned to turn innovation into meaningful improvements in outcomes for patients everywhere.”

As the world’s leading academic medical center specializing in musculoskeletal health, HSS maintains among the lowest hospital readmission rates for orthopedics in the nation, and among the lowest rates for infection and complications. HSS is the worlds most awarded hospital in orthopedics by Newsweek each year since the “World’s Best Specialized Hospitals” survey was introduced in 2020.

In 2025, HSS clinicians and surgeons provided specialized care to more than 258,016 patients with orthopedic or rheumatologic conditions, such as pain or injury to the back, neck, or joints; osteoarthritis; rheumatoid arthritis; lupus; scleroderma; and psoriatic arthritis. HSS performed more than 45,864 orthopedic surgical procedures in 2025.

HSS is the official hospital of and provides team physicians to more than 25 high-performing sports teams and leagues, including the New York Giants, New York Knicks, New York Liberty, Brooklyn Nets, New York Mets, New York Red Bulls, TCS New York City Marathon, National Basketball Players Association, Major League Pickleball, US Youth Soccer, and UFC. It is designated a Medical Center of Excellence by Fédération Internationale de Football Association (FIFA).

The study, published in Science Translational Medicine, reveals that a subset of immune cells known as SPP1ʰⁱ macrophages work in tandem with structural cells and protein scaffolds to promote excessive tissue expansion in the joints of patients with RA.

RA is a chronic autoimmune disease that causes inflammation of the synovium—the tissue lining the joints—leading to pain, swelling, and eventual damage to cartilage and bone. While current therapies largely focus on controlling inflammation, the mechanisms that drive the abnormal growth of synovial tissue—and its invasive portion, known as pannus, which erodes cartilage and bone—have remained poorly understood.

A New Model of Tissue Growth in RA

Using advanced spatial transcriptomics to analyze human tissue samples, the HSS research team discovered that SPP1ʰⁱmacrophages cluster within fibrin-rich niches in the synovium. Fibrin, a protein typically involved in blood clotting and wound healing, appears to act as a temporary scaffold that supports new tissue formation.

Within these niches, the macrophages were found to:

• break down fibrin scaffolds through enzymatic activity and cellular uptake;
• stimulate nearby fibroblasts, key structural cells, to proliferate; and
• promote tissue remodeling and expansion independent of traditional inflammatory pathways.

“This work suggests that rheumatoid arthritis is not only driven by inflammation, but also by dysregulated tissue repair processes,” said Laura Donlin, PhD, senior author and scientist at the HSS Research Institute. “We are seeing a coordinated interaction between immune cells, structural cells, and the extracellular matrix that fuels abnormal growth.”

Beyond Fibrosis: A Distinct Pathway

Interestingly, while SPP1ʰⁱmacrophages resemble cells involved in fibrotic diseases such as lung or liver fibrosis, the RA tissue environment lacks the dense collagen buildup characteristic of fibrosis. Instead, the researchers describe this process as “pro-generative” tissue remodeling, more closely resembling wound healing gone awry.

Therapeutic Implications

The findings also suggest that targeting SPP1ʰⁱmacrophages and their signaling pathways could represent a new therapeutic approach. The study highlights the role of IL-6 signaling in sustaining these cells, offering further insight into why IL-6–targeting therapies, already used in RA, may be particularly effective in certain patient populations.

“Current treatments focus on suppressing inflammation, but our findings point to additional pathways that drive disease progression,” said Dr. Donlin. “Targeting these tissue remodeling processes could open the door to more precise and effective therapies.”

Broader Impact

The study’s findings may extend beyond RA. Similar immune cell populations and fibrin-based remodeling processes have been implicated in other conditions, including interstitial lung disease, lupus, cancer, and traumatic injury, suggesting a broader role for this pathway in human disease.

RA is a chronic disease characterized by inflammation in the synovium, the tissue that covers the inner surface of the joint cavity. Although usually accompanied by joint pain, swelling and deterioration, the level of inflammation varies from patient to patient, potentially requiring customized treatment plans. “What is surprising to us is that there are some patients who have clinical remission, yet continue to experience pain and show radiographic progression of the disease with high levels of synovial inflammation, while others have high disease activity with many swollen and tender joints and little inflammation in the synovial tissue” said Susan M. Goodman, MD, rheumatologist at HSS and principal investigator of the study. She explained that even when standard tests suggest the disease is under control, the joint fluid can still show high levels of inflammation. “By analyzing synovial fluid characteristics, we expected it might give us some insight into the disparity between disease progression and apparent remission,” she added.

The team analyzed samples from 64 patients with RA, 90.6% of whom were women, and with a median age of 65.3 ±11.7 years. The physicians collected synovial fluid samples to analyze and compare with the synovial tissue biopsy counterpart, which defines the inflammatory profile of the disease.

Dr. Goodman and the team measured the total white blood cell count, as well as the percentage of neutrophils, lymphocytes and monocytes in each synovial fluid sample. They then compared those findings to two additional key pieces of clinical information: the patient’s disease activity (such as joint swelling, pain, etc.) and the level of inflammation seen in the tissue.

