Developing SR-878, a novel monoclonal antibody drug candidate targeting inflammation

SR-878, which builds upon foundational basic research discoveries made in the lab of Carl P. Blobel, MD, PhD, director of the Arthritis and Tissue Degeneration Program at the HSS Research Institute, is a monoclonal antibody drug candidate that targets inflammation in a new way.  More specifically, SR-878 targets a complex consisting of inactive Rhomboid 2 (iRhom2) and TACE/ADAM17 (ADAM17), a “master switch” for regulating the inflammatory response that is overactive in many autoimmune diseases.

ADAM17 is an enzyme involved in accelerating the body’s immune response, which has long held the interest of researchers due to its close association with an already proven target in the treatment of rheumatoid arthritis and other inflammatory diseases, the molecule TNF-alpha.

Researchers hypothesized that going after ADAM17 could prove even more effective than targeting TNF-alpha alone. “Beginning in the late 90s, there was an interest in targeting ADAM17 as another way to reduce TNF-alpha,” Dr. Blobel explains, “but it turns out, on its own, it wasn’t an optimal target because ADAM17 holds other important functions — such as protecting the skin and intestinal barrier.”

However, studies at HSS have since revealed that ADAM17 is regulated by its binding partner iRhom2. When iRhom2 is inactivated, those studies have demonstrated that the related iRhom1 can still protect against the problems observed when ADAM17 is blocked.  This research suggested that iRhom2 could be a safer and more effective target for drugs than ADAM17.

Collaborations with HSS rheumatologist Jane E. Salmon, MD, HSS Chief Scientific Officer Lionel B. Ivashkiv, MD, and HSS Physician-in-Chief Emerita Mary K. (Peggy) Crow, MD further supported this notion.  Those studies explored the effects of knocking out iRhom2 in preclinical mouse models with inflammatory arthritis as well as an autoimmune kidney disease called lupus glomerulonephritis. Their research demonstrated that the mouse models were protected from disease by blocking the TNF-alpha pathway and, in the case of lupus glomerulonephritis, also by inhibiting another pathway that contributes to inflammation, called the EGFR pathway. “We eventually realized that iRhom2 could be a very exciting target,” Dr. Blobel says.

The development of SR-878 underscores the importance of doing basic science research at academic institutions like HSS,” says Michael P. Ast, MD, orthopedic surgeon and Chief Medical Innovation Officer at HSS. “Scientific breakthroughs uncovered in the lab can be used to shape further studies that advance our understanding of complex diseases. Through the knowledge and expertise of investigators at HSS and SciRhom, we can build on the insights made together to ultimately benefit patients worldwide.”

Co-Founding & Advancing SciRhom

During a visiting professorship in 2015 in Munich, Germany, Dr. Blobel met two researchers, Drs. Jens Ruhe and Matthias Schneider, who have extensive experience in preclinical development of early to clinical stage antibody projects.

Together, HSS, the three researchers, and other experienced biotech entrepreneurs and investors, co-founded SciRhom in 2016 to translate Dr. Blobel’s scientific findings into novel therapies for autoimmune diseases.

Proof of concept studies performed by HSS scientist Gisela Weskamp, PhD, have since strongly supported the notions that targeting iRhom2 with SR-878 in a preclinical model of inflammatory arthritis is more effective than targeting TNF-alpha alone and is at least as effective as blocking both TNF-alpha and the EGFR pathway together. In addition, treatment with SR-878 also has potential to block another target of existing therapies, the interleukin-6 receptor. “We anticipate that SR-878 will simultaneously block multiple disease-causing pathways and therefore has potential for superior efficacy relative to current monotherapies,” she adds.

Following on the footsteps of its pre-clinical findings, SciRhom has since expanded its board and management ranks with former executives from the global pharmaceutical industry, including Chief Executive Officer Dr. Jan Poth, former Therapeutic Area Head Immunology at Boehringer Ingelheim, and board member Dr. Wolfgang Baiker, former CEO of Boehringer Ingelheim USA.

“SciRhom’s recent Series A financing and its approval to start clinical trials are pivotal milestones in the company’s journey towards commercialization” says Vijay Nair, Managing Director at the HSS Innovation Institute. “Bringing a discovery from the lab to patients requires immense dedication and collaboration across HSS and with the biotech entrepreneurial and investment communities. Their leadership and external validation have been critical in launching the company, securing funding, attracting world-class talent, pursuing pre-clinical development, and reaching this inflection point.”

