The goal of the lupus research program at NYU Langone’s Division of Rheumatology is to reduce the toll lupus takes on patients and their families.
Under the leadership of Jill P. Buyon, MD, program director, and H. Michael Belmont, MD, our researchers conduct a variety of basic, translational, clinical, and epidemiological studies. Amit Saxena, MD, clinical trials director, oversees more than a dozen lupus clinical trials.
Some of our current research topics include the following:
- lupus medications
- lupus flares in women
- congenital heart block
- platelets, endothelial cells, and lupus-associated cardiovascular disease
- the microbiome and lupus nephritis
- imaging for osteoporosis risk in patients with lupus
- racial and ethnic disparities in lupus outcomes
Our researchers are investigating promising new medications for the treatment of lupus.
Anifrolumab for Nonrenal Lupus
Our division is participating in an industry-sponsored, multicenter, randomized, phase 3 trial of the monoclonal antibody anifrolumab. The aim is to evaluate its ability to treat nonrenal manifestations of lupus, in comparison with standard care. Anifrolumab inhibits the activation of interferon proteins, widely viewed as a driving force in lupus, and has received a U.S. Food and Drug Administration (FDA) fast track designation. A related study, also in phase 3, is studying the effects of anifrolumab on renal manifestations of the disease.
Voclosporin for Lupus Nephritis
A second industry-sponsored, multicenter, phase 3 clinical trial is studying the effects of the immunosuppressant voclosporin on lupus nephritis. Medications such as tacrolimus and cyclosporine are typically reserved as second- or third-line treatments for kidney disease because of unfavorable side effects such as high blood pressure and kidney damage. Promising phase 2 trial data suggest that voclosporin compares favorably with the standard of care in achieving remission but with significantly reduced side effects. The investigational drug could be an important add-on to improve remission rates.
Lupus Flares in Women
Researchers are also investigating why lupus flares repeatedly in some female patients but not in other at-risk individuals.
Immunogenetics and the Microbiome
Through the new Translational Center of Molecular Profiling in Preclinical and Established Lupus (COMPEL), Robert Clancy, PhD, and his colleagues are assessing associations between immunogenetics and the microbiome to determine why lupus flares or remains dormant in at-risk women. Work conducted at COMPEL is aided by the NYU Langone–led national Research Registry for Neonatal Lupus, the world’s largest data bank of its kind.
Gut-Associated B-Cell Response
Scientists led by Gregg Silverman, MD, are sequencing patient microbiomes and analyzing the gut-associated B-cell response to determine why some women with established lupus develop flares or kidney disease.
DNASE1L3 Enzyme Defect
Boris Reizis, PhD, is investigating whether lupus in women may originate from a defect in the DNASE1L3 enzyme. Data from a mouse model suggest that knocking out the DNASE1L3 enzyme, thereby preventing the degradation of DNA debris from apoptotic cells, results in lupus-like disease. In humans, a recessive loss-of-function mutation for the enzyme runs in some families, causing lupus, which suggests a crucial role for this enzyme in preventing human lupus.
Asymptomatic Women with Anti-Ro Autoantibodies
Researchers are also evaluating a cohort of women with a child diagnosed with congenital heart block or a skin rash. These women have anti-Ro autoantibodies but were asymptomatic at the time their child was diagnosed. Although multiple research efforts have focused on the children of such patients, researchers know relatively little about the factors that contribute to the mothers’ outcomes.
Congenital Heart Block
Division researchers are making strides in understanding the causes and prevention of congenital heart block.
Genetic Variant Linked to Congenital Heart Block
Scientists have found that the onset of congenital heart block may be linked to a genetic variant of a major histocompatibility complex class I protein that impairs surveillance by natural killer (NK) cells, resulting in unchecked cardiac inflammation and scarring. Based on a genetic comparison of affected and unaffected siblings, an international collaboration led by Robert Clancy, PhD, discovered that the disease is associated with alleles of the HLA-C gene. Children with congenital heart block—but not their anti-Ro–exposed, unaffected siblings—carry an Asn80Lys gene allele.