Their analysis revealed that the total white blood cell count in the synovial fluid did not correlate with disease activity, however, the counting of individual cell types gave insights into tissue inflammation. As such, a higher percentage of neutrophils was associated with increased inflammation in the tissue, while a higher percentage of monocytes was associated with lower inflammation in the tissue.

Because the white blood cell counts in synovial fluid provided distinct and different information from standard disease activity measures and correlated well with tissue inflammation, the team believes it could help guide the selection of personalized anti-inflammatory therapies more efficiently.

“Synovial fluid extraction is already a routine part of care, but until now, it has never been used to analyze disease state in this way,” explained Dr. Goodman. In other words, the approach could be adopted without placing additional burden on healthcare providers.

"It's important that we're gaining new methods of investigating patients with RA,” Dr. Goodman added, “since choosing the appropriate therapy and choosing it in an efficient way is clearly the best way to achieve the best outcomes.”

According to Dr. Goodman, the next phase of this study, led by HSS rheumatologists Melanie H. Smith, MD, MPH, and Dana Orange, MD, MS, will look at both the proteomics and genetics of the cells within the fluid with more molecular and immunologic techniques, with the goal of finding even more clinically relevant and important information.

Poster details

Title: Can synovial fluid features be used to predict synovial tissue pathotype?

Authors: Susan M. Goodman, Michael Parides, Solana Cushing, Daniel Ramirez, Edward DiCarlo, Rebecca B. Blank, Laura Donlin, Anna Helena Jonsson, Amit Lakhanpal, Bella Mehta, Dana Orange, Melanie Smith.

Abstract n°: 2057

Presentation: June 12^th, 2025. 2:45 PM CEST

Scleroderma affects approximately 300,000 people in the U.S., with about one-third developing systemic disease, which can affect major organs such as the lungs, kidneys or heart. Women are four times more likely than men to be diagnosed with the disease, but until now, the underlying reason for this gender disparity had remained elusive. 

In one study, a team of researchers led by Franck Barrat, PhD, found that two genetic receptors called TLR7 and TLR8, which are present on the X chromosome, are important drivers for the activation of plasmacytoid dendritic cells (pDCs), fueling chronic fibrosis. pDCs are immune cells found in fibrotic skin but not in healthy skin and have previously been shown to contribute to scleroderma. 

In healthy cells, one X chromosome is typically deactivated, however, the study revealed that in patients with scleroderma, this process is disrupted due to the ability of TLR7 and TLR8 to escape X chromosome deactivation in pDCs. 
"The magnitude of this escape was striking," says Dr. Barrat. 

In healthy individuals, 10 to 15 percent of cells can evade the deactivation process. But in scleroderma patients, the escape occurred in more than 35 percent of the pDCs. This was a significant and unexpected difference. 

“The expression of two copies of the TLR7 and TLR8 in such a large number of cells can very well explain the chronic activation of these immune cells and why this disease is so prevalent in female patients,” concludes Dr. Barrat. 

In a separate study, armed with insights about the role of pDCs in driving fibrosis, Dr. Barrat and colleagues set out to understand why the body’s natural mechanisms fail to shut down inflammation in scleroderma patients. Normally, following a wound in the skin, immune cells infiltrate the skin and trigger an inflammatory response until the scarring process begins. A pause signal is then delivered to the immune cells to resolve the inflammation. But in scleroderma patients, this process stalls. 

The culprit? A cytokine (a type of protein that helps control inflammation in the body) called CXCL4, which researchers found to be highly expressed in the skin of scleroderma patients. Instead of allowing inflammation to subside, CXCL4 prevents immune suppression, keeping pDCs in a state of chronic activation and promoting skin fibrosis. 

“We show that CXCL4 prevents the normal termination of the immune response in the skin,” explains Dr. Barrat. “Basically, the pDCs are attracted by the fibrosis, but instead of being suppressed as they should be, CXCL4 keeps them active, in turn contributing to the cycle of fibrosis in these patients.” 

While there is currently no cure for scleroderma, the research highlights the potential of several therapeutic strategies. 
“This body of research makes a very strong case for exploring drugs that target and interfere with pDCs. There are already drugs in development that we can try,” says Dr. Barrat, noting that several therapies in clinical trials have shown promise in blocking pDCs and preventing skin lesions in patients with lupus. 

Both new studies were a collaborative work. Co-authors from the first study include Dr. Jean-Charles Guéry, PhD, of the University of Toulouse, as well as clinicians from the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS and investigators from the HSS Research Institute. Co-authors from the second study include investigators from the HSS Research Institute; the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS; Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, INSERM, France; Institut Cochin, Université Paris Cité, INSERM, France; and ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, France. 

“This is a new approach to understanding how we might maintain bone strength by affecting the committed precursor cells that are responsible for a lot of the damage and destruction that happens in bone, either in joints or generally in osteoporosis,” said Richard Bockman, MD, PhD, endocrinologist at HSS and co-author of the study. “This study also revealed a new target for managing bone health in metabolic bone and many orthopedic disorders.”

Osteoporosis, which affects approximately 10 million people aged 50 and older in the United States, is characterized by low bone mass and weakened bones. It is known as a “silent disease” because it doesn’t cause symptoms. “People don’t usually find out until they experience a fracture, at which point the bone is already gone, Thus, identifying an individual at high risk is really needed to prevent these adverse events.” said Kyung Hyun Park-Min, PhD, scientist, Arthritis and Tissue Degeneration Program at HSS, and a lead author of the paper.

