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.

Research highlights include studies that have found an initial high-risk antibody profile for antiphospholipid syndrome (APS) tended to remain high in pediatric patients, a correlation between obesity and more severe disease flare symptoms in patients with early rheumatoid arthritis (RA), people with inflammatory arthritis face challenges in maintaining employment, a link between aging and physical activity, and people with vasculitis frequently suffer from frailty, new research findings in antiphospholipid syndrome (APS)  insights on improving communications with diverse patient populations, and and new research on reproductive health.

A High-Risk Antiphospholipid Antibody Profile Matters in Pediatric Patients with Antiphospholipid Syndrome

A new study by HSS investigators including Jheel Pandya, MD, Karen Onel, MD, Doruk Erkan, MD, MPH has found that an initial high-risk antibody profile for APS tended to remain high in pediatric patients.

HSS Research Shows Obesity Is Associated with Worse Flare Symptoms and Quality of Life in People with Early Rheumatoid Arthritis 

A recent study from HSS and others has found a correlation between obesity and more severe disease flare symptoms that negatively affect quality of life in patients with early RA, a systemic, autoimmune, inflammatory disorder affecting multiple joints in the body. 

Study Finds People with Inflammatory Arthritis Face Significant Psychological Challenges in Maintaining Employment

An HSS study presented by Joan Westreich, MSW, LCSW, social work coordinator, Early Arthritis Initiative at HSS reveals a significant psychological impact related to inflammatory arthritis patients’ efforts to maintain employment while coping with the challenges of their illness.

New Study Shows Perception of Aging is Linked to Level of Physical Activity in Arthritis Patients

People with arthritis who report more negative feelings about how they are aging tend to get less physical activity and perceive themselves as less healthy, according to a new study by researchers at HSS and Weill Cornell Medicine. However, self-perception of good health explained the effect of negative thinking – providing an opportunity for clinicians to focus on a patient’s outlook on aging as well as their overall health. 

New Study Identifies Outcomes Associated With Frailty in Patients With Vasculitis

According to a new study from researchers at HSS and colleagues from the University of Pittsburgh and the University of Pennsylvania, people with vasculitis frequently suffer from frailty, a process that can affect our ability to recover after an illness or a fall, which in turn is linked to poor health outcomes.

New Antiphospholipid Syndrome Research Findings Presented at ACR Convergence 2023

Investigators from the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) presented new research findings in antiphospholipid syndrome (APS) at the American College of Rheumatology (ACR) Convergence 2023, the ACR’s annual meeting.

HSS Shares Strategies to Enhance and Enable Communication with Language-Diverse Patients at Annual ACR Convergence

Bella Elogoodin, vice president, Service Excellence & Language Access at HSS, shared strategies to enhance and enable communication with language-diverse patients at the American College of Rheumatology (ACR) Convergence 2023 in a session titled, “Lost in Translation: Creating Access Pathways for Language-Diverse Patients in Rheumatic Care Settings.”

HSS Presents New Reproductive Health Research at the ACR Convergence 2023  

At this year’s American College of Rheumatology (ACR) annual meeting, HSS presented a number of studies focused on reproductive health for patients with systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases, including issues related to fertility, sexual function, use of contraception and HPV vaccination.

In their paper, published online ahead of print on November 30, 2020, in Arthritis Care & Research, the investigators reported on the first two of four phases of criteria development. Phase I and II involved generating 261 candidate criteria for defining APS and reducing the list to 27 finalist criteria, grouped into six specific categories: laboratory tests, macrovascular, microvascular, obstetric, cardiac and hematologic. The ultimate goal is to develop a threshold-based scoring system that will allow researchers worldwide to determine which patients most likely have APS and should be included in research studies.