“There is a lot of enthusiasm for this approach among members of the medical and investment communities. We are tremendously excited that we can now advance the study of this drug to human trials,” says Dr. Blobel.

Current treatments for autoimmune diseases focus on suppressing the parts of the immune system that trigger inflammation and cause disease symptoms. But the immune-suppressing activity of these drugs also leads to side effects, including an increased susceptibility to infections.  New therapies are needed that are anti-inflammatory without being immunosuppressive.    The new study suggests that if immune cells and autoantibodies can be kept within the bloodstream, inflammatory damage is prevented.

“The idea is that if we can bolster the integrity of the blood vessels, we can prevent the immune components that trigger and mediate inflammation from entering tissues and attenuate disease ” says first author Nathalie Burg, MD, a rheumatologist and assistant scientist in the HSS Research Institute.

“This would be a completely new approach to treat or prevent organ damage in autoimmune diseases,” adds senior author Jane Salmon, MD, a rheumatologist and senior scientist at HSS.

The key to this research is a molecule called S1PR1 (Sphingosine 1-Phosphate Receptor 1). S1PR1 is important for maintaining vascular integrity — meaning it helps the endothelial cells lining the walls of the blood vessels stick together.

As part of the study, the scientists first developed mouse models with S1PR1 knocked out specifically in endothelial cells and determined that when these mice were exposed to serum that causes arthritis, there was more inflammation and damage in their joints.  In contrast, drugs that augment S1PR1 signaling and tighten the junctions between endothelial cells attenuated arthritis in experimental models.  Subsequently, an analysis of samples from patients with rheumatoid arthritis confirmed decreased levels of S1PR1 in the micro vessel endothelial cells lining the joints as well as lower levels of S1P and Sa1P, molecules that stimulate S1PR1, circulating in the bloodstream.

“This helps to confirm the role that S1PR1 plays,” Dr. Salmon explains.

While doing this research, Dr. Burg also discovered a mechanism by which S1PR1 regulates the integrity of the blood vessel walls: It helps to restrain the cleavage of a molecule called VE- cadherin, which acts like Velcro in holding the endothelial cells together. Thus, when S1PR1 is deleted or its function is blocked, the VE cadherin molecules are broken and the blood vessels become leaky.

“This research is truly multidisciplinary and also unconventional,” Dr. Salmon says. “It represents the capacity to apply one field — vascular biology — to another — immunology. It is really done at the interface of the two disciplines.” Dr. Burg learned many of the techniques used in this research in the laboratory of Timothy Hla, PhD, a leading vascular biologist and investigator at Harvard Medical School. Dr. Hla and members of his team are co-authors of The Journal of Clinical Investigation Insight paper.

The investigators plan to continue studying this approach, with the goal of designing clinical trials of drugs that boost endothelial cell S1PR1. Such drugs already exist.  

Drs. Burg and Salmon posit that these interventions would likely be used in combination with existing drugs, especially in early disease, before longstanding damage has occurred. “We don’t think this pathway is powerful enough to prevent these diseases on its own, but by combining this type of drug with an immunosuppressant, we might get a synergistic effect,” Dr. Burg says. “This might allow us to reduce the amount of immunosuppression that is needed to keep autoimmune disease under control.   We are testing the role of endothelial S1PR1 in other models of inflammatory arthritis.

Dr. Salmon and her team completed an observational study of 775 pregnancies to determine the strongest predictors of pregnancy complications in patients with lupus and/or APS. The presence of certain autoantibodies in women with APS with or without lupus is associated with a nearly 50% risk for serious adverse pregnancy outcomes. The IMPACT trial will determine whether treatment with Certolizumab, a monoclonal anti-TNF antibody that blocks inflammation, will prevent serious pregnancy complications. Studies in experimental animal models show that blocking this inflammatory mediator prevents preeclampsia, fetal death and fetal growth restriction – all problems seen in patients with lupus and with APS.

The grants from the NIH and Lupus Foundation of America come at a pivotal time in the study as they have recently enrolled 40 patients, and, so far, they are seeing promising results. The trial is spearheaded by the HSS Research Institute and University of Utah, where Dr. David Ware Branch serves study Co-Principal Investigator.  Patients across the nation are eligible to enroll in the trial. To do so, they or their physicians can contact Drs. Salmon or Branch.