Bone is constantly being remodeled through a process of resorption, in which old bone tissue is removed by osteoclasts, and formation, in which the old bone tissue is replaced with new tissue created by cells called osteoblasts; bone begins to weaken when bone resorption exceeds bone formation. Circulating osteoclast precursor cells exacerbate bone resorption and loss by traveling through the bloodstream to the bones, where they fuse with resident osteoclasts.

In collaboration with HSS Endocrinology & Metabolic Bone Service, Drs. Park-Min and Bockman recruited 44 postmenopausal women, 16 of whom had untreated osteoporosis. Nine of the women had normal bone density and 19 had osteopenia (low bone mass). Blood tests were used to measure the quantity of cOCPs in the participants’ blood. The women with osteoporosis had significantly higher levels of cOCPs than those with normal bone density.

While the study sample was small and came from one center, the findings have implications for screening and treating osteoporosis.

Currently, bone density is measured by the DEXA scan, which is costly and typically only performed only every two years in older populations.

“The advantage of determining cOCPs is that it may identify individuals at high risk who may not yet have osteoporosis but have low bone density,” says Dr. Park-Min. “If we can identify these individuals before they suffer a fracture, we can recommend treatment options to promote healthy bones. Additionally, compared to current screening methods, detecting cOCPs through a simple blood test would be economically effective.”

The study also points to the significance of circulating cOCPs in joint replacement surgery outcomes.  

“One potential complication of joint replacements is subsidence, or aseptic loosening,” Dr. Bockman said. “When this happens, it often necessitates surgical revision after arthroplasty.”

Dr. Park-Min’s team, in collaboration with the Complex Joint Reconstruction Center at HSS, is currently conducting research to determine the association between cOCPs and the incidence of aseptic loosening. “High osteoclast activity is one of the main factors contributing to aseptic loosening,” Dr. Park-Min said. “If we can detect changes in osteoclast activity after surgery, we can identify patients who are at risk for poor surgical outcomes. By identifying and targeting committed precursor cells, we may be able to improve surgery outcomes.”

Hospital for Special Surgery (HSS), one of the leading centers in the United States providing care for adults and children with APS, is the lead coordinating center for APS ACTION, an international research network of 47academic institutions dedicated to advancing the understanding and management of APS. APS ACTION conducts large, multicenter clinical studies and trials in patients with positive antiphospholipid antibodies (aPL). 

APS is a systemic autoimmune disorder characterized by the production of aPL, which attacks proteins binding the cell walls of blood cells located on the inner layer of veins and arteries. APS increases the risk of dangerous blood clots, strokes, heart attacks and pregnancy complications. 

APS ACTION created the APS ACTION Clinical Database and Repository (APS ACTION Registry) to study the natural course of disease in patients with persistently positive aPL, with or without other systemic autoimmune diseases. Investigators worldwide collect blood samples and clinical data annually and follow patients for at least 10 years. As of November 2023, the registry included samples and data for about 1,200 patients. 

“Since the registry began in 2010, APS ACTION investigators have published 32 studies in peer-reviewed journals and delivered 71 podium and poster presentations at international congresses,” said Doruk Erkan, MD, MPH, a physician-scientist at the Barbara Volker Center for Women and Rheumatic Diseases and rheumatologist at HSS. Dr. Erkan is also a founding member of APS ACTION and the current chair of its Executive Committee. “We are thrilled to see seven new APS ACTION studies presented at ACR Convergence 2024, which will further advance our understanding of APS and it’s complexities.” 

Three of These Studies Based on APS ACTION Registry Clinical Data: 

Antiphospholipid Antibody-related Clinical Manifestations Presenting During Childhood versus Adulthood: Descriptive Results from the APS ACTION Registry

Antiphospholipid syndrome (APS) in pediatric patients remains largely understudied due to the rarity of APS in children. This APS ACTION study investigates the initial presentation of antiphospholipid antibody-positive patients, and compares the clinical characteristics of pediatric- (0-17 year old) versus adult-(18-75 year-old) onset disease. Unlike adults who often experience vascular events such as blood clotting, pediatric-onset patients show a notably higher frequency of non-vascular events, such as autoimmune hemolytic anemia or autoimmune thrombocytopenia (low platelet counts), at the time of diagnosis. The findings reveal that autoimmune blood disorders are common in children with APS at diagnosis. This study is important for helping physicians diagnose APS in children, highlighting the need to pay closer attention to non-vascular events, which may be often overlooked as diagnostic features of APS.

Clinical and Biologic Predictors of Thrombosis in Persistently Antiphospholipid Antibody Positive Patients: Prospective Analysis of the APS ACTION Registry

While antiphospholipid antibodies increase the risk of thrombosis, it is important to note that many of the individuals who have them do not experience a blood clot in a given year. This research aims to identify which patients carrying these antibodies are a high risk for blood clotting. The findings reveal that a history of blood clotting and autoimmune blood disorders such as autoimmune hemolytic anemia or autoimmune thrombocytopenia (low platelet counts) approximately doubles the risk of experiencing a new clotting event in patients with these antibodies. This study helps physicians in determining which patients are at higher risk of thrombosis, enabling more targeted monitoring and management strategies.

