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.

This is the 13^th consecutive year in a row that HSS has attained the top position nationally in orthopedics. Its No. 3 spot in rheumatology nationwide is the highest ranking for the specialty in the Northeast. This follows the U.S. News Best Children’s Hospitals© rankings announced last month, in which HSS surged into the Top 10 nationally and was highest ranked in NY, NJ and CT for Pediatric Orthopedics.

"When faced with musculoskeletal conditions or complex surgery, choosing a hospital is one of the most important decisions one will ever make,” said Louis A. Shapiro, president and CEO of HSS. “Our rankings in orthopedics and rheumatology by U.S. News are not only a great honor but a testament to each staff member’s commitment to do their best — and to improve on their best every day. The result is the highest-quality care for every patient who places their trust in HSS.”

For the 2022-2023 rankings, U.S. News evaluated more than 4,500 hospitals in 15 specialties using a variety of measures, ranging from outcomes, level of nursing care, and patient experience to the availability of technology such as computer-assisted orthopedic surgery. The methodology also factored in data from the Centers for Medicare & Medicaid Services, American Hospital Association, professional organizations, and medical specialists.

According to the survey, HSS outperformed in back surgery and spinal fusion, hip fracture, hip replacement and knee replacement.

“Our extraordinary focus on musculoskeletal conditions enables us to provide highly specialized, patient-centered care to help people get back to what they need and love to do,” said Bryan T. Kelly, MD, MBA, surgeon-in-chief and medical director at HSS. “A combination of factors has enabled HSS to achieve outstanding outcomes: the highest standards in patient care and safety; our dedication to evidence-based medicine, including advances in technology; our seminal research in the treatment of musculoskeletal conditions; and our commitment to training the physicians, surgeons and investigators who will help shape the future of musculoskeletal care.”  

“We are proud to be recognized by U.S. News for outstanding care,” said S. Louis Bridges, Jr., MD, PhD, physician-in-chief and chief of the Division of Rheumatology at HSS, noting the significant growth of rheumatology at HSS to meet the increasing demand for its services. “We will continue to respond to changes and challenges in health care by embracing an integrative care approach that addresses the needs of the whole person. Our goal is to improve our patients’ lives with innovative, evidence-based treatments and dedicated research to advance the field.”

In 2021, HSS surgical teams performed 36,870 orthopedic procedures; HSS clinicians provided nearly 446,000 nonsurgical consultations for conditions including joint pain, trauma and sports injuries, osteoarthritis, rheumatoid arthritis, back pain, spinal disorders, and conditions of the hand, upper extremities, foot and ankle.

HSS provides care to the highest-performing professional, collegiate and amateur athletes and organizations around the world, including USA Basketball, Fédération Internationale de Football Association (FIFA), UFC, the Brooklyn Nets, the New York Giants, the New York Knicks, the New York Mets and the New York Red Bulls, among others.

* Copyright © 2022 U.S. News & World Report, L.P. Data reprinted with permission from U.S. News.

The studies focus on the tapering of treatment in patients whose disease is well controlled, real-world outcomes for targeted therapies, assessing the effects of biologic treatments on immune cells from patients with RA, and the underlying mechanisms of arthritis triggered by immune checkpoint therapies used to treat cancer.

What follows are some highlights from the meeting:

Effectiveness of Upadacitinib in the Treatment of Rheumatoid Arthritis: Analysis of 6-Month Real-World Data from the United Rheumatology Normalized Integrated Community Evidence (UR-NICETM) Database

Upadacitinib, an oral Janus kinase (JAK) inhibitor, was approved for the treatment of RA in 2019 after clinical trials suggested that it reduced symptoms and had acceptable side effects. But since that time, few real-world data have been reported on how patients respond to upadacitinib outside of clinical trials. This six-month study looked at outcomes for 140 patients receiving upadacitinib alone and 223 receiving upadacitinib plus conventional synthetic disease-modifying antirheumatic drugs (DMARDs). The investigators, led by HSS rheumatologist Allan Gibofsky MD, JD, MACR, FACP, FCLM, found that overall 46% of patients receiving upadacitinib achieved low disease activity and 14% achieved remission, with better results for patients in the combination therapy group than those who got upadacitinib alone. The effectiveness of upadacitinib was not impacted by prior therapy with a tumor necrosis factor inhibitor or tofacitinib. This study supported the use of upadacitinib in clinical practice, including in patients with prior exposure to advanced therapy.

