ACR Convergence 2024 Highlights

Members of the APS Research Labs not only presented their own investigative work at ACR Convergence 2024 in Washington, D.C., but also gained valuable insights from the work of others. These exchanges sparked fresh ideas and opened the door to new collaborations with brilliant researchers who have a shared enthusiasm for advancing APS research.

To communicate some of this excitement, our lab members who attended the conference have written short summaries about what they learned and key takeaways.

ACR Convergence 2024 Highlights from the APS Research Team

Abstract: Efficacy and Safety of Nipocalimab, an Anti-FcRn Monoclonal Antibody, in Primary Sjogren’s Disease: Results from a Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study (DAHLIAS)
Summary: Dr. Jason Knight

Though not about APS, this clinical trial for Sjögren's Disease caught our eye. Nipocalimab is a biologic drug that blocks the “neonatal Fc receptor.” This receptor (despite its historical name) plays a critical role across the lifespan by significantly extending the time that antibodies circulate in the blood. How does this work?

It turns out that the endothelial cells lining our blood vessels are constantly soaking up and digesting blood proteins, including antibodies. The neonatal Fc receptor saves the antibodies by grabbing them out of digestive organelles and spitting them back into the bloodstream. This allows antibodies to survive much longer than other blood proteins. Therefore, blocking the neonatal Fc receptor reduces circulating antibody levels, an approach to treatment that could make a lot of sense for antibody-mediated diseases like APS. We anticipate you will see more on this topic in the coming years!

Abstract: Phenotypic Characterization of Patients with IgM Antibodies in Antiphospholipid Syndrome
Summary: Dr. Ray Zuo

The recently published APS classification criteria have deemphasized the role of IgM antiphospholipid antibodies (compared with IgG antiphospholipid antibodies) in identifying APS patients for research purposes. However, as Dr. Madison recently explained, classification criteria are not the same as diagnostic criteria. Indeed, many believe that IgM antiphospholipid antibodies still hold diagnostic value. In a timely study conducted by our friends from Brazil and Italy, 202 patients believed to have APS were studied, including 17 with positive testing for only IgM antiphospholipid antibodies.

The research team found that the patients with IgM antibodies still tended to experience venous clots, pregnancy complications, skin symptoms, and brain changes. These findings suggest that even when present alone, IgM antiphospholipid antibodies may play a significant role in APS. Further mechanistic research is needed, and this is a topic our newest lab member (Dr. Yiran Shen) is just starting to dive into. Look for more on this soon!

Abstract: The Impact of Sedentary Behavior and Physical Activity Level on Clinical Parameters and Quality of Life in Patients with Primary Antiphospholipid Syndrome
Summary: Dr. Katarína Kmeťová and Dr. Kavya Sugur

Despite treatment, many patients with APS continue to face significant health challenges. For us as physicians, finding ways (beyond medications) to improve the quality of life and overall well-being of individuals living with APS remains a key goal. In a study led by our friend, Dr. Andrade, researchers investigated the impact of physical activity and sedentary behavior on health outcomes in APS patients. They focused on 62 patients with primary APS - those with APS but no other autoimmune diseases like lupus. The group was mostly women (89%) with an average age of 44 years; over half (53%) were classified as obese.

Using wearable devices, the researchers tracked activity levels for a week. Only 13% met the recommended goal of 150 minutes of moderate-to-vigorous physical activity (such as brisk walking) per week. The study found that patients who were more physically active tended to have less disease-related damage and were more likely to report better quality of life, including improvements in physical and emotional well-being. Though more work is needed to understand the cause-and-effect relationship of the noted associations, these findings suggest that regular physical activity may benefit at least some patients with APS.

Abstract: Scavenging Isolevuglandins with 2-HOBA Decreases In Vitro Neutrophil Extracellular Traps in Cells from Patients with Rheumatoid Arthritis
Summary: Dr. Ramadan Ali

This interesting abstract identified a potential strategy to combat the formation of toxic organic compounds called isolevuglandins in patient neutrophils. The researchers focused on a nutraceutical called 2-HOBA. They found neutrophils isolated from patients with rheumatoid arthritis failed to form neutrophil extracellular traps (NETs) when treated with 2-HOBA. The 2-HOBA presumably reduces stress on the nucleus and thereby stops the massive chromatin relaxation needed for NET formation.