APS is an autoimmune disorder in which the immune system produces antibodies against specific normal proteins in the blood, causing clots in blood vessels, low platelet counts, heart valve abnormalities and pregnancy complications. It is the leading cause of stroke in young people, causing one in three strokes in people under the age of 50, one in five recurrent miscarriages and up to 20 percent of all deep vein thromboses. The disease is often found in patients with other autoimmune conditions, especially lupus.

The current APS Sapporo Classification System was published in 1999, validated in 2000, and revised in 2006. “The previous classification system was based on the available evidence at the time,” says lead author Medha Barbhaiya, MD, MPH, rheumatologist at the Barbara Volcker Center for Women and Rheumatic Diseases at HSS and assistant professor of medicine and population health sciences at Weill Cornell Medicine. “In the last decade, researchers have identified additional features of APS that deserve inclusion. We also now have more rigorous methods for developing and validating disease classification criteria.”

The international initiative is jointly funded by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), in recognition of the need for improving the method of classifying patients for APS research to be used worldwide. Doruk Erkan, MD, MPH, rheumatologist at the Barbara Volcker Center for Women and Rheumatic Diseases at HSS and associate professor of medicine at Weill Cornell Medicine, is the senior author and co-principal investigator together with Stephane Zuily, MD, MPH, PhD, a vascular medicine specialist and professor of medicine at the Université de Lorraine, Nancy, France.

Emphasizing the difference between classification versus diagnosis criteria for APS, Dr. Erkan says, “Classification criteria are intended to be used in a research setting whereas diagnostic criteria are used in a clinical setting for the purpose of managing diseases; the two sets of criteria may have overlapping elements, but they have separate goals. The goal of classification criteria is to ensure that patients with common characteristics, thought to be specific for a certain disease, are included in appropriate research studies. In contrast, the goal of diagnostic criteria is to identify, as accurately as possible, whether patients have that particular disease.”

The next phase of the new APS classification criteria methodology involves defining, refining, and weighting the candidate criteria and assigning a threshold score for identifying APS using real-world cases and a computer-based decision tool. Following the final validation phase of the project, researchers plan to report their results in 2021. Dr. Barbhaiya is also supported by a separate but related grant, the 2018 Rheumatology Research Foundation Investigator Award, to investigate risk factors for APS using the data collected during new classification criteria development.

“We are excited to be developing validated classification criteria for APS as previously done for other rheumatologic diseases, such as lupus and rheumatoid arthritis,” says Dr. Erkan, who is also co-chair of the AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION). “A threshold score for identifying patients with the disease will go a long way to advancing APS research, with the ultimate goal of high-quality research to improve APS prevention and treatment options for patients.”

HSS is the world’s largest academic medical center specialized in musculoskeletal health, spanning orthopedics, rheumatology and related disciplines. The HSS Research Institute maintains 20 laboratories dedicated to solving debilitating orthopedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities. There, more than 300 dedicated personnel focus on tissue repair, improving surgical outcomes, autoimmunity and inflammation, genomics, new treatments, and precision medicine.

“HSS has a long history of contributing to the collective base of clinical and basic science knowledge and finding healthcare solutions for complex conditions,” said Louis A. Shapiro, President and CEO, HSS. “We’re proud that through the joint efforts of our institution and philanthropic support, we will have the ability to make a strong impact on this growing and vital area of research.”

“As experts in inflammatory disorders and in the development of interventions for overactive immune responses, the clinicians and researchers at HSS are well-positioned to investigate many of the adverse effects of COVID-19,” says Lionel B. Ivashkiv, MD, Chief Scientific Officer at the HSS Research Institute. “This includes studying the causes of these adverse effects as well as how to prevent and treat them.”What follows are descriptions of the first group of funded projects in basic/translational research:

Activation of pDCs by SARS-CoV-2 and Its Impact on Macrophage Response

Principal Investigator: Franck Barrat, PhD

Co-Investigator: Marie-Dominique Ah Kioon, PhD

This project will study cell types that are responsible for cytokine storm syndrome — the hyperactive immune response seen in people with COVID-19 — by looking at how certain immune cells are activated by SARS-CoV-2. Research in mice infected with SARS-CoV, a coronavirus similar to the one that causes COVID-19, has suggested that plasmacytoid dendritic cell precursors (pDCs) are key to the immune response to infection. These pDCs activate macrophages, which in turn secrete cytokines. In the SARS-CoV research, depletion of pDCs appeared to protect the mice from lethal lung injury. Using blood samples from donors, the investigators will study the pathway by which pDCs activate macrophages and look at ways to therapeutically block that process.

