November 15, 2021
The Lupus Research Alliance (LRA) supports research into causes and mechanisms of lupus, and identification of targets supporting the development of new therapies or cures for lupus patients. At this year’s meeting of the American College of Rheumatology (ACR), 17 LRA-funded researchers presented their work to share discoveries with the thousands of rheumatologists in attendance around the world. Following are just a few highlights of the studies that LRA researchers presented:
Precision medicine and personalized treatments may offer superior care for lupus patients
One of the main questions for researchers is why lupus treatments fail if the mechanisms of disease that the current therapies target are right? This was the central question Dr. Virginia Pascual, the Director of the Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine, posed at the beginning of her presentation titled Precision Medicine in Lupus 2021.
Lupus is a heterogeneous disease – differing widely from person to person, with both genetic and environmental causes. Understanding how lupus develops and how it causes different symptoms in different people are critical for the development of personalized and precision medicine treatments that could be far more effective than the existing one-size-fits-all lupus therapies.
To study lupus heterogeneity, Dr. Pascual and collaborators followed 158 children with lupus, each of them individually, for up to four years through flares and remissions. They found that while lupus is worsening in these patients when they are assessed as a group, pediatric lupus patients studied in this investigation could be separated into at least three patient subgroups that differed in what may cause their disease to progress.
In the first subgroup of lupus patients, the disease activity was associated with elevated interferon production and increased neutrophil activity. Neutrophils are immune cells that in lupus patients produce interferons. These molecules cause and promote inflammation. Another way neutrophils make lupus worse is by releasing mitochondria that are the “powerplants” inside our cells which convert energy from food into chemical fuel. Neutrophils also make inflammation in lupus bad by releasing extracellular traps or NETs that act like “sticky spider webs”, catching infectious bugs that invade our bodies.
In the second subgroup of patients, the lupus disease activity was associated with neutrophil activity and presence of “plasmablasts,” unique immune cells which mature to B cells that in lupus patients produce the autoantibodies that attack and damage body’s own organs.
Interestingly, in the third subgroup of patients, lupus disease severity was related mostly to plasmablasts and not to increased interferon production or unwanted neutrophil activity.
Dr. Pascual noted that the study demonstrated that following lupus patients individually and separating them into subgroups based on what makes their lupus worse gave a research team better insight into patients’ disease than if her team and collaborators had studied all 158 pediatric lupus patients together as one group.
Dr. Pascual further strengthened her argument that lupus patients should be studied in disease activity groups by presenting a recent finding on how red blood cells (RBCs) contribute to the development of lupus in a unique group of pediatric patients with active disease. Normal RBCs carry oxygen around the body and remove their mitochondria as they mature in the bone marrow. However, in some pediatric patients with lupus, RBCs keep their mitochondria. In fact, the presence of RBCs containing mitochondria was linked to higher lupus disease activity in these patients. Since mature RBCs with mitochondria that circulate in blood are “considered” “broken” by the immune system, they are removed from blood by macrophages, which are immune cells that essentially eat and destroy dysfunctional, dying, or dead cells as well as foreign invaders such as bacteria. In lupus, however, removal of mature RBCs that retain mitochondria by macrophages causes a flood of interferons that promote autoimmune inflammation which is very damaging for patients.
Dr. Pascual’s research clearly suggests that separating lupus patients into subgroups and treating them with more personalized, precision medicine approaches, which specifically target events that make lupus in their disease group worse could be more effective than just treating all lupus patients with the same therapy. This is important because causes and drivers of lupus are not the same in all patients.
The role of neutrophils and NETosis in lupus
During the session titled The Many Faces of Cell Death, a presentation by Jason Knight, MD, PhD, an Associate Professor at the University of Michigan,titled “NETosis in lupus and APS” discussed how neutrophils via NETosis may contribute to lupus progression.
Neutrophils are white blood cells deployed by the immune system that act as first responders against infectious microbes, including bacteria and fungi. One mechanism used by neutrophils to capture invaders is the release of neutrophil extracellular traps or NETs via a process known as NETosis, following which neutrophils die. NETs resemble “spider web-like” structures that effectively capture infectious microbes. Dr. Knight highlighted that in healthy people when the neutrophils capture and kill invaders by NETs, these are cleared from blood or tissues together with the captured microbes. However, in some lupus patients who are prone to lupus nephritis, the removal of neutrophil NETs is “broken”, which allows NETs to accumulate in blood, tissues or organs, causing increased interferon production, damage to the blood vessels or inflammation in the kidneys. Dr. Knight pointed out that one prominent reason the clearance of NETs is inefficient in some lupus patients is the presence of genetic variants which cause the neutrophils to overproduce NETs that cannot be cleared properly.