Dr. Salmon, Co-Principal Investigator of the trial, said, “In addition to helping lupus and APS patients carry babies to term – a feat once deemed near impossible—we hope to eventually apply the results of our study to non-autoimmune patients at risk for preeclampsia, a life-threatening and common condition with no treatment.”

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).

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.

At present, only one drug is approved for SLE based on a successful randomized, placebo-controlled trial. Numerous immunomodulatory treatments have failed in phase III trials, and patients continue to be burdened with complications from their disease.

While the positive results from the TULIP-2 trial were met with great excitement, there is concern because TULIP-1, a simultaneous trial of anifrolumab, an antibody that inhibits all signaling through the type I interferon receptor — failed to meet its primary endpoint. In an editorial also published in this week’s NEJM, ahead of print, Jane E. Salmon, MD, the Collette Kean Research Chair at Hospital for Special Surgery (HSS), makes the case that future study designs should allow greater flexibility in defining success. Dr. Salmon was asked to discuss the differences between TULIP-1 and TULIP-2 along with Timothy Niewold, MD, the Judith and Stewart Colton Professor of Medicine and Pathology at the Colton Center for Autoimmunity at NYU School of Medicine.

Multiple investigators, including Mary K. Crow, MD, physician-in-chief and chief of the Division of Rheumatology at HSS and NewYork-Presbyterian/Weill Cornell Medical Center, have shown that activation of type I interferon is a central pathogenic mediator of SLE. While TULIP-2 delivered positive results using both instruments for assessing drug efficacy, the BILAG-Based Composite Lupus Assessment (BICLA) and Systemic Lupus Erythematosus Responder Index (SRI), TULIP-1 was positive only on BICLA (a secondary outcome) and did not show a significant response in SRI, the predetermined primary outcome.

SRI and BICLA used in TULIP-1 and -2 are rigorous composite responder indices used to test drugs for SLE. “To have successful lupus trials, we need to be more flexible in how to define success. Our goal is to prevent organ damage and help patients live with lupus. It is not clear that a BICLA response differs from an SRI response in this regard,” said Dr. Salmon, who is also professor of medicine and professor of and associate dean, faculty affairs, at Weill Cornell College of Medicine.

Lupus is clinically very heterogeneous. Disease activity in SLE is manifest in up to eight organ systems, and response is difficult to assess without the use of complex outcomes measures. The BICLA and SRI instruments incorporate several dichotomous endpoints that classify patients as responders based on discrete components of subsidiary scales. Both composite indices require that responders demonstrate global improvement, that they cannot significantly worsen in individual domains (mainly organ dysfunction), and that they do not require use of restricted medications. Efficacy in SRI is determined by a reduction in the SLE Disease Activity Index (SLEDAI) total score, whereas improvement in British Isles Lupus Assessment Group (BILAG) is defined by efficacy in the BICLA.

Since concordance between SRI and BICLA has been demonstrated, it would be expected that these indices should provide comparable results, but this has not been true in all lupus clinical trials. Dr. Salmon noted the selection of outcomes instruments is a challenge in designing clinical trials for lupus. Because TULIP-1 showed a BICLA response, the primary end point for TULIP-2 was changed from SRI to BICLA response before the trial was unblinded. During the design of both phase III TULIP trials, SRI and BICLA response were candidates for primary end points; SRI was selected on the basis of precedence from phase III trials of belimumab.

“If one considers the BICLA and SRI response rates used in the three anifrolumab trials, the phase II trial and two TULIP trials, five of six primary and key secondary outcomes favored the drug compared with placebo,” cited Dr. Salmon. She suggested that regulators should require that only one of two outcomes need to be met — SRI or BICLA — to declare a drug effective in a disease as complex as lupus. “Such strategies might accelerate drug development in lupus until we have universally accepted response measures and biomarkers that allow grouping of SLE patients by biological pathways that drive their disease,” said Dr. Salmon.

The study, published April 8 in the Journal of Experimental Medicine, was designed to find early molecular predictors of the hypertension syndrome preeclampsia, miscarriage and other adverse pregnancy outcomes in women with the autoimmune disorder lupus, who face a relatively high risk of such outcomes. Over half of the more than 200 women studied were lupus patients. But the results suggest that modulation of the immune system during pregnancy is very similar in women with and without lupus.