Authors: Allan Gibofsky, MD, JD, MACR, FACP, FCLM (HSS), Mark E. Pearson, MD (West Suburban Center for Arthritis), Andrew Concoff, MD (United Rheumatology), Anna Shmagel, MD, Patrick Zueger, PhD, Yanna Song, MS, Lauren D. Smith, MD (AbbVie Inc.), Grace C. Wright, MD, PhD (Grace C. Wright MD PC, Association of Women in Rheumatology).

Can Patients with Controlled RA Receiving Any Class of Targeted Therapy with Methotrexate (MTX) Sustain Disease Control after Tapering MTX? A Systematic Review and Meta-Analysis 

People with RA frequently wish to taper the use of methotrexate therapy due to its side effects, but there are questions about the best way to do that. Guidelines that recommend tapering methotrexate before tapering biologic DMARDs are not based on direct evidence. In this study, a team of HSS investigators led by rheumatologist Charis F. Meng, MD, and Director of the Inflammatory Arthritis Center Vivian P. Bykerk, MD, FRCPC, conducted a literature search to look at whether patients who are taking the combination of methotrexate and targeted therapy (biologic therapies and JAK-inhibitors) can taper methotrexate and still be in remission from their RA, while continuing their targeted therapies. They identified 10 studies that met their inclusion criteria. These studies included a number of different targeted therapies. Based on their analysis, the team concluded that patients with controlled RA have a high probability of maintaining disease control for at least 18 months after tapering their methotrexate and continuing targeted therapies. They noted that this review may inform patients who are experiencing controlled disease while taking methotrexate in combination with any of a range of targeted therapies and who are struggling with methotrexate-related side effects. However, they concluded longer follow-up studies are needed to confirm the disease will not worsen over time and that patients should be told about this possibility.

Authors: Charis F. Meng, MD, Diviya Rajesh, Deanna Jannat-Khah, DrPH, Omar Bruce, MPH, Bridget Jivanelli, MLIS, Vivian P. Bykerk, BSc, MD, FRCPC (HSS).

Differential Pharmacodynamic Alterations After Treatment with Abatacept or Adalimumab in MTX-Inadequate Responder Patients with Early RA: Whole Blood RNA-Seq Analysis of the Early AMPLE Study

A number of novel agents for RA are now available for treatment, but tools to predict which patients are likely to respond to specific drugs are lacking. To ensure that patients are matched with the best treatment, more research is needed to determine the molecular signatures of these drugs and their mechanisms of action. In this study, part of a Phase 4 trial called Early AMPLE, investigators including HSS Physician-in-Chief and Chair of the Department of Medicine S. Louis Bridges, Jr., MD, PhD, and Director of the Inflammatory Arthritis Center Vivian P. Bykerk, MD, FRCPC, looked at pharmacodynamic changes in patients in response to treatment with either abatacept or adalimumab. The aim was to identify and differentiate the impact of each drug on modulation of immune cells at the molecular level. The investigators performed pharmacodynamic and other analyses for 14,540 protein-coding genes in 664 RNA- Seq samples, with materials collected from 79 patients with RA who were predicted to respond better to abatacept. They found that after treatment, twice as many genes and pathways were significantly altered in the adalimumab arm versus the abatacept arm and that abatacept treatment decreased immune cell cycle gene expression while adalimumab treatment increased expression of these genes. The differential gene expression was seen in genes known to correlate with RA disease activity. The investigators concluded that these findings may explain the greater clinical improvements seen with abatacept versus adalimumab. Because patients in the Early AMPLE study were predicted to respond differentially to abatacept, these findings may be relevant only to this subgroup of patients. These findings warrant further studies to investigate the potential positive correlation between RA-relevant effects and better therapeutic outcomes.