Inhibiting RNA Polymerase II Transcription Complexes in Macrophages to Target COVID-19–Associated Cytokine Storm

Principal Investigator: Inez Rogatsky, PhD

Co-Investigators: Steven Josefowicz, PhD, and Robert P. Fisher, MD, PhD

This pilot project will dissect the role of macrophages in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS), the main driver of COVID-19-associated mortality. We will test small-molecule inhibitors of RNA Polymerase II (Pol II) transcription complexes for their ability to modulate type I interferon and inflammatory pathways in monocytes/macrophages. This research will be done using cultured macrophages as well as donor blood and blood from COVID-19 patients.

Mechanisms of Cytokine Storm in Patients with COVID-19

Principal Investigator: Mary K. Crow, MD

Co-Investigators: Mikhail Olferiev, MD, and Lionel B. Ivashkiv, MD

The objectives of this study are to describe the process of the cytokine storm in people with COVID-19 and to identify biologic predictors of a favorable outcome in patients with severe cases of the disease. The project aims to characterize immune cell populations seen in COVID-19 patients who experience cytokine storm and compare them to those patients who do not, to compare the immune response before and after patients are given the anti-inflammatory drug anakinra, and to identify measures that suggest patients are more likely to decline and eventually require mechanical ventilation. The research will employ blood samples from HSS patients who are being treated for COVID-19 at New York–Presbyterian Hospital and who meet certain other qualifications.

What follows are descriptions of the first group of funded projects in the areas of clinical and health outcomes research:

Response to and Recovery from TKA in Patients with Antibodies to SARS-CoV-2

Principal Investigator: Miguel Otero, PhD

Co-Investigators: Meghan Kirksey, MD, PhD, and Peter K. Sculco, MD

It is unknown if people who have been exposed to COVID-19 may be at higher risk of experiencing an abnormal immune response following surgery, resulting in poor outcomes. This study will evaluate the response to and recovery from total knee arthroplasty (TKA) in people who have antibodies to COVID-19 — a marker of exposure. This study will include both patients who have COVID-19 antibodies and those who don’t, to act as controls. Patients will be followed for six weeks after surgery and evaluated for the presence of certain immune markers in the blood, as well as symptoms of inflammation including pain and stiffness in the joint.

SARS-CoV-2 Exposure and the Role of Vitamin D Among Hospital Employees

Principal Investigator: Emily M. Stein, MD, MS

Co-Investigators: Theresa T. Lu, MD, PhD; Andy O. Miller, MD; Jeri Nieves, PhD; and Alana Serota, MD

It is unknown if people with vitamin D deficiency may be more likely to become infected with COVID-19. This study will investigate vitamin D status and associated immune markers as risk factors for COVID-19 infection in a cohort of healthcare workers. Healthcare workers are at higher risk of contracting COVID-19 than the general population, making them a good group to study. Vitamin D is critical for immune function and is known to be protective against respiratory-tract infection and tuberculosis. This prospective, observational study will follow healthcare workers at HSS and at other healthcare facilities for one year, to determine whether levels of vitamin D and certain immune cells in the blood make someone more susceptible to COVID-19 infection.