“These findings help us understand not only pregnancy for women with lupus but pregnancy generally,” said study co-senior author Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine. Dr. Pascual has received a research grant and consulting honorarium from Sanofi-Pasteur.

“There are implications here for predicting adverse pregnancy outcomes and also for identifying therapeutic targets to prevent those outcomes,” said co-senior author Dr. Jane Salmon, a professor of medicine and of medicine in obstetrics and gynecology at Weill Cornell Medicine, and the Collette Kean Research Professor at HSS. Dr. Salmon has received an investigator-initiated grant from UCB Pharmaceuticals.

Lupus affects more than 500,000 people in the United States alone, and about 90 percent of them are women. The disorder features attacks by antibodies and other immune elements on the skin, heart, kidneys and other organs. Women with lupus who become pregnant face a roughly 20 percent chance of serious complications including miscarriage, preterm birth, stillbirth, and preeclampsia, a condition that endangers both the mother and unborn child. Prior research suggests that such complications, even in women without lupus, are at least partly caused by improper regulation of the maternal immune system—which must be tamed somewhat during pregnancy to allow tolerance of partly “foreign” fetal tissue.

From 2003 and for more than a decade afterwards, Dr. Salmon and colleagues enrolled more than 700 women, about half of them pregnant women with lupus, for a multi-center study called PROMISSE designed to uncover risk factors for adverse pregnancy outcomes. For the new study, Drs. Salmon and Pascual and their colleagues made use of blood samples and other clinical data from a subset of that cohort enrolled in 2003-13, including 92 pregnant women who had lupus and 43 pregnant women who didn’t have the disorder.

Analyses of the patterns of gene activity in these women’s white blood cells during the course of pregnancy showed that in healthy women with uncomplicated pregnancies, key elements of the immune system tended to be quieted shortly after the establishment of pregnancy, and tended to remain relatively quiet throughout the pregnancy. These were largely the same sets of genes that are overactive in lupus, and include genes relating to the production of molecules called type I interferons that marshal an immune response to viral infections.

“The surprise for us was when we looked at the data for women with lupus who had uncomplicated pregnancies,” Dr. Pascual said. “They started, as expected, with a higher level of activity in these immune pathways, but once they got pregnant these immune pathways were modulated much as they were in pregnant women without lupus.”

By contrast, in pregnant women who developed preeclampsia or other serious complications, these immune pathways were downregulated to a smaller extent from their baseline levels, or not at all.

In a separate study of 25 healthy women undergoing in vitro fertilization, the researchers observed the same healthy-pregnancy and complicated-pregnancy immune-gene signatures, and found that these patterns began to emerge at the very outset of pregnancy, with embryo implantation.

The findings, if confirmed in larger groups of pregnant women, could lead to the development of early diagnostic tests predicting pregnancy complications, and ultimately treatments that quiet specific elements of the immune system to protect women from complications. “If we could identify a pathway to target with drugs to prevent preeclampsia in lupus patients,” Dr. Salmon said, “we could immediately consider the same treatment approach to protect women who don’t have lupus but have similar high-risk biomarkers early in pregnancy."

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Weill Cornell Medicine is committed to excellence in patient care, scientific discovery and the education of future physicians in New York City and around the world. The doctors and scientists of Weill Cornell Medicine — faculty from Weill Cornell Medical College, Weill Cornell Graduate School of Medical Sciences, and Weill Cornell Physician Organization—are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. Located in the heart of the Upper East Side's scientific corridor, Weill Cornell Medicine's powerful network of collaborators extends to its parent university Cornell University; to Qatar, where Weill Cornell Medicine-Qatar offers a Cornell University medical degree; and to programs in Tanzania, Haiti, Brazil, Austria and Turkey. Weill Cornell Medicine faculty provide comprehensive patient care at NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian Lower Manhattan Hospital, NewYork-Presbyterian Queens and NewYork-Presbyterian Brooklyn Methodist Hospital. Weill Cornell Medicine is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

"Omega-3 fatty acids in krill oil inhibit a number of aspects of inflammation, and krill oil supplementation has been proposed as an over-the-counter supplement for many different indications, including cardiovascular disease. In this trial, we are formally testing its potential to lessen the severity of symptoms associated with lupus," said Jane Salmon, MD, coordinating investigator of the multicenter trial and Director of the Lupus APS Center of Excellence and Co-Director of the Mary Kirkland Center for Lupus Research, both at HSS. "This multicenter clinical trial reflects our responsiveness to the wishes of our patients, a safe option that has the potential to attenuate lupus disease activity and the cardiovascular complications associated with it."