The research supports a model in which this genetic variant, the C2 allele, binds with high affinity to an inhibitory receptor, called a killer cell immunoglobulin-like receptor (KIR), on NK cells. The binding impairs the ability of KIR to regulate the killing function of NK cells, leaving the immune surveillance system unable to detect abnormal cells and limit cardiac inflammation and injury. The scientists are the first to describe the potentially adverse role of checkpoint inhibitors in autoimmune-associated tissue injury.
A Preventive Approach
Division researchers are also conducting a study, called Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH), because hydroxychloroquine, which crosses the placenta, may decrease the inflammation initiated by the passage of anti-Ro antibodies to the fetus. Investigators hope that the information obtained from this study can help physicians counsel women with anti-Ro/La antibodies who are considering pregnancy.
Platelets, Endothelial Cells, and Lupus-Associated Cardiovascular Disease
Our scientists are also investigating the relationship between platelets and endothelial cells and lupus-associated cardiovascular disease.
Platelets and Endothelial Cells
A research team led by Robert Clancy, PhD, has uncovered new evidence of a critical interaction between platelets and endothelial cells. This interaction could accelerate the pathogenesis of cardiovascular disease in lupus patients. An RNA microarray of normal human umbilical vein endothelial cells, co-incubated with platelets from systemic lupus erythematosus patients, revealed an abnormal platelet-mediated effect on endothelial gene pathways involved in cell activation. In contrast, platelets from healthy volunteers did not yield similar activation of co-incubated endothelial cells.
Researchers also found that the platelets from lupus patients release interleukin-1 (IL-1) beta, which is normally not present in healthy individuals. Because people with lupus can have chronic production of IL-1 beta from platelets in their blood vessels, the research suggests that the triggered endothelium could take on atherosclerosis-like phenotypes. Beyond the up-regulation of proinflammatory surface markers, endothelial cells activated by platelets in vitro begin processing lipids abnormally, as compared with untreated endothelial cells.
Jeffrey S. Berger, MD, who specializes in platelet research, helped the research team uncover these previously hidden platelet–endothelial cell links.
Platelets and Lupus-Associated Cardiovascular Disease
A follow-up collaboration is investigating what factors may be activating platelets in lupus. So far, researchers have identified a key player, an Fc receptor on the platelet surface that binds infection-fighting immune complexes. These immune complexes, normally only transiently produced and then cleared, remain elevated in lupus patients.
The team’s ongoing research suggests that a genetic variant of the Fc receptor, in which an arginine amino acid has been changed to a histidine, yields a highly reactive form of the immune complex. The latter form, present in 40 percent of the U.S. population, interacts aggressively with immune complexes, potentially further delaying their clearance and activating platelets. The research could one day mean that genetic testing might identify the risk of accelerated atherosclerosis for people with lupus, allowing earlier interventions.
The Microbiome and Lupus Nephritis
An interdisciplinary research team led by Gregg Silverman, MD, has found evidence that the immune response to a single commensal bacterial strain in the human gut may be a primary driver for lupus nephritis. This association was observed in four separate cohorts of patients with lupus—white, Asian, African American, and Hispanic.
Lachnospiraceae Bacterial Family
By examining the gut microbiome of people with lupus, the research team discovered that a specific strain of a species within the Lachnospiraceae bacterial family, known as Ruminococcus gnavus, makes a toxin that may contribute to immune complex–mediated kidney disease in lupus nephritis. Compared with controls, the gut microbiome of patients with systemic lupus erythematosus had a fivefold greater representation of Ruminococcus gnavus. The bacterial abundance was even higher in patients with active lupus nephritis. Unraveling the underling disease mechanism could lead to more targeted and effective therapies.