Natural History and Clinical Implications of Lupus Autoantibodies in Primary Antiphospholipid Antibody Positive Patients: Results from the APS ACTION Registry

While antibodies play a crucial role in our immune defense against infection, autoantibodies – found in autoimmune diseases – can mistakenly target the body’s own cells and tissues, leading to inflammation and, in the case of antiphospholipid antibodies, an increased risk of blood clots. In this study, patients with antiphospholipid antibodies were tested for other autoantibodies that are typically linked to lupus. Although it is known that many lupus patients also have antiphospholipid antibodies, less is understood about whether patients with only antiphospholipid antibodies (but no lupus diagnosis) may also have lupus-related antibodies. This study found that the prevalence of lupus autoantibodies in these patients ranged from 0% to 18%, depending on the specific autoantibody type, with anti-dsDNA, ANA and anti-SSA being the most common, while anti-Sm antibodies were not present. Patients with both antiphospholipid and lupus autoantibodies were more likely to have certain autoimmune blood disorders (low platelet counts or anemia), or microvascular disease. This research points to an important subgroup of patients who may need careful monitoring for potential complications.

The study published August 29 in Nature Communications shows that artificial intelligence and machine learning technologies can effectively and efficiently subtype pathology samples from patients with RA.

For this study, Dr. Richard Bell, an Instructor in the HSS Research Institute and Arthritis and Tissue Degeneration Program, and Lionel B. Ivashkiv,  MD, Chief Scientific Officer at HSS teamed up with  Dr. Fei Wang, a professor of population health sciences and the founding director of the Institute of AI for Digital Health (AIDH) in the Department of Population Health Sciences at Weill Cornell Medicine. 

“Our study addresses the analytical bottleneck of pathology research,” Dr. Bell said. “It is very time-consuming and tedious.” “Our tool automates the analysis of pathology slides, which may one day lead to more precise and efficient disease diagnosis and personalized treatment for RA,” said Dr. Wang. “It shows that machine learning can potentially transform pathological assessment of many diseases.”

There are several existing machine learning tools for automatic analysis of pathology slides in oncology. Dr. Wang and his colleagues have been working to expand the use of this technology in other clinical specialties.

Digital Pathology and Precision Medicine in RA

Distinguishing between the three subtypes of RA may help clinicians choose which therapy is most likely to be effective for a particular patient. This personalized medicine approach would represent a breakthrough in the care of patients with RA, and is a major goal of the Research Institute and Division of Rheumatology at HSS, which involves multiple laboratory and clinical investigators. “It’s the first step towards more personalized RA care,” Dr. Bell said. “If you can build an algorithm that identifies a patient’s subtype, you’ll be able to get patients the treatments they need more quickly.”

 The technology may provide new insights into the disease by detecting unexpected tissue changes that humans might miss. By saving pathologists time on subtyping, the tool may also decrease the cost and increase the efficiency of clinical trials testing treatments for patients with different subtypes of RA. “This work represents an important advance in analyzing RA tissues that can be applied for the benefit of patients” Dr. Ivashkiv said.

 Pathologists currently manually classify arthritis subtypes using a rubric to identify cell and tissue characteristics in biopsy samples from human patients—a slow process that adds to the cost of research and may lead to inconsistencies between pathologists.

 The team first trained its algorithm on RA samples from one set of preclinical models, optimizing its ability to distinguish tissue and cell types in the sample and sort them by subtype. They validated the tool on a second set of samples. The tool also yielded new insights into treatment effects in the models, such as reduced cartilage degradation within six weeks of administering commonly used RA treatments.

Then, they deployed the tool on patient biopsy samples from the NIH-supported Accelerating Medicines Partnership Rheumatoid Arthritis research consortium, of which HSS is a major participating site in research led by Laura Donlin, PhD, scientist and co-director of the HSS Precision Medicine Program and rheumatologist Susan  M. Goodman, MD. The new digital pathology approach could effectively and efficiently type human clinical samples. The researchers are now validating the tool with additional patient samples and determining the best way to incorporate this new tool into pathologists’ workflows.

 The team is working to develop similar tools for evaluating osteoarthritis, disc degeneration and tendinopathy.

The research reported in this story was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the National Institute on Aging, all part of the National Institutes of Health, through grant numbers R21AR071670, R01AI175212, UH2AR067690, UC2AR081025, F30AG076326, T32GM007356, AR046713, AR050401, R01AR078268, UC2AR081025, UL1TR001866 and R01AR056702.

Loosening of joint implants, such as hips and knees, without infection or trauma is responsible for as many as 40 percent of failed joint replacements. In these cases, called aseptic loosening, scar tissue accumulates around the implant instead of the bone, preventing the new joint from regaining stability. Revision surgery to remove the original implant, clear the fibrosis and place a new prosthesis can correct the problem. However, avoiding a second operation, and the strain of additional recovery, would be a preferred option.

“Revision surgery is akin to pressing a ‘reset button’ on the cells in the patient’s body, in the hopes that this time the cells will correctly form bone around the implant rather than fibrous tissue,” said Vincentius (Jeremy) Suhardi, MD, PhD, an orthopedic surgical resident at HSS, and first author of the study.