Authors: Chun Wu (Bristol Myers Squibb), Yicong Li (Parexel International), Neelanjana Ray, Michael A. Maldonado, Peter Schafer (Bristol Myers Squibb), S. Louis Bridges, Jr., MD, PhD (HSS), William Rigby (Dartmouth-Hitchcock Medical Center), Vivian P. Bykerk, MD, FRCPC (HSS), Jane Buckner (Benaroya Research Institute at Virginia Mason), Jinqi Liu (Bristol Myers Squibb).

The Probability of Sustaining Rheumatoid Arthritis Remission in Patients Tapering Targeted Therapy Used as Monotherapy: a Systematic Review and Meta-Analysis 

A second study led by HSS rheumatologist Charis F. Meng, MD, and Director of the Inflammatory Arthritis Center Vivian P. Bykerk, MD, FRCPC, also used a literature review to look at the effects of tapering drugs for RA in people whose disease is well controlled. This study focused on patients receiving either biologic DMARDs or JAK inhibitors being used alone. A search resulted in five studies that compared tapering of targeted monotherapy (TNF-i, tocilizumab, abatacept, or baricitinib) with continuing therapy or other tapering regimens. A meta-analysis including data from 800 patients found a trend for lower odds of disease remission with targeted therapies versus comparator treatment regimens, but these data were not conclusive. The investigators noted that the lack of trials designed to compare tapering targeted monotherapy to continuing it led to a significant gap in knowledge in an area of research that is increasingly relevant for patients. Their review suggests that stopping targeted monotherapy is unlikely to maintain disease control, but that more gradual tapering schemes, dose reduction, and early treatment of disease may be associated with more successful tapering. More studies are needed to better inform patients, and it is not recommended to stop targeted monotherapy in RA based on this analysis.

Authors: Charis F. Meng, MD, Diviya Rajesh, Deanna Jannat-Khah, DrPH, Omar Bruce, MPH, Bridget Jivanelli, MLIS, Vivian P. Bykerk, MD, FRCPC (HSS).

Less ACPA Epitope Expansion Is Found in ACPA-Positive Immune Checkpoint Inhibitor Arthritis Patients Compared to ACPA-Positive Rheumatoid Arthritis Patients

Immune checkpoint inhibitors (ICI) have improved the treatment of many advanced cancers. However, they can lead to immune-related adverse events, including treatment-induced arthritis. This form of arthritis is similar to RA. About 9% of people with this condition test positive for the anti-citrullinated peptide antibody (ACPA). In RA, the increase in ACPA occurs over the years prior to onset of clinical disease. In this study, led by HSS rheumatologist Nilasha Ghosh, MD, MS, investigators examined the degree of ACPA epitope expansion in patients receiving ICI to determine whether treatment-induced arthritis is similar to early RA, or more suggestive of the pre-clinical phase of disease. The analysis employed clinical data and serum samples from 12 patients with ICI arthritis (ICI-A) as well as from 39 ACPA-positive RA patients. There were a number of differences between the patients in the two groups, including age and smoking history. The investigators reported that, overall, people with ICI-A had lower ACPA titers and targeted fewer ACPA epitopes than people with early RA, suggesting that ICI-A may represent an accelerated model of RA pathogenesis with ICI triggering an early transition from pre-clinical to clinical disease. They noted that sequential sampling and analysis are warranted to further determine how the pathogenesis of ICI-A relates to that of RA.

Authors: Diviya Rajesh, Nilasha Ghosh, MD, MS (HSS), Jessica Kirschmann (Stanford University), Karmela Kim Chan, MD, Deanna Jannat-Khah, Susan M. Goodman, MD, Vivian P. Bykerk, BSc, MD, FRCPC (HSS), William Robinson, MD, PhD (Stanford University), Anne R. Bass, MD (HSS).

TKR is often the only management option for patients with severe knee joint damage. Identifying which disease caused the joint damage is essential for guiding treatment plans, given that RA is a systemic, inflammatory disease that may also affect the eyes or lining around the heart, while OA affects just the joints. “We know there are many more immune cells present in the synovium, or joint tissue, of patients with RA compared to those with OA,” said Bella Mehta, MBBS, MS, rheumatologist at HSS and lead author of the study. “But precisely how many more has not been clear.”