Association of Immunomodulatory Medication Use and Social Determinants of Health with COVID-19 Infection in Systemic Rheumatic Disease Patients in New York City

Principal Investigator: Medha Barbhaiya, MD, MPH

Co-Investigators from HSS: Lisa Mandl, MD, MPH; Catherine MacLean, MD, PhD; Vinicius Antao, MD, PhD; Jane Salmon, MD; and Mayu Sasaki, MPH

Other Co-Investigators: Candace Feldman, MD, MPH (of Brigham and Women’s Hospital); Debra D’Angelo, MS (of Weill Cornell Medicine)

Using data from the INSIGHT Clinical Research Network, a central repository containing longitudinal electronic health data for residents of New York City, investigators will assemble a cohort of patients being treated with immunomodulatory medications for rheumatic disease. This patient population will then be used to study the effect of these medications on COVID-19 incidence and outcomes. Retrospective data will be used to evaluate the incidence and severity of COVID-19 in these patients. Patients will also be studied prospectively to determine whether there’s a relationship between COVID-19 infection and future rheumatic disease as well as to study connections between infection and future psycho-social issues.

Assessment of Surgical Outcomes in the COVID-19 Pandemic Era

Principal Investigator: Andy O. Miller, MD

Co-Investigators: Scott A. Rodeo, MD, and Mark Fontana, PhD

Investigators will implement a patient registry to evaluate how COVID-19 affects outcomes and complication rates after orthopedic surgery. This registry, along with COVID-19 screening procedures, will provide the tools to address specific research questions. Among these questions are determining the incidence of current and prior infection among the HSS surgical population, the clinical features associated with current and prior infections in this patient population, and whether COVID-19 status affects short-term complication rates.

What follows is a description of an integrated multidisciplinary study being undertaken jointly by the Adult Reconstruction and Joint Replacement (ARJR) Perioperative Research Group, Anesthesiology and Rheumatology:

Prediction and Prevention of Postoperative Blood Clots in COVID-19 Patients

Principal Investigators: Friedrich Boettner, MD; Kethy M. Jules-Elysee, MD; Lisa A. Mandl, MD, MPH

Co-Investigators: ARJR surgeons: Alejandro Gonzalez Della Valle, MD; Jason Blevins, MD; David J. Mayman, MD; Peter K. Sculco, MD; Geoffrey H. Westrich, MD and Thomas P. Sculco, MD

Medicine/Rheumatology: Medha Barbhaiya, MD, MPH; Doruk Erkan, MD, MPH; Deanna Jannat-Khah, DrPH

Pathology: Thomas W. Bauer, MD, PhD

Anesthesiology: Stavros G. Memtsoudis, MD, PhD, MBA; Alexandra Sideris, PhD

ARJR: Amethia Joseph, MHA; Ethan Krell, MS

Weill Cornell Medicine: Raymond David Pastore, MD

Recent literature suggests that one of the major complications seen in people with COVID-19 is thrombosis (the formation of blood clots) due to endothelial dysfunction, persistent inflammation and potentially antiphospholipid antibodies. As elective surgeries resume, those with prior exposure to SARS-CoV-2 will inevitably present for treatment, and some may have perioperative management considerations related to their risk of deep-vein thrombosis. This project will use, a noninvasive device that can determine clotting risks, to investigate whether people who have had COVID-19 have a more dysfunctional endothelium preoperatively and at 24 hours after surgery. The investigators will measure antiphospholipid antibodies and inflammatory markers, and evaluate the prevalence of asymptomatic post-operative deep-vein thrombosis in people who undergo TKR and have SARS-CoV-2 antibodies.

COVID-19 Translational Research Core at HSS

Principal Investigator: Theresa Lu, MD, PhD

Co-Investigators: Jessica Andrés-Bergós, PhD; Miguel Otero, PhD and Emily M. Stein, MD, MS

The COVID-19 Translational Research Core (TRC) was designed to fill critical gaps in the resources needed to promote the broad range of COVID-19–related clinical and translational research at HSS. The TRC will provide consultation on the design and implementation of COVID-19 research in the areas of orthopedics, rheumatology and metabolic bone disease; support for a COVID-19 biobank; and technical expertise and facilities required for clinical and translational researchers working on COVID-19–related projects. The TRC staff will help to acquire, house, and track biospecimens from investigator-initiated COVID-19–related research studies.