 Using a preclinical model to simulate joint replacement surgeries in people, Suhardi and the team of investigators discovered that a group of cells involved in the production of new bone are also responsible for forming scar tissue around joint implants.

“We found that local bone progenitor cells, specifically leptin receptor-expressing cells, are necessary and sufficient for scar tissue formation around the implant that leads to aseptic loosening,” Dr. Suhardi said.

The researchers showed that the leptin receptor-expressing cells activate a gene/protein pathway called Adhesion G Protein-Coupled Receptor F5 (ADGRF5). They also found that blocking the ADGRF5 pathway with daily intra-articular injections of an antibody that inhibits the gene can both prevent fibrous tissue from forming and shrink existing fibrosis in the area of a joint implant. Blocking ADGRF5 in preclinical models also increased the formation of peri-implant bone.

“This finding for the first time opens up the possibility of treating aseptic loosening with a drug that inhibits ADGRF5,” Dr. Suhardi said. We are planning to collaborate with strategic partner to further develop this therapy and to test its efficacy not just in aseptic loosening but also in other orthopedic-related fibrotic pathologies.

Building on its established leadership in functional genomics research in autoimmune and musculoskeletal conditions, the aims of the next phase of the Rosensweig Center are to elevate precision medicine efforts through the application of “big data” approaches, explore how the dysregulation of certain immune cells drives autoimmune diseases, and understand how immune cells regulate musculoskeletal stem cell function—an emerging field known as immunoregeneration.

The overarching goals of this research are to enhance patient mobility and decrease pain by increasing clinicians’ ability to predict the best treatments for individual patients, and to discover transformative new therapies through enhanced understanding of disease mechanisms and modulating immune musculoskeletal cell crosstalk. The Rosensweig Center will continue to focus on diseases that are major causes of pain and disability in which HSS has a unique combination of clinical and research expertise: rheumatoid arthritis, scleroderma, lupus, osteoarthritis, and anterior cruciate ligament injury, as well as the pathological bone loss that occurs in osteoporosis, arthritis, and orthopedic implant loosening.

“We are honored to receive this extraordinary grant from The Tow Foundation to build upon our unparalleled knowledge, and extensive data sets and patient populations to conduct transformational new research with high impact and potential for translation to improved patient care,” said Lionel B. Ivashkiv, MD, Chief Scientific Officer and Director of the Rosensweig Center. “The expanded Rosensweig Center will harness HSS’s unique strengths by bringing together world-class scientists in the typically distinct areas of immunology and musculoskeletal biology, and by leveraging our genomics expertise together with the expertise of our collaborators in data analytics, AI/machine learning, advanced genomics technologies, and stem cell biology.”

“We’ve been incredibly impressed by the progress that Dr. Ivashkiv and his team have made in advancing cutting-edge genomics research since we first began our partnership over a decade ago,” said Emily Tow, President of The Foundation.  “We are pleased and proud to support the Rosensweig Center’s evolution as they continue to lead genomics research aimed at improving lives and are pleased that we can honor our dear friend David’s memory through this gift.”

“Orthopedic and rheumatologic conditions are the world’s leading cause of disability worldwide, and HSS has a special responsibility and opportunity to relieve their burden on people, businesses, and society as a whole,” said Bryan T. Kelly, MD, MBA, HSS President and CEO and Surgeon-in-Chief Emeritus.

“We are deeply grateful to The Tow Foundation for its incredible continued partnership as Dr. Ivashkiv and the Rosensweig Center team work to pioneer genomics research to accelerate the discovery of new treatment options to preserve the mobility and quality of life of patients here and across the globe.”

About The Tow Foundation

The Tow Foundation was established in 1988 by Leonard and Claire Tow as a way to give back to the communities that shaped them. Its five primary impact areas are equity and justice, medicine and public health, arts and culture, higher education, and civic engagement. Grounded in its decades of work in Connecticut and New York and based in New Canaan, CT, the foundation supports visionary leaders and nonprofit organizations to find and enact innovative solutions to persistent inequality. It works to ensure people can become full participants in their communities, achieve transformative and lasting progress, and develop approaches that allow everyone to reach their full potential. 

For a long time, physicians believed all bones formed in the same way – through a universal process of ossification. However, this study, led by primary investigator Matthew Greenblatt, MD, PhD, associate professor of pathology and laboratory medicine at Weill Cornell Medicine and assistant scientist in the HSS research division, alongside clinical collaborator Sravisht Iyer MD, spine surgeon at HSS, illuminated that certain vertebral skeletal stem cells play a unique and formative role in the development and life cycle of spinal vertebrae. Specifically, the investigators identified a stem cell that is responsible for bone formation in the vertebrae. Their research was made possible by support from a Pershing Square Foundation Cancer Research Prize and a special program established by the Anna-Maria and Stephen Kellen Foundation and Marina Kellen French, Vice President of the Foundation and an HSS trustee, that provides support for clinicians pursuing research as a significant component of their careers.

This significant finding carries profound implications for the field of spine health, including spinal healing, degeneration, treatment approaches, comprehension of degenerative spine disorders – and the potential to lead to breakthroughs in the prevention and treatment of vertebral osteoporosis and cancer metastasis.