Kyriakos Kirou, MD, rheumatologist at HSS and site coordinator for the trial, said that if the trial is positive, he foresees using krill oil in people with active and inactive lupus. "This supplement is predicted to help the lipids in the bodies of patients with lupus," said Dr. Kirou. "People with lupus may develop premature cardiovascular disease because of dyslipidemia, problems with levels of lipids. When people affected by lupus are in their 40s, they are more at risk for developing heart attacks or strokes than others without the disease. Even people whose lupus has become quiet may develop atherosclerosis and heart disease."

Lupus, most often diagnosed between the ages of 15 and 45, is an acute and a chronic autoimmune, multisystem illness in which the body attacks its healthy tissues, resulting in redness or swelling, pain, and organ damage. It affects each person differently and can be very mild or severe. A panoply of symptoms, such as facial rash, painful or swollen joints, and inflammation of organs may come and go without warning. 

Researchers are launching the new trial, in part, because there is evidence that polyunsaturated fatty acids (PUFA) such as omega-3s inhibit inflammation, that people diagnosed with lupus are deficient in omega-3 PUFA, and that krill oil decreases disease activity in patients with rheumatoid arthritis. "Polyunsaturated fatty acids in animal models of lupus and lupus nephritis have shown improvement in survival, kidney disease, and levels of autoantibodies," said Dr. Kirou. "Omega-3s are the backbone for the synthesis of Specialized Pro-Resolving Molecules (SPM), anti-inflammatory mediators." In particular, krill oil contains omega-3 fatty acids that are bound to phospholipids, which significantly helps your body’s cells absorb the omega-3s better.

Patients in the double-blind trial will be randomized to receive either a soft gel formulation of krill oil (Aker BioMarine [AKBM]-3031, Omega-3 Phospholipids from krill) or placebo for 6 months and then all patients will receive the active supplement for another six months. "It is a safe supplement. There is strong rationale that it will effectively decrease inflammation in lupus," said Dr. Kirou.

Matts Johansen, CEO at Aker BioMarine said, "Lupus is a frustrating, chronic disease with no known cure which affects millions of people all over the world. We are so excited that molecules from krill can potentially reduce the symptoms associated with lupus."

The trial’s primary objective is to assess the ability of the supplements to replenish the omega-3 dietary deficiency in people with lupus, by measuring the omega-3 index and red blood cells in patients. Secondary objectives include assessing safety and quality of life, whether the correction of the omega-3 deficiency may reduce disease activity in patients with lupus, and whether it has a steroid-sparing effect.

HSS began enrolling patients on January 11. While in the clinical trial, patients will be maintained on stable doses of other medications, except for glucocorticoids; decreases in doses of glucocorticoids will be encouraged during the first 20-weeks of both the randomized and open-label extension portions of the trial. The trial will exclude patients on anticoagulants and those with shellfish allergies.

FDA-approved treatments for lupus are very limited, with only one new drug approved in that last 60 years. Researchers don’t expect krill oil to reverse very serious, life-threatening organ damage, but think it could be used an adjuvant and that it could attenuate disease by increasing the production of specializing pro-resolving molecules, thus decreasing the symptoms of lupus. 

"Krill oil may help the natural mechanisms of healing," said Dr. Salmon. "Steroids and immunosuppressive drugs have a range of side effects that people with lupus find hard to tolerate. If we can give them alternative therapies that allow them to take lower doses of their traditional drugs, it would make a very big difference to their quality of life. I don’t expect krill oil to be as potent as the immunosuppressive therapies we administer, but if it is even modestly effective, we may be able to maintain low disease activity with less medication."

Jane E. Salmon, MD, rheumatologist at HSS, notes that a take home message of the study is that "better and more consistent use of immunosuppressive therapy seems to decrease end-stage renal disease".