“In APS, we haven’t known what triggers the antiphospholipid antibodies. This study sheds light on an important area to understand the mechanisms of APS,” said Doruk Erkan, MD, MPH, a rheumatologist at the Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, in New York City, an APS expert, and a coauthor of the research. “Millions of microorganisms exist in our gastrointestinal system, and usually these microorganisms are harmless. However if they elicit systemic immune responses, these microorganisms can be problematic by triggering autoimmunity outside the gut.”

APS can occur in patients with or without other systemic autoimmune diseases, such as lupus. In addition to blood clots, APS increases the risk for pregnancy complications, low platelet counts, anemia, kidney disease, and heart valve disease. Antiphospholipid antibodies mainly bind to the antigen β₂-glycoprotein-I, a phospholipid binding protein in the blood, and this binding triggers blood clotting and inflammation.

In the new study, the researchers investigated whether APS can be triggered by gut microorganisms, because other research has implicated the role of certain gut bacteria in autoimmune diseases such as lupus. The investigators searched a bacterial protein database to identify bacteria that had a similar snippet in their molecules to the APS-associated self molecule β₂-glycoprotein-I targeted in patients by their immune system. This snippet, called epitope, is the part of an antigen molecule to which an antibody attaches itself. They found that core epitopes of β₂-glycoprotein-I are conserved in Roseburia intestinalis, paving the way for cross reactivity. In other words, antibodies produced against this bacteria can also dock and bind on β₂-glycoprotein-I.

The researchers then recruited, from HSS and Yale, 20 healthy controls and 15 individuals who were persistently antiphospholipid antibody-positive. Cassyane Aguiar, MD a previous HSS fellow and currently a pediatric rheumatologist at Children’s Hospital for the King’s Daughters, Norfolk, VA, was also part of the research team helping with the HSS patient recruitment and follow-up. They collected blood and stool samples at baseline (month 1), and then at month 2 and month 3, to capture microbial and immune marker variability over time. They gathered information on health status, medications, 24-hour diet history, and APS-relevant genetic and immune markers such as other antibodies against self molecules.

Based on studies completed in the laboratory of Martin Kriegel, MD, PhD, at Yale School of Medicine, researchers found that Roseburia intestinalis was capable of eliciting an immune response in humans and that T cells from APS patients respond systemically to the bacteria in a manner that depended on the patient’s genetic predisposition. They found long-lasting T and B cell immune responses against this bug in APS patients. Studies in mice further supported this hypothesis and linked the cross-reactive immune responses with tissue damage. “Benign cross-reactive immune responses to gut microbes is probably very common given that we have so many of them living inside of us,” said Dr. Kriegel, who is the lead investigator on the project. “Some of them, however, can lead to damaging immune responses in predisposed individuals, which we have shown here.”

“This study is important because if we can eliminate Roseburia, then we may be able to decrease the levels of antiphospholipid antibodies,” said Dr. Erkan. “The similar epitopes between β₂-glycoprotein-I and the gut microbiome can help us better understand the mechanisms of antiphospholipid antibody production and also open doors for future treatment options.” This includes the use of antibiotics or the development of vaccines for APS and APS-associated autoimmune diseases.

According to Michael Lockshin, MD, Director of Barbara Volcker Center for Women and Rheumatic Diseases, at Hospital for Special Surgery, moving the research forward will require verifying that Roseburia intestinalis is a major, if not the most important, trigger for antiphospholipid antibodies. Since most people with this bacterium do not develop antiphospholipid syndrome, the next step will be to determine why patients develop disease.