“Understanding how vertebrae develop will help us more effectively treat patients, screen them before surgical intervention, and will ultimately lead to more effective preventive care and optimized bone health,” said Dr. Iyer. “The identification of this unique stem cell in the spine has the potential to significantly enhance our patients' outcomes in spine fusion surgery–a procedure performed hundreds of thousands of times in the United States each year–because it may allow for us to screen for problems ahead of time,” he continued. “The findings may also advance care for people with osteoporosis and, specifically, the 30 to 50 percent of the global population who suffer a vertebral fracture at some point in their lives.”

By manipulating bone-like “organoids” made from vertebral stem cells, this study also explored the disparities in metastasis rates between spinal bones and long bones, which include bones of the thigh, leg, arm and forearm. "Traditionally, it was believed that cancer cells were attracted to the spine due to directed blood flow. However, our discovery of this vertebral stem cell provides a likely explanation of why some cancers most often spread to the spine,” stated Dr. Greenblatt. “We predict this discovery will lead to the targeting of these cells to disrupt the function and ultimately reduce the spread of cancer to the spine."

The research team for this study included Jun Sun, PhD, first author and a postdoctoral associate at Weill Cornell; Kyle Morse, MD, an orthopedic surgery resident at HSS; and Lingling Hu, PhD, researcher at HSS, and has implications extending far beyond the laboratory and has the potential to impact patient care worldwide. Armed with insights into spine development and evolution, physicians will be able to tailor treatments and surgical intervention with more precision, with hope for improved patient outcomes across the board.

Physician-scientist Timothy B. Niewold, MD, FACR, Vice Chair for Research in the HSS Department of Medicine, recently received a nearly $4.2 million grant from the National Institutes of Health to learn more about the complex genetics that contribute to lupus. The ultimate goal of this research is to figure out how changes in certain regions of the genome affect the disease, with the hope of eventually understanding immune-related diseases more broadly.

Recently, Dr. Niewold spoke about his plans for this research project, including why he thinks probing the “dark matter” of the genome will lead to a better understanding of what causes lupus.

 What have you already learned through your research?

 Unfortunately, there are no simple answers to questions about which genes cause lupus and the ways in which they cause the disease to arise. We need to take a very broad look across the genome.

 In recent years, the wider scientific community has developed more advanced and high-throughput ways to study people’s whole genomes. In the lupus research community, we’ve come together to use that genomic data to create large registries that can help to ask broad questions about the causes of the disease.

 Thanks to those registries, we are able to compare the genomes of large numbers of people with lupus to large numbers of healthy controls — people who don’t have lupus. Then we can look at which areas of the genome are different between these two groups.

 What we have been able to learn so far is that there are certain regions of the genome where changes are clearly associated with an increased risk of lupus. Notably, many of these changes are found in a region that is often called the “dark matter” of the genome.

 What is the dark matter of the genome?

 When we talk about “genes,” we mean sections of genetic material that contain instructions for making specific proteins. We have about 20,000 genes, which carry the code for all the proteins that are needed to build a whole human being.

 But only about 1% of our genetic material contains genes that get directly made into proteins. The other 99% of our genetic material — the dark matter — has other functions. We are still learning what these are.

 One of the functions of dark matter we have been studying in the context of lupus is the production of molecules called long noncoding RNAs (lncRNAs). These RNAs do not get translated into proteins, but they perform many other jobs that help regulate how genes get transcribed and how proteins get made. Some lncRNAs can affect the immune system.

 What is the focus of your current project?

 We decided to focus on a region of chromosome 12 where we know people with lupus have a lot of variations. There aren’t a lot of genes in this area. But despite that, we expect to find that the genetic variations in these regions are doing something important. It’s likely they are leading to changes that ultimately affect how the immune system is controlled and regulated, including carrying instructions for lncRNAs.

 Although this project is focused on lupus, the big picture is also exciting. Studying how changes in the dark matter affect the immune system could apply to many other autoimmune diseases as well.

 What kinds of studies do you have planned?

 All of this research will be done in human cells. We will be using a registry created by the Feinstein Institutes for Medical Research, a research center on Long Island, as well as a registry at HSS. These registries contain samples from people with lupus and from healthy control subjects.

 Much of the work of this project will focus on samples from the healthy controls. That’s because we need to look at the basic principles of how lncRNAs are supposed to regulate the immune system before we can understand how this process goes wrong in a disease like lupus.

 We will also do work in cell lines. We plan to use CRISPR gene editing tools to study what happens to healthy cells when we remove sections of the dark matter that make lncRNAs. This work will be done with our collaborators at the University of Pittsburgh.

 In particular, we’ll focus on how changes in the dark matter affect certain types of immune cells, especially those that are important for detecting and eliminating infections. We know that both B cells and monocytes in particular are strongly implicated in lupus.

This is a five-year grant. Where do you hope to be with this work in 2028?

I think we’ll have a much better understanding of how the genetic material contained within the dark matter can touch a number of different parts of the immune system.