“Pathologists typically assess images of synovium to determine the extent of inflammation using a combination of approaches, including assigning the level of immune cell infiltration on a scale from 0 to 4,” said Dana Orange, MD, MS, rheumatologist at HSS, assistant professor at Rockefeller University and senior author of the study. “However, these methods are imperfect.” For example, a recent study by HSS investigators found that assessments from two highly experienced pathologists evaluating the infiltration of one type of immune cells known as lymphocytes on the same slides agreed only 67 percent of the time.¹

Drs. Orange, Mehta and colleagues at HSS and collaborating institutions developed and validated a computer vision tool that rapidly counts tens of thousands of cell nuclei in whole-slide images of synovium.² For their present study, they measured 14 different pathologist-scored features in synovium from 60 patients with RA and 147 patients with OA who underwent TKR, and used the computer vision tool to determine cell density.

The investigators identified significant differences between RA and OA features in synovium. The RA samples showed increased cell density; low numbers of mast cells, a type of white blood cell; and lower evidence of fibrosis or scarring compared to the OA samples. The probability of correctly distinguishing between RA and OA in synovium was 85 percent when using the 14 pathologist-scored features alone, 88 percent when using the computer’s score for cell density alone and 91 percent when the researchers combined the pathologists’ scores and the computer’s cell density calculation. The researchers determined a cutoff point for distinguishing RA from OA, determining that synovium containing more than 3,400 cells per mm² should be classified as RA.

“While our innovation is not ready for clinical use yet, it holds promise for assisting pathologists in the future,” Dr. Orange said. “Right now, we see it as a valuable tool for research purposes because it provides an accurate and 100% reproducible score of inflammation and look forward to developing it further.”

Dr. Orange added that in the future computer vision could be trained to glean other types of information from tissue samples, including which types of cells are present and whether they are close enough together that they are likely to be communicating with each other. This more granular assessment might enable clinicians to know more precisely which cells are causing tissue damage and tailor treatments accordingly.

Authors: Bella Mehta, MBBS, MS, Susan M. Goodman, MD, Edward F. DiCarlo, MD, Deanna Jannat-Khah, J. Alex Gibbons, Miguel Otero, PhD, Laura Donlin, PhD (HSS), Tania Pannellini, MD, PhD (Weill Cornell Medicine), William Robinson, MD, PhD (Stanford University), Peter K. Sculco, MD, Mark P. Figgie, MD, Jose A. Rodriguez, MD (HSS), Jessica Kirschmann (Stanford University), James Thompson, David Slater, Damon Frezza (The MITRE Corporation), Zhenxing Xu, Fei Wang, PhD (Weill Cornell Medicine), Dana Orange, MD, MS (HSS and Rockefeller University).

References

1. Orange DE, Agius P, DiCarlo EF, et al. Identification of Three Rheumatoid Arthritis Disease Subtypes by Machine Learning Integration of Synovial Histologic Features and RNA Sequencing Data. Arthritis Rheumatol. 2018;70(5):690-701. doi:10.1002/art.40428

2. Guan S, Mehta B, Slater D, et al. Rheumatoid Arthritis Synovial Inflammation Quantification Using Computer Vision. ACR Open Rheumatol. 2022;4(4):322-331. doi:10.1002/acr2.11381

“We have been interested in studying UCTD because it’s commonly encountered in clinical practice but not well characterized,” said lead study author Caroline Siegel, MD, a rheumatology fellow at HSS. “UCTD is inherently challenging to define, but it’s very important to understand what features differentiate patients with UCTD from those with defined connective tissue diseases (CTD) such as lupus so that we can better manage patients with this condition and ultimately predict who may go on to develop more severe clinical manifestations.”

The study included 89 patients aged 18 years and older treated at HSS between 2018 and 2022 who had rheumatologist-diagnosed UCTD with positive antinuclear antibody and at least one sign or symptom of CTD. The researchers reviewed medical records to identify those who fulfilled established classification criteria for systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis, primary Sjögren’s, idiopathic inflammatory myopathy, or antiphospholipid syndrome (APS). The researchers compared sociodemographic, clinical, serologic, and treatment variables between 59 patients with UCTD and 30 patients who fulfilled criteria for CTD.