“The microbiome itself and the concept of cross-reactivity is hard to study in humans,” said Dr. Kriegel. “We have used molecular approaches and supported our culture dish findings with animal models to show that cross-reactivity induced by a common gut bacterium in APS patients can lead to tissue damage. This study thus went far beyond the typical microbiome surveying studies and made causal links to disease, something still lacking in many studies in the field.”

The current study was a collaborative effort with researchers from HSS; Yale School of Medicine, in New Haven, Connecticut; Benaroya Research Institute, in Seattle, Washington; the Frederick National Laboratory for Cancer Research, in Frederick, Maryland; and Sackler School of Medicine, in Tel Aviv, Israel.

"We need to increase the recognition of APS among general physicians," said Doruk Erkan, MD, MPH, a rheumatologist at the Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, in New York City, an APS expert, and a coauthor of the article. "We need physicians to think about the disease in their differential diagnosis, first, and second, make the correct diagnosis as the interpretation of the blood tests can be tricky."

Patients who are positive for antiphospholipid antibodies (aPL) may present with no related symptoms and are usually identified during an evaluation for systemic autoimmune diseases, low platelet counts, recurrent miscarriages, an elevated activated partial-thromboplastin time (a test commonly ordered before surgeries to determine the bleeding risk), or a false-positive screening result of a syphilis test. Symptomatic patients seek medical attention for blood clots pregnancy complications, or other clinical problems as a consequence of aPL. Stroke and transient ischemic attack are the most common arterial events in patients with APS. Patients with venous events most commonly present with lower-extremity deep vein thrombosis (DVT), pulmonary embolism, or both. Antiphospholipid-antibody-related complications of pregnancy generally develop after 10 weeks of gestation, which include miscarriages or intrauterine growth restriction.

The NEJM article was coauthored by David Garcia, MD, Associate Medical Director of Anti-Thrombotic Therapy at the University of Washington School of Medicine, Seattle. "Antiphospholipid antibodies are not only a diagnostic marker for APS, but also a risk factor for blood clots and pregnancy complications, which are commonly multifactorial,” said Dr. Garcia. “For instance, the risk of blood clots is magnified when there are multiple risk factors, such as the combination of birth control pill use and the presence of antiphospholipid antibodies."

"A common complaint heard from patients with APS is that doctors did not diagnose their disease in a timely fashion or their doctors do not understand their disease. A typical example is a young woman with platelet counts that are slightly low and miscarriages; however, aPL tests are not ordered until they present with stroke," said Dr. Erkan. "Another example is a young patient that comes in with DVT with no other blood clot risk factors, and aPL is not considered as part of the diagnostic work-up."

In addition to the underrecognition of APS, overdiagnosis is another concern, as not every positive aPL test is clinically significant," said Dr. Erkan. Although aPL are detected in 10 percent to 15 percent of the general population with blood clots or pregnancy problems, clinicians should consider both the aPL test profile and additional blood clotting risk factors in evaluating aPL-positive patients.

Tests to detect aPLs include the lupus anticoagulant (LA) test, anticardiolipin antibody (aCL) enzyme-linked immunosorbent assay (ELISA), and anti-β2-glycoprotein-I (aβ2GPI ) ELISA. The NEJM article provides guidance for clinicians about the interpretation of these aPL tests, including how to assess the individual aPL tests and aPL profile. For instance, transient low-level aPL-positivity is common during infections, which is not clinically important, whereas persistent moderate-to-high titers of aCL and aβ2GPI correlate better with aPL-related clinical events.  

"We hope that our APS review article published in a high-impact journal will help increase the recognition of APS worldwide," said Dr. Erkan, who is also the co-chair of the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION). APS Action is a collaborative effort to prevent, treat, and cure aPL-associated clinical manifestations through high-quality, multicenter, and multidisciplinary clinical research.

Hospital for Special Surgery in the United States is one of the major referral centers for APS, and also the lead coordinating center for APS ACTION (www.apsaction.org).

The article can be found at https://www.nejm.org/doi/full/10.1056/NEJMra1705454.