I’m also excited that we’ll be able to begin to build a roadmap of how different regions of the genome come together in different ways to result in lupus. This will help to inform our understanding of disease and could suggest possible

The Department of Defense has granted a three-year grant to study the proteins emitted from the skin that affect lymph nodes, the downstream immune tissues, while a two-year grant from the NIH will aid the investigation into non-protein molecules and changes of fibroblasts in lymph nodes. The team will do this by examining skin components including interstitial fluid.

“My lab is focused on understanding the pathogenesis of lupus. Lupus skin rashes affect the quality of life of patients and can be connected to systemic disease that can be life-threatening. Therapeutic options in lupus are limited, and it is important that we understand pathologic mechanisms so that we can develop better therapeutic options,” said lead investigator Theresa T. Lu, MD, PhD, from HSS Research Institute.

The grants and research will be executed at HSS Research Institute, the largest musculoskeletal research facility in the world.

About HSS Research Institute

HSS Research Institute is the largest musculoskeletal research facility in the world. With over 300 dedicated researchers and 20 laboratories, HSS Research Institute has been a leader in research aimed at improving the lives of patients suffering from debilitating orthopedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities.

In a study published September 9 in Science Immunology, the investigators outline what controls the cytokine storm by lung-infiltrating macrophages, as these cells are not efficiently infected by SARS-CoV-2.

Researchers found that an immune cell type, called plasmacytoid dendritic cells (pDCs), are infected by SARS-CoV-2 and produce interferons that can provoke epigenetic changes in the nearby macrophages in the lungs of patients. Hence, this priming of macrophages by interferons leads to their exacerbated response to environmental stimuli, inducing the cytokine storm in the lungs of COVID-19 patients.

This is surprising as interferons and pDCs have been demonstrated to protect patients infected by SARS-CoV-2 – but this new research uncovers that they can also provoke damaging cytokine storms.

“There is still a lot we don’t know about the pathogenesis of COVID-19, and why macrophages can produce these cytokine storms that can have such dramatic consequences for patients. We hope that this research will bring us closer to that understanding and will lead to better treatment options for patients with severe COVID-19,” said Dr. Franck J. Barrat (Michael R. Bloomberg Chair, Hospital for Special Surgery; Professor of Microbiology and Immunology, Weill Cornell Medicine).

This work was supported by a grant from the HSS Research Institute to study the role of pDCs in SARS-CoV-2 pathogenesis as well as grants from the National Institute of Health, the Scleroderma Research Foundation, the Scleroderma Foundation, the Starr Cancer Consortium, the Irma Hirschl Trust Research Award and The Tow Foundation.

COVID-19 is primarily a respiratory illness. Most individuals who become sick experience mild to moderate pulmonary symptoms, such as dry cough and shortness of breath lasting about six weeks. However, it has become increasingly clear that COVID-19 can have a significant impact on multiple body systems, most frequently the cardiac, musculoskeletal, gastrointestinal and hematologic systems.

For example, in addition to continued breathing difficulties, some patients experience extreme fatigue, irregular heart rhythms, inflammation of the heart muscle, muscle aches, gastrointestinal upset and blood clots. These symptoms have occurred even in previously healthy individuals and elite athletes who suffered mild to moderate COVID-19 and did not require hospitalization. Some individuals, called “long-haulers,” have lingering symptoms for weeks or even months after they clear infection by SARS-CoV-2, the virus that causes COVID-19.

“As sports medicine doctors we are always encouraging our patients to be active, but we realized that a one-size-fits-all plan for return to sport would not work well for those who had COVID-19,” said Jordan D. Metzl, MD, a sports medicine physician at HSS and lead author of the guidelines. “We’re excited to share this evidence-based framework to help recreational athletes resume activity safely.”

Dr. Metzl and five colleagues with experience treating recreational and professional athletes across various sports at the HSS Sports Medicine Institute created the new guidelines, published August 10, 2020, online in the HSS Journal.

According to the guidelines, patients who want to return to exercise should be aware that there is no typical recovery pattern after COVID-19. The severity of disease appears to affect the duration of recovery, but this has not yet been proven scientifically.

The guidelines recommend patients with COVID-19 should not resume exercise if they still have COVID-19 related symptoms. Those with an underlying cardiovascular or pulmonary condition should consult with their doctors before returning to any physical activity, even if COVID-19 symptoms have resolved.

Otherwise healthy patients who had mild or moderate COVID-19 and have not had symptoms for seven days may consider resuming physical activity by starting at 50 percent of their usual frequency and intensity. They should approach their return to exercise in a gradual, stepwise fashion, listen to their bodies, and speak with their healthcare providers if they develop chest pain, fever, palpitations or shortness of breath.

Physicians writing exercise prescriptions should take into account any symptoms affecting any of the involved body systems. They should carefully monitor patients who had respiratory symptoms. Patients with cardiac symptoms should rest for two to three weeks after symptoms resolve, except those with inflammation of the heart muscle (myocarditis), who should rest for three to six months and have their readiness to return to exercise confirmed with echocardiography, rhythm monitoring and exercise testing.

Patients with musculoskeletal issues can return to exercise after their symptoms resolve and gradually progress to normal activity levels. Low-intensity exercise and less time sitting may reduce the risk of blood clots in patients with mild clotting issues. Finally, fluid and calorie intake must be monitored carefully upon return to activity for patients who experienced gastrointestinal problems.