The next step would seem to be asking whether the consumption of 2-HOBA by patients can have the same impact on overly active neutrophils circulating in their blood. If so, this could potentially be a helpful approach for treating not only rheumatoid arthritis but also disorders like APS and lupus.

Abstract: Delivering the Goods at Nanoscale: Novel Biomaterials as Therapies for Autoimmune Diseases
Summary: Dr. Ajay Tambralli

Delivering drugs to exactly where they are needed is a way to reduce side effects while still maintaining drug effectiveness. One approach to do this is encapsulating a drug in a bioengineered material designed to deliver the drug to a specific target. This session featured two talks about such approaches, and the talks pointed us to a previous manuscript describing a method to deliver hydroxychloroquine (i.e., Plaquenil) directly to activated neutrophils and platelets.

The authors made a biomaterial with protein segments that could bind to both neutrophil elastase (present at high levels on activated neutrophils) and P-selectin (present on activated platelets). Neutrophils and platelets interact with each other during blood clot formation, including in APS. The authors showed that when their biomaterial was loaded with hydroxychloroquine, it decreased the size of blood clots. Even though this was not tested in models of APS, such an approach could have a promising future in our field.

Abstract: Placental Developmental Defects in a Humanized-TLR8 Mouse Model of Spontaneous Anti-Phospholipid Antibody Induced Pregnancy Loss
Summary: Thalia Newman

Though it is well known that antiphospholipid antibodies contribute to pregnancy complications, there is limited information about the specific mechanisms that lead to these bad outcomes. This recent work out of the Feinstein Institutes for Medical Research in New York reports establishing the first spontaneous model of antiphospholipid antibody-induced pregnancy loss. To accomplish this, the researchers incorporated a human transgene for Toll-like receptor (TLR) 8, a protein not functionally expressed by mice, into an established mouse model of lupus known to harbor antiphospholipid antibodies.

The new mouse strain demonstrated increased pregnancy losses that appeared to be linked to defective recruitment and proliferation of natural killer (NK) cells, which play an important role in normal placental development. These findings suggest that TLR8, previously understudied in APS, may play a role in antiphospholipid antibody-associated pregnancy complications through its effects on NK cells, highlighting its potential as a novel therapeutic target.

Abstract: Imvotamab, a CD20-Targeted Bispecific IgM T Cell Engager, Effectively Depletes Low-Expressing CD20+ B Cells in Preclinical Models of Autoimmune Disease
Summary: Dr. Somanathapura NaveenKumar

Drugs that cause B-cell depletion exhibit potential efficacy for some less typical manifestations of APS like thrombocytopenia, autoimmune hemolytic anemia, skin ulcers, and APS nephropathy. This makes sense, given that some of these B cells make antiphospholipid antibodies. An exciting abstract presented by Dr. Domingo-Gonzalez investigated a new type of drug that might be useful for B-cell depletion, specifically an engineered bispecific anti-CD20 IgM antibody called imvotamab (IGM-2323).

The authors presented data to suggest the new antibody has a much higher affinity for CD20 compared with standard antibodies, which should lead to deeper B cell depletion than established drugs like rituximab and obinutuzumab. Deeper B-cell depletion might lead to better outcomes for antibody-mediated diseases like APS. This will be an interesting area to watch in the coming years!

Abstract: APOH Locus Associated with Higher Anti-Beta-2-Glycoprotein 1 Antibody Levels Paradoxically Protects Against Venous Thromboembolism
Summary: Dr. Wenying Liang

Anti-beta-2 glycoprotein I (anti-β₂GPI) antibodies are an important type of autoantibody used to diagnose APS. And, from work in the lab, we know these antibodies are not just markers of the disorder but actually cause direct problems. As their name suggests, anti-β₂GPI antibodies recognize the β₂GPI protein, encoded by a gene named APOH. In this study, Dr. Luo and team identified that some people have a mutation in the APOH gene, called W335S, that leads to higher levels of anti-β₂GPI antibodies, but with a paradoxically lower risk of developing dangerous blood clots.