"At Hospital for Special Surgery, we have always been concerned when we see hypertension, increased creatinine and lack of consistent baseline immunosuppression in lupus nephritis patients. Further confirmation that these features are associated with a worse prognosis for renal disease underscores our need to continue to aggressively monitor and treat them," Dr. Salmon says.

Read the full article at The-Rheumatologist.com.

"Earlier physicians had done wonderful work and wrote eloquent descriptions distinguishing lupus erythematosus from tuberculosis and other entities. But it was Dr. Kaposi who identified lupus as a disease of young women that was systemic and life-threatening. For this reason, I think this paper is really interesting," said Dr. Salmon.

According to Dr. Salmon, Dr. Kaposi established an early version of classification criteria for lupus. "Now, we use validated classification criteria to help us have consistent definitions of patients for clinical trials. We are beginning to look at subsets of responders to specific therapies, using tools beyond the physical examination, clinical laboratory tests and the microscope, to approach treatment from the perspective of disease mechanism," she said.

Read the full article at the-rheumatologist.org.

"This trial reflects our responsiveness to patient wishes — a treatment that is safe and has the potential to attenuate lupus disease as well as the associated cardiovascular complications associated with it," said Dr. Salmon.

According to the article, the goal of the study is to evaluate changes in levels of blood omega-3 and omega-6 fat molecules over the course of the trial.

Read the full article at lupusnewstoday.com.

Founded in 1947, EULAR’s mission is to reduce the burden of rheumatic conditions and to improve the treatment, prevention and rehabilitation of musculoskeletal diseases. EULAR represents the scientific societies of rheumatology in all the European nations, health professional associations, and organizations for people with rheumatism.

As a mark of distinction, EULAR elects honorary members based on their outstanding service in accomplishing the organization’s objectives and in 2017, began nominating its first overseas individuals. Dr. Crow is among the first two Americans honored in 2017, and Dr. Salmon is the third American recognized.

About Dr. Crow

As physician-in-chief and chief of Rheumatology, Dr. Crow leads 66 full-time physicians including both adult and pediatric rheumatologists. Additionally, Dr. Crow’s academic and research career has focused on the molecular mechanisms that underlie systemic autoimmune diseases with a focus systemic lupus erythematosus and rheumatoid arthritis.

About Dr. Salmon

At HSS, Dr. Salmon is the director of the Lupus and APS Center of Excellence, co-director of the Mary Kirkland Center for Lupus Research, and director of the FOCIS Center of Excellence. Dr. Salmon’s research has focused on the mechanisms of tissue injury in lupus and other autoimmune conditions.

She interviews Jane E. Salmon, MD, rheumatologist at HSS, who explains that statins have pleiotropic effects, both lipid lowering and anti-inflammatory.

"Although the risk for CVD [cardiovascular disease] in [people with RA] is elevated, similar to patients with diabetes, CV risk management is generally not implemented. Attention to comorbidities such as hypertension, hyperlipidemia, and smoking is essential [for people with] RA. Control of RA disease activity is also likely to attenuate or decrease CVD risk in RA," says Dr. Salmon.

Read the full article at RheumatologyAdvisor.com.

Study author Jane E. Salmon, MD, rheumatologist at HSS, explained that these research findings uncovered a possible new target for selective and simultaneous inhibition of two major pathological pathways in the effector arm of lupus nephritis.

"Moreover, the intensity of HB-EGF expression in interstitial cells in lupus nephritis positively correlated with disease chronicity index, an indicator of irreversible damage and poor prognosis," added Dr. Salmon.

Read the full article at Healio.com/Rheumatology.

Findings indicated that the protein ADAM17 plays a key role in inflammatory disorders, and iRhom2 regulates the production of the ADAM17 protein.

"They separate out the protective and pro-inflammatory functions of the gene. iRhom2 is meant to immediately respond to bacterial invaders by activating ADAM17," said HSS senior scientist and co-senior study author Carl Blobel, MD, PhD.

"A mechanism to block or inhibit iRhom2 would inhibit two key pathways for renal [kidney] injury in patients with lupus without significant side effects," said HSS rheumatologist and co-senior study author Jane E. Salmon, MD.

According to the article, this approach could be the basis of new treatments for kidney damage in lupus patients.

"From a medical point of view, that's what makes this approach so attractive," said Xiaoping Qing, MD, PhD, the study's first author.