HSS rheumatologist Michael D. Lockshin, MD, and director of the Center, shared his conversations with patient Barbara Volcker, wife of former U.S. Federal Reserve Chairman Paul Volcker. According to the article, Mrs. Volcker met Dr. Lockshin in the 1970s to treat her rheumatoid arthritis.

"She was the type of patient that I really enjoyed taking care of because she challenged me on everything. She would say, 'But that answer doesn't make sense. Give me the information behind it. Convince me.' She drove me to question my own assumptions to respond to her," said Dr. Lockshin.

In the late 1990s, Mrs. Volcker's health worsened, and the Volckers offered to establish a center at HSS to honor her. Dr. Steven Paget, who was physician in chief at HSS, and Dr. Charles Christian, who was the emeritus physician in chief, invited Dr. Lockshin, then acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), to discuss the center's mission, and he was ultimately offered the job as director, a position he still holds.

The Center was established in 1997. Mrs. Volcker passed away the following year at the age of 68.

"Her questions are the core of the Center that bears her name," noted Dr. Lockshin.

The Center convened a conference on the biology of sex differences in autoimmune illness—the first of its kind—within a year of opening its doors, notes Dr. Lockshin. The topic later gained national attention for all human health when the Institute of Medicine (later renamed the National Academy of Medicine) convened a committee to address the same question and published a report in 2001, according to Dr. Lockshin, who served on the committee. Doruk Erkan, MD, MPH, a rheumatologist at HSS whose early research focused on antiphospholipid syndrome, joined the Center in 2005 as physician-scientist.

Today, the Center is marking 20 years of research and clinical work devoted to women with various rheumatic conditions. According to Dr. Lockshin, physicians at the Center see more than 3,000 individual patients for issues of pregnancy and contraception, antiphospholipid syndrome, and other rheumatic illnesses.

As part of the Center's research, HSS rheumatologists Jane E. Salmon, MD and Lisa R. Sammaritano, MD are co-investigators of a study on hormone treatment in lupus as well as pregnancy in lupus patients.

Additionally, HSS research associate Mikhail Olferiev, MD received a grant from the center to study the expression of genes across health donors and patients with lupus. "I hope that my study will contribute to a better understanding of an autoimmune disease and possibly identify new therapeutic targets," Dr. Olferiev said.

HSS scientist Theresa T. Lu, MD, PhD also received a grant to study whether fat tissue might influence stromal cells in lymph nodes to contribute to sex differences in rheumatic diseases.

Dr. Lockshin explained that concepts and ideas about pregnancy and issues related to women with rheumatic diseases have changed over time in part because of research discoveries coming out of HSS.

Additionally, the Center recently welcomed a new member, HSS rheumatologist Medha Barbhaiya, MD, MPH. Dr. Barbhaiya explained that she joined HSS because of the Center's strong emphasis on clinical care and clinical research related to lupus, antiphospholipid syndrome, and pregnancy in rheumatic diseases.

Several of its members hold leadership positions associated with the Center's mission, according to Dr. Lockshin. For example, Dr. Erkan chairs both the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, headquartered at the Center, and the 15th International Congress on Antiphospholipid Antibodies. Kyriakos Kirou, MD, conducts lupus nephritis clinical trials, and Dr. Sammaritano chairs the ACR Reproductive Health Guideline Project. With a background in environmental causes of autoimmune illnesses, Dr. Barbhaiya is involved with the ACR. In addition, Dr. Lockshin served on committees with a focus on pregnancy, sex differences, and other aspects of autoimmune illness and he is past editor in chief of Arthritis & Rheumatism (now Arthritis & Rheumatology).

In a phone interview, Mr. Volcker said that he is delighted with the Center's accomplishments over the years. Furthermore, he said he is sure if Mrs. Volcker were alive she would be "very pleased and happy that her name was attached to it, no doubt in my mind".

Read the full article at the-rheumatologist.org. This also appeared in the January 2018 print issue.