Laboratory Testing to Evaluate the Human Immune Response
Researchers have developed a simple lab test to evaluate the human immune response to and recognition of the bacteria that colonize the intestine but don’t cause local intestinal damage. The research is moving rapidly toward refining a test for clinical use, as well as developing an animal model that would allow the team to test experimental therapies and further investigate root causes of the disease.
Imaging for Osteoporosis Risk in Patients with Lupus
An investigator-initiated collaboration with NYU Langone’s Department of Radiology to evaluate the osteoporosis risk in patients with inflammatory diseases, particularly lupus, is under way. Steroid medications can increase the risk of osteoporosis, and dual-energy X-ray absorptiometry (DXA) scans are the current standard for diagnosing the condition.
However, DXA can underestimate osteoporosis risk. The researchers hypothesize that patients’ bone architecture might reveal more telling differences between osteoporosis induced by steroids, and osteoporosis associated with other factors. Gregory Chang, MD, MBA, has developed a 3 Tesla MRI technique to reveal such differences. An NYU Langone study, funded by the National Institutes of Health, is using this imaging method to compare bone structure in patients with lupus receiving chronic steroid therapy with that of patients not taking steroids and patients diagnosed with other autoimmune diseases.
Racial and Ethnic Disparities in Lupus Outcomes
Our division conducts studies to help resolve long-standing questions of why some minority patients with lupus may experience poorer outcomes. We also seek ways researchers and doctors might better address these disparities and enhance care for underserved populations.
Disparities Among Hispanic and Asian Patients
Through the Manhattan Lupus Surveillance Program, Peter M. Izmirly, MD, and colleagues examined the incidence and prevalence of lupus in the borough, uncovering glaring racial and ethnic disparities in lupus prevalence and aggressiveness, as did a sister study conducted by the California Lupus Surveillance Project.
The research suggests that the prevalence and aggressiveness of lupus are significantly higher among Hispanic and Asian residents than among their white counterparts—although not as high as among black inhabitants. In addition, across all demographics, the burden was found to be far higher in women than in men.
Genetic Variants in African Americans
A second line of research, led by Ashira Blazer, MD, demonstrates that risk variants of the Apolipoprotein L1 (APOL1) gene are associated with prevalent atherosclerotic cardiovascular disease in African Americans with systemic lupus erythematosus. Scientists are assessing whether and how APOL1 risk variants increase the vulnerability of human umbilical vein endothelial cells. One of the variant proteins studied increases risk of damage to endothelial cells when exposed to lupus-relevant inflammatory stimuli such as interferons or autoantigens.
The inflammatory insult of lupus activates the immune system, which causes increased expression of the APOL1 gene. Beyond a certain threshold, the immune factor becomes toxic. The endothelial cell dysfunction includes decreased mitochondrial respiration and reduced angiogenesis, partly because of an impaired ability to complete autophagy. Paradoxically, some of the APOL1 risk variant–carrying patients with lupus have lower inflammatory signals than other patients. The research suggests that some of the damage accrual blamed on lupus, such as cardiovascular and kidney disease, may be more related to the APOL1-related risk factors themselves.
In addition to her work on the well-characterized lupus cohort at NYU Langone, Dr. Blazer is helping build patient cohorts in Ghana and Nigeria to enable further characterization of genetic variants.
Kidney Involvement, Pregnancy, and Minorities
Through the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus study, Jill P. Buyon, MD, and her research team have found that de novo kidney involvement in lupus, even in ethnic or racial minorities, is uncommon during pregnancy. This knowledge could help combat patients’ misconception that becoming pregnant could trigger lupus nephritis.
In other research, the team found that that past kidney disease and low C4 protein levels at baseline were independently associated with a higher risk of developing active lupus nephritis. However, the researchers concluded that the presence of antibodies to double-stranded DNA alone should not raise concerns regarding pregnant patients with past kidney disease, as long as they are in remission.
For more information about our lupus research program, contact firstname.lastname@example.org.