Read the full article at lupusnewstoday.com

Researchers at the Hospital for Special Surgery (HSS) and their colleagues found that inactivating the protein, called iRhom2, prevented kidney injury in mice vulnerable to developing lupus. Particularly promising, according to the researchers, is that the kidneys of mice lacking the iRhom2 gene were shielded by both a reduction in general inflammation and the prevention of irreversible scarring of the organs -- a powerful two-for-one effect.

"A mechanism to block or inhibit iRhom2 would inhibit two key pathways for renal injury in patients with lupus without significant side effects," said Jane Salmon, MD, Collette Kean Research Chair and Senior Research Scientist at the Hospital for Special Surgery, and Professor of Medicine at Weill Cornell Medicine, who led the study in collaboration with Carl Blobel, MD, PhD, the V. F. and W. R. Salomon Chair in Musculoskeletal Research and Director of the Arthritis and Tissue Degeneration Program at HSS and Professor of Medicine at Weill Cornell Medicine.

The researchers reported their findings in the March 5th issue of the Journal of Clinical Investigation.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects an estimated 1.5 million people in the United States. The condition frequently leads to severe and potentially lethal damage to a variety of organs including the skin, brain, lungs, heart and kidneys. Women are roughly 10 times more likely than men to develop lupus.

Kidney damage from lupus, called lupus nephritis, affects between 40 percent and 60 percent of adults with SLE. Injury to this organ, which filters waste from the bloodstream and helps regulate blood pressure, involves the gradual accumulation of molecules called immune complexes. These clusters trigger inflammation that can lead to irreversible scarring and eventual failure of the organ. Patients with kidney failure must undergo regular dialysis until a transplant is available.

Over the past 20 years, researchers have identified several proteins that contribute to chronic kidney disease. One of these, a disintegrin and metalloprotease 17 (Adam17), acts like a pair of molecular scissors on the surface of cells. Its job is to clip off, or shed, substances that act as signals to other cells. Among these signaling molecules are a potent driver of inflammation called tumor necrosis factor-alpha (TNF-α), and heparin-binding epidermal growth factor (HB-EGF), a protein that helps maintain the skin and intestinal integrity.

However, in autoimmune diseases such as lupus, HB-EGF is directly linked to irreversible scarring, or fibrosis, of kidney tissue, while having too much TNF-α marshals the immune system to wage perpetual war against the body itself by activating inflammatory cells to attack the organs.

Scientists have tried inhibiting Adam17 in the hopes of reducing or eliminating the excessive shedding of TNF-α that leads to tissue injury in autoimmune illnesses. But Dr. Salmon points out that Adam17 is involved in so many processes – including essential functions such as keeping the skin and gut protected against microbial invaders – that blocking it could prove catastrophic.

In earlier work, Dr. Blobel and colleagues found that iRhom2 and a related gene, iRhom1, control the expression of Adam17. "They separate out the protective and pro-inflammatory functions of the gene. iRhom2 is meant to immediately respond to bacterial invaders by activating Adam17, which tells cells to release defensive substances (TNF-α) and strengthen the integrity of the skin and intestines by releasing HB-EGF," he said. "If you have a breach of the barrier, you want to do two things: You want to rebuild the barrier and you want to activate the immune system."

For the new study, the HSS investigators sought to learn if they could ratchet down Adam17 by manipulating iRhom2. "In patients with lupus nephritis, you see an increase in expression of iRhom2," Dr. Salmon said. "But if you have more iRhom2, you have more Adam17, and therefore more shedding of TNF-α and HB-EGF."

Xiaoping Qing, MD, PhD, an Instructor in Autoimmunity and Inflammation Program studied a strain of mice with a mutation that predisposes them to lupus and kidney injury. Blocking iRhom2 prevented the organ damage. Analysis of the kidney tissue showed greatly reduced inflammation, scarring and other signs of harm.

The researchers also treated the same strain of mice either with a drug that suppresses the activity of TNF-α or a drug that blocks signaling by the receptor for HB-EGF, the EGFR. Treated animals showed significantly less evidence of kidney damage than untreated rodents, indicating that TNF-α and the EGFR play important roles in the disease process of lupus.