It turns out that the W335S mutation disrupts β₂GPI’s ability to bind to cell membranes, a critical step in forming harmful blood clots when anti-β₂GPI antibodies are present. Interestingly, this structural alteration might expose normally hidden parts of β₂GPI, making it more recognizable to the immune system and leading to higher antibody levels. Taken together, the study suggests a potential explanation for why some people do not have blood clots despite having high anti-β₂GPI antibody levels. Work like this will hopefully pave the way for future research to more smartly individualize treatment for APS.

Abstract: Identification of Risk Factors for Incident Cardiomyopathy in Patients with Systemic Sclerosis
Summary: Dr. Chao Liu

The most common causes of death associated with scleroderma, also known as systemic sclerosis, are lung and blood vessel complications like pulmonary hypertension, pulmonary fibrosis, and scleroderma renal crisis. Meanwhile, cardiac (heart) involvement has not been as carefully studied. In this interesting abstract, the authors studied 2,303 scleroderma patients with at least two echocardiograms from a large North American longitudinal cohort.

The authors looked for evidence of new heart failure (ejection fraction changing from ≥50% to <50%) or progression to severe heart failure (ejection fraction changing from >35% to ≤35%). They found that heart failure, with an incidence of 11%, is a relatively common complication of scleroderma. They identified several risk factors for heart problems, including certain immune responses like the formation of anti-Ku antibodies. Meanwhile, having anti-RNA polymerase Ill antibodies may suggest a better likelihood of cardiac recovery once heart failure has developed. This type of large collaborative biomarker study is something we can hope to see more of in the APS space.

Abstract: Climate Change, the Environment, and What We Must Do as Clinicians for our Patients 
Summary: Kaitlyn Sabb

One interesting lecture discussed how climate change has immense implications, especially for individuals with autoimmune and inflammatory diseases like APS. Rising temperatures, extreme weather events, and increased air pollution can exacerbate day-to-day symptoms such as joint pain and fatigue, while also triggering flares in conditions like rheumatoid arthritis or lupus.

Since physicians are one of the most trusted sources of health information, they have a unique opportunity to educate patients about these emerging challenges. By understanding the relevant connections, clinicians can help patients reduce the risks associated with climate change, such as improving air quality in their homes, adjusting physical activity levels during extreme weather, or adopting an environment-friendly plant-based diet. Addressing challenges associated with climate change will require collaboration, further research, and a commitment to further integrating environmental awareness into clinical practice.

Abstract: Safety and Long-Term Efficacy of CD19-CAR T-cell Therapy in 30 Patients with Autoimmune Disease
Summary: Dr. Jacqueline Madison

In the last few years, cancer treatments known as “cellular therapies” or “CAR T-cell therapies” have begun to be studied for autoimmune diseases. In this type of treatment, T cells, which normally attack and destroy cells infected with viruses or bacteria, are instead reprogrammed to kill cancer cells (or, potentially, cells that cause autoimmunity). The T cells to be reprogrammed have classically been isolated from the patient who needs treatment, although newer approaches being studied might allow these cells to be made in advance and available “off the shelf.”

In the referenced abstract, 30 autoimmune patients were treated with patient T cells reprogrammed to find and kill the B cells that make autoantibodies. Remarkably, the treatment eliminated nearly all signs of autoimmunity in patients with lupus, scleroderma, and myositis. There were some side effects, most notably infections. It should also be noted that this is currently a very intensive treatment regimen that requires a form of strong chemotherapy at the start. Nevertheless, it appears we might be close to having a new treatment to offer certain patients with severe disease features. And, if the treatment can be made safer, it might eventually be reasonable to extend this approach to individuals with milder disease features. To our knowledge, this approach has yet to be tested in APS, though it certainly seems like this could be coming down the road. Stay tuned!

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