These findings suggest that better understanding of neutrophil NETosis is needed to identify novel targets that could be used to restore impaired clearance of neutrophil NETs, which would allow for better management of lupus symptoms.
Interferons in cutaneous (skin) lupus
In the session titled New Cytokine Targets in Autoimmunity, J. Michelle Kahlenberg, MD, PhD, an Associate Professor at the University of Michigan, in her presentation titled “Interferons in Cutaneous Lupus: Beyond Alpha, Beta and Gamma” highlighted the importance of various interferons in patients with cutaneous lupus erythematosus (CLE). CLE is a form of lupus affecting the skin, causing rashes or sores that often occur on sun-exposed areas such as the face, ears, neck, arms, and legs.
Cutaneous lupus patients have high levels of types I and II interferons that cause the immune cells to become overactive, force skin cells to die prematurely and increase patient’s sensitivity to sunlight. But how type I and II interferons promote CLE remains unclear.
Dr. Kahlenberg aimed to find out how interferon kappa, which is type I interferon, causes or makes CLE worse and found that lupus keratinocytes, cells in the outermost layer of the skin, die much faster when exposed to a form of sunlight called ultraviolet light compared to healthy keratinocytes. Moreover, Dr. Kahlenberg also produced mice that make high amounts of interferon kappa in the outer layer of the skin called epidermis and observed that exposure of these mice to ultraviolet light causes massive death of keratinocytes. These findings suggest that interferon kappa increases keratinocyte sensitivity to sunlight and promotes keratinocyte death when these cells are exposed to ultraviolet light. These events cause skin inflammation that makes cutaneous lupus worse. Dr. Kahlenberg also pointed out that type III interferons, specifically interferon lambda, was also found elevated in the skin of patients with cutaneous lupus. The role of interferon lambda in CLE remains to be studied, but Dr. Kahlenberg predicts that interferon lambda like other interferons could contribute to skin inflammation which promotes CLE.
Understanding how various interferons affect the skin could identify targets used to prevent or treat active skin inflammation in CLE that would put patients with cutaneous lupus one step closer to living without fear or flare from the sunlight.
“We are highly enthusiastic about the research progress the Lupus Research Alliance-funded investigators have made in the past twelve months as we anticipate that the discoveries will aid in the development of new approaches to study lupus that could improve our ability to diagnose and treat this disease as well as in identification of novel targets for new treatments” noted Dr. Teodora Staeva, Chief Scientific Officer at the Lupus Research Alliance.
Late-Breaking News for Lupus Community at ACR
Immunosuppressive Drugs Linked to COVID-19 Breakthrough Infections
In one late-breaking abstract, investigators reported that their study of 115 patients with rheumatic diseases such as lupus showed that most fully vaccinated patients who experienced breakthrough infections were those treated with immunosuppressive drugs. These included anti-metabolite drugs such as methotrexate that prevent the immune system to attack joints, and B cell depletion therapies that remove immune cells producing antibodies and rheumatoid factors that cause damage in the joints.
The team analyzed 115 patients with rheumatic diseases, including rheumatoid arthritis, lupus and psoriatic arthritis, reported to the COVID-19 Global Rheumatology Alliance registry who developed COVID-19 after being either partially or fully vaccinated against SARS-CoV-2 virus. Treatments that suppress the overactive immune system which causes joint damage in rheumatoid arthritis render these patients immunocompromised and unable to build the vaccine-induced immunity against SARS-CoV-2 virus. Thus, patients with rheumatic diseases such as lupus, who are on immunosuppressive drugs, often experience breakthrough infections with SARS-CoV-2 virus. The study found that most fully vaccinated rheumatic disease patients who experienced breakthrough infections were treated with anti-metabolite drugs such as methotrexate that prevent the immune system to attack joints, and B cell depletion therapies such as belimumab that remove immune cells producing antibodies and rheumatoid factors that cause damage in the joints. See Abstract
Health Literacy Affects Lupus Care
In this study of 267 black females with SLE, researchers found that individuals’ understanding, knowledge and awareness of their disease also known as health literacy impacts clinical and patient-reported outcomes in SLE patients. Studies have shown that low or limited health literacy is associated with increased hospitalizations and emergency care use, as well as higher disease activity.
Among all study participants, 33 percent had limited health literacy due to disadvantageous socioeconomic status, below-poverty annual household income, and lower employment rates compared to those who showed adequate health literacy. The study found that SLE patients with low or limited health literacy are a very vulnerable population, having much worse health outcomes, worse patient-centered care and inefficient physician-patient communication; are not proactive about their disease; and have higher lupus disease activity compared to SLE patients with adequate health literacy. See Abstract