Using tissue samples from kidney biopsies, they found that elevated expressions of HB-EGF with the highest levels are associated with irreversible damage. In addition, exploring data from a large national databank revealed that kidney cells from patients with lupus express abnormally high amounts of iRhom2, another indicator of the role of this molecule in the development of lupus nephritis.

The findings are particularly promising, the researchers added, because despite hitting two extremely important molecular pathways at the same time, blocking iRhom2 appears to be quite safe. "From a medical point of view, that’s what makes this approach so attractive," Dr. Qing said. "Nobody can find anything wrong with mice that have no iRhom2, but they seem to be protected from autoimmune diseases."

In future research, the HSS team hopes to test various methods of suppressing iRhom2.

"The complement activation pathway is involved in the pathogenesis of pregnancy complications in patients with lupus and antiphospholipid antibodies. Higher levels of complement activation are associated with problems in pregnancy," said lead study author Jane Salmon, MD, Collette Kean Research Chair at Hospital for Special Surgery, in New York City. The study is confirmatory of mice studies that have implicated inflammation, particularly complement activation and recruitment of neutrophils, as a causative factor in placental insufficiency, fetal loss, and growth restriction.

Currently, Dr. Salmon said, the findings cannot be used to identify women at risk in the clinic, because the tests measuring complement activation are only available for research and they don’t have the sensitivity or specificity to be used alone to predict outcome. However, said Dr. Salmon, the identification of biomarkers that put patients with lupus or aPL at risk will allow the identification of a subset of patients who can be considered for an intervention trial.

"What I would most like to do is a trial to block complement activation in high-risk patients. There are many companies developing such drugs," said Dr. Salmon.

Lupus is a chronic inflammatory disease, in which the body’s own immune system attacks tissues of the body and can cause complications during pregnancy. Antiphospholipid antibodies interfere with phospholipids, a type of fat found in all living cells and cell membranes, including blood cells and the lining of blood vessels. Patients with these antibodies are at risk for blood clots, stroke and pregnancy complications, but some patients with these antibodies can be completely healthy.

The multicenter, prospective PROMISSE trial has been comparing the pregnancies of women with aPL, lupus, both aPL and lupus, and healthy controls. Between 20 percent and 25 percent of patients with lupus and/or aPL have pregnancy complications and the study aimed to identify which patients are at risk.

The study enrolled 487 pregnant women with SLE and/or aPL and 204 pregnant healthy controls (n=204) who were less than 12 weeks from gestation and evaluated them monthly. Researchers measured complement activation products, including Bb and sC5b-9, on serial blood samples at each monthly visit. They tracked adverse pregnancy outcomes, which were defined as fetal/neonatal death, preterm delivery less than 36 weeks because of placental insufficiency or preeclampsia and/or growth restriction less than the fifth percentile.

Adverse pregnancy outcomes occurred in 20.5 percent of patients with SLE and/or aPL. As early as 12 to 15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with adverse pregnancy outcomes and remained elevated through 31 weeks, compared with those with normal outcomes. When analyses were restricted to patients with aPL, associations between Bb at 12 to 15 weeks and adverse pregnancy outcomes were stronger.

"Low levels of complement activation go on in many patients with lupus, but higher levels of complement activation are associated with problems in pregnancy," explained Dr. Salmon. "There are many pathways to activate complement. Our identification of Bb strongly argues that this alternative pathway to activate complement is very important in disease, supporting the mouse studies, but it also focuses a potential therapy on this pathway as opposed to some of the others." She said researchers can test the benefits of an intervention by measuring whether it can decrease levels of complement activation.

The PROMISSE study was funded by the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health in 2003 to identify biomarkers that would predict poor pregnancy outcomes in lupus patients. PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) involves nine centers in North America.

According to the article, Dr. Salmon and her colleagues reviewed data from the PROMISSE study, Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus.

Dr. Salmon noted that this study confirms past research that has implicated inflammation, particularly complement activation and recruitment of neutrophils, as a causative factor in placental insufficiency, fetal loss and growth restriction.

Additionally, Dr. Salmon said that "although our findings cannot now be used to identify women at risk in the clinic, because the tests these measuring complement activation products are only available for research and they don't have the sensitivity or specificity to be used alone to predict outcome, the identification of biomarkers associated with risk in pregnant patients with lupus or aPL will allow identification of specific patients for trials targeting complement and downstream mediators."

Read the full article at healio.com [registration required].

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.