The guidelines are intended for recreational athletes of all ages. “I anticipate an increase in pediatric patients who will want to know when they can go back to organized sports after testing positive for COVID-19 as return to various forms of school and the availability of COVID-19 testing increases,” said guidelines co-author Kathryn McElheny, MD, a primary sports medicine specialist at the HSS Sports Medicine Institute who has a particular interest in the youth athlete. “These guidelines will serve as a useful tool for patient discussions and managing individual expectations for returning to play safely.”

“As a new disease, the landscape around COVID-19 has been changing rapidly,” said Dr. Metzl. “We plan to update these guidelines as our understanding of the disease evolves.”

Lead investigator Theresa Lu, MD, PhD, senior scientist in the Autoimmunity and Inflammation Program at the HSS Research Institute, answered questions about her group’s study.

1 - What prompted you to launch this study?

We aim to gain a better understanding of how the immune system works. A healthy immune system defends the body against diseases and infection. When someone has an autoimmune disease, the immune system malfunctions and the body mistakenly attacks healthy cells, tissues and organs. Rheumatoid arthritis, lupus and scleroderma are examples of autoimmune diseases.

If we can elucidate the underlying mechanism that causes autoimmune and inflammatory conditions, we can develop ways to correct the immune system flaws that lead to disease.

2 – What was the focus of your study?

Our study focused on the lymphoid tissues, which house immune cells and are the sites of immune cell activation. The lymphoid tissues include the tonsils, spleen and lymph nodes.

3 - What were the main findings of your study?

The lymphoid tissues contain structural elements, such as fibroblasts and blood vessels. These structural elements were thought to mainly provide an infrastructure for the immune cells, but recent advances in the field have shown that they actively shape immune cell responses, and multiple populations of fibroblasts have different functions.

We found that one fibroblast population expressed a molecule called CCL2 in the area of antibody-secreting immune cells, called plasma cells. We focused on the CCL2-expressing fibroblasts to see if they regulate plasma cell function. We found that CCL2 limits the magnitude of plasma cell responses by acting on an intermediary cell to reduce plasma cell survival. This was surprising in some ways, as CCL2 can also promote inflammation, and yet we are finding a role in limiting immune responses. This underscores the multiple functions that any molecule can have in different contexts.

Our findings have implications for better understanding autoimmune diseases. Plasma cells in autoimmune diseases generate autoantibodies that then deposit and cause inflammation in organs such as the kidneys and skin.

4 - Why are your findings important?

By understanding that plasma cells can be controlled by this subset of fibroblasts, we can study these fibroblasts to see if they are perhaps not working properly in autoimmune and inflammatory diseases. We can then search for a way correct the malfunction, so they are less likely to cause disease.

As the immune system is so central to how well our bodies function and often acts in similar ways in a number of different settings, what we are learning about manipulating fibroblasts can also help the biomedical community better understand how to treat related processes, such as healing after musculoskeletal injury, fighting cancer and fighting infections. For example, medications used in adults and children with different forms of autoimmune inflammatory arthritis or lupus are being examined in the setting of coronavirus infections. We all learn from each other.

5 - Why is this an exciting line of research, and how long have you been studying this topic?

We have been studying the vasculature and fibroblasts of lymph nodes for 16 years.

Research entails a lot of people working together: Dragos Dasoveanu, PhD, was the first author of the study, and he did the work in my lab at HSS with Will Shipman, PhD; Susan Chyou, BA; and Varsha Kumar, PhD. In addition, we had collaborators at research centers in New York, Switzerland and Australia for this study.

A new basic science study led by Scott A. Rodeo, MD, clinician-scientist at HSS, looked to evaluate the effects of the novel population of muscle-derived activated endothelial cells (mECs) implanted at the repair site to analyze the gene expression comprehensively by means of RNA sequencing. 

Through cell tracking, the researchers found that there were green fluorescent protein (GFP)-positive viable mECs at the repair site of the supraspinatus tendon (SST) at three days with decreasing positive cell numbers at seven days.

This is the first study to show that activated endothelial cells derived from muscle tissue can enhance healing of tendon-to-bone in as early as 14 days.

"This pre-clinical data demonstrates the potential for these cells to stimulate the intrinsic progenitor cells in tendons. Ultimately, umbilical vein endothelial cells can now be used in a clinical trial of patients undergoing rotator cuff repair," said Dr. Rodeo, who adds that further studies are needed to identify the ideal patient, timing of dosing, and best way to deliver the cells to treat various types of tissue injuries.

This paper received the Charles Neer award from the American Shoulder and Elbow Surgeons Society (ASES) and was presented at ASES 2019 Specialty Day as part of the American Academy of Orthopedic Surgeons conference.

Abstract Title: Muscle-Derived Activated Endothelial Cells as A New Cell Source to Enhance Tendon-To-Bone Healing: In Vivo Study In A Murine Rotator Cuff Repair Model

Authors: Scott A. Rodeo, MD; Susumu Wada, MD, PhD; Amir Lebaschi, MD; Yusuke Nakagawa, MD, PhD; Xiang-Hua Deng, MD; Camila Carballo, PhD, PT; Daniel Nemirov, BA; Dean Wang, MD; Zoe Album, BS; Liang Ying