Patients in both groups had similar non-criteria manifestations, most commonly joint pain and fatigue. However, patients with UCTD were less likely to have arthritis, criteria-based hematologic manifestations, anti-double stranded DNA or anti-Smith antibodies, and hypocomplementemia. The frequency of RA, Sjögren’s, and APS-related serologies did not differ between groups. Compared to those with CTD, UCTD patients were less likely to have ever received systemic corticosteroids.

“Our main findings were that patients who met a strict definition of UCTD versus those who met classification criteria for other CTDs were less likely to have clinical and laboratory features such as arthritis and hematologic abnormalities, as well as certain autoantibodies that are commonly seen in lupus,” said Dr. Siegel. “They were also less likely to have received treatment with steroids,” she added.

The results reveal that even among patients diagnosed by their treating physician with UCTD, some may meet classification criteria for other rheumatic diseases. Within this group, patients with strictly defined UCTD may differ in meaningful ways.

“We are starting to recognize features of strictly defined UCTD that will allow us to better identify and manage this condition,” said senior study author Medha Barbhaiya MD, MPH, rheumatologist at HSS. “Patients struggle with the uncertainty of a UCTD diagnosis and our study aimed to demonstrate that UCTD may be a distinct entity from other rheumatic conditions. These findings lend support to the claim that patients who have UCTD require separate study, and their disease manifestations warrant further understanding.”

Bella Mehta, MBBS, MS, a rheumatologist at HSS and lead author of the study, presented the results today at the European Alliance of Associations for Rheumatology (EULAR) 2022 Congress in Copenhagen. “Lupus is a chronic autoimmune disorder that often affects women in their childbearing years,” explained Dr. Mehta. “In our previous work, we demonstrated that over the years, maternal and fetal mortality in lupus patients have improved significantly, and that was very reassuring to patients. However, less was known about morbidity. We set out to evaluate and quantify the indicators of fetal and maternal morbidity in women with lupus compared to those who did not have the disease.”

Using retrospective data from the National Inpatient Sample database, the researchers identified delivery-related hospital admissions from 2008 to 2017. Fetal morbidity indicators included preterm delivery and intrauterine growth restriction. Twenty-one indicators of severe maternal morbidity were identified and defined as unexpected outcomes of labor and delivery that result in significant short- or long-term consequences to a woman’s health.

Among the 40 million delivery-related hospital admissions, 51,161 patients were reported to have lupus. These patients were more likely to be older than women who did not have lupus (30.1 years versus 28.2 years), to be African American (25% versus 15%), and to receive Medicare (5% versus 1%).

During delivery, women with lupus were 15 times more likely to develop acute renal failure than those who did not have lupus (1.5% versus 0.1%), four times more likely to develop a cerebrovascular disorder (4.8% versus 1.1%), and nearly four times more likely to require a blood transfusion (4.0% versus 1.1%). Women with lupus were also more likely to develop cardiovascular and peripheral vascular disorders (1.1% versus 0.1%).

In terms of fetal morbidity, mothers with lupus were twice as likely to deliver prematurely (14.5% versus 7.3%) and nearly three times more likely to experience growth restriction in the womb compared to pregnant patients without lupus (8.0% versus 2.7%).

“The number of co-existing health conditions in pregnant women with lupus was much higher compared to women who did not have lupus. It seems likely that these comorbidities are responsible – at least in part – for the increased risk of fetal and maternal morbidity in lupus patients,” Dr. Mehta said. “It is noteworthy that a large percentage of deliveries by women with lupus were at large hospitals and urban teaching hospitals, reflecting the complexities of managing these patients.”

Dr. Mehta continued, “Our study is not meant to discourage women with lupus from getting pregnant. We believe our findings can help both patients and their physicians to assess risk, establish appropriate interventions and ensure that a multidisciplinary medical team is in place to counsel patients and manage their care.”

Authors: Bella Mehta, MBBS, MS, Katharine Kayla J. Glaser, Deanna Jannat-Khah (HSS), Yiming Luo (National Institutes of Health, Medicine, Bethesda), Lisa R. Sammaritano, MD, Jane E. Salmon, MD, Susan M. Goodman, MD (HSS), Fei Wang (Weill Cornell Medicine).