ACR CONVERGENCE 2020—The ACR’s first fully virtual annual meeting kicked off on Thursday, Nov. 5. During the Opening Session, ACR President Ellen M. Gravallese, MD, talked about how the specialty’s response during the pandemic has provided great hope and will help rheumatology become an even more essential specialty.
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At the first Plenary Session on Friday, Nov. 6, speakers highlighted findings relevant to the COVID-19 pandemic: the potential pathogenicity of antiphospholipid antibodies and the risks of poor outcomes in infected people with rheumatic diseases. Another key topic: Racial differences in lupus patients with respect to potential disease markers and outcomes in stroke and ischemic heart disease.
Antiphospholipid Antibodies in COVID-19
Accumulating evidence has raised concerns about the risks of arterial and venous thrombosis in patients with COVID-19. Yu (Ray) Zuo, MD, a clinical assistant professor in the Division of Rheumatology, University of Michigan, Ann Arbor, discussed the role prothrombotic antiphospholipid antibodies may be playing in COVID-19 pathophysiology.
As a part of acquired antiphospholipid syndrome, such antibodies promote thrombus formation. “Catastrophic antiphospholipid syndrome is the most severe type and is frequently fatal,” Dr. Zuo noted. “Clinically, it bears some similarities with severe COVID-19, such as cytokine storms and diffuse coagulopathy.”
Previous small case reports and series suggested antiphospholipid antibodies might be present in COVID-19 patients and might be contributing to thrombosis. Viral infections generally are a well-known trigger for the transient appearance of these antibodies, but their overall pathogenicity remains poorly understood.
Dr. Zuo and colleagues obtained serum from 172 patients who had been hospitalized for COVID-19 and checked for eight different types of antiphospholipid antibodies. Fifty-two percent were positive for at least one.
“To our surprise, the most prevalent antiphospholipid antibody among COVID patients was not a well-studied one: [anti-phosphatidylserine/prothrombin] IgG,” Dr. Zuo related. This antibody is not currently part of standard antiphospholipid syndrome criteria, but it is thought to correlate with rates of thrombosis.
In other analyses, the team found higher levels of antiphospholipid antibodies in patients with more severe manifestations of COVID-19. Positivity for various antiphospholipid antibodies was associated with higher levels of neutrophil extracellular trap (NET) formation, as well as with a lower estimated glomerular filtration rate and more severe respiratory disease. High levels of NETs have also been demonstrated in hospitalized COVID-19 patients with severe respiratory impairment. Past work in antiphospholipid syndrome patients has demonstrated higher levels of circulating NETs, which may play a role in thrombosis.
The team also found that when they purified the IgG fractions from COVID-19 patients with antiphospholipid antibodies, it triggered NET release in healthy control neutrophils, similar to the way this occurs in fractions isolated from people with established antiphospholipid syndrome.
Dr. Zuo also discussed the team’s work in mouse thrombosis models, which also showed that purified injected antiphospholipid antibodies from COVID-19 patients accelerated thrombus formation and the formation of NETs.
“In summary, our data suggest that some patients with COVID-19 do become at least transiently positive for antiphospholipid antibodies, and these antibodies are potentially pathogenic,” concluded Dr. Zuo.
Outcomes in Rheumatology Patients with COVID-19 Infection
Kristin M. D’Silva, MD, a research fellow at Massachusetts General Hospital, Boston, discussed a study suggesting patients with systemic autoimmune rheumatic diseases may have greater risk of complications from COVID-19 compared to the general population.
“Patients with rheumatic diseases and their providers continue to have concerns about a potentially increased risk of poor COVID-19 outcomes due to immunosuppression, a chronic inflammatory state, comorbidities and racial, ethnic and socioeconomic disparities,” she noted.
Studies out of Wuhan, China, and Boston have reported up to a three-fold higher risk of need for mechanical ventilation in COVID-19 patients with rheumatic diseases. Dr. D’Silva also remarked on a study from the COVID-19 Global Rheumatology Alliance that reported no higher rates of hospitalization for rheumatic patients taking any type of disease-modifying anti-rheumatic drug or biologic, compared to those who were not. The study had, however, reported a higher risk of hospitalization in rheumatic patients who had who had more comorbid conditions.1
Unlike the study from the Global Rheumatology Alliance, which had solely analyzed outcomes from rheumatic disease patients, Dr. D’Silva and colleagues designed their analysis to determine differences in COVID-19 outcomes in patients with systemic autoimmune rheumatic disease, compared to people in the general population who had been matched based on age, sex, race and ethnicity.
The group used electronic health data from a multicenter research network encompassing over 52 million patients across the U.S. They used International Classification of Diseases (ICD) codes or positive COVID-19 testing to assess COVID-19 status. The rheumatic diseases studied included a wide variety of types of inflammatory arthritis, connective tissue diseases and systemic vasculitides, with rheumatoid arthritis and lupus being the most common.
In their extended analysis at six months, a total of 2,379 patients with systemic autoimmune rheumatic disease were matched to an equivalent number of comparators and used to create a risk ratio for various medical outcomes. The patients with systemic autoimmune rheumatic disease had higher prevalence of several medical morbidities, including hypertension, diabetes, chronic kidney disease and asthma.
Dr. D’Silva and colleagues found patients with systemic autoimmune rheumatic diseases had a 14% higher risk of hospitalization and a 32% higher risk of intensive care unit admission compared to patients without systemic autoimmune rheumatic disease in their primary model. These patients had an 81% higher risk of acute kidney injury and need for renal replacement therapy, and a 74% higher risk of venous thromboembolism. However, the team found no significantly increased risk of ischemic stroke or death.
“These risks were attenuated after adjusting for comorbidities, which are likely causal intermediates,” Dr. D’Silva explained.
There was a persistently higher risk of venous thromboembolism, even after adjusting for comorbidities. Therefore, patients with rheumatic disease should be closely monitored for venous thromboembolism during COVID-19 infection.”
In future studies, the team hopes to see if different levels of risk emerge among different kinds of systemic autoimmune rheumatic diseases.
Racial Disparities in Patients with Lupus
Shivani Garg, MD, MS, assistant professor in the Division of Rheumatology, University of Wisconsin, Madison, presented data that built on information presented at a 2019 Plenary Session. At that time, her group reported the risk of cardiovascular disease was 18-fold higher in patients with lupus who are Black than in those who are white.
Discrepancies in the medical literature about the timing of the greatest risk of stroke and myocardial ischemia in lupus patients led them to investigate this finding, as well as potential predictors of these events, in Black patients with lupus. Dr. Garg and colleagues used a population-based registry of lupus patients from Atlanta and found 336 new incident cases of lupus from 2002–04, of which 87% were women and 75% were Black. They matched these data with information from two other population databases to identify cardiovascular disease events.
Using a Cox proportional hazards model, the researchers compared the timing of stroke and ischemic heart disease events in their cohort. Dr. Garg said, “We found there were a disproportionately higher number of stroke-related deaths or events during the second year of lupus diagnosis, while the peak of ischemic heart disease or deaths was seen much later, during the 14th year of lupus diagnosis.”
Next, the team examined disparities in stroke risk. “We found that Black patients had a threefold higher risk of stroke compared to non-Black patients, with maximum events occurring earlier during the disease course,” Dr. Garg continued. Other analyses revealed that Black lupus patients had a 24-fold higher risk of ischemic heart disease compared to non-Black patients. Moreover, the timeline of stroke and ischemic heart disease was significantly accelerated in Black patients compared with non-Blacks.
The team also identified other predictors of stroke and of ischemic heart disease. “Discoid rash at time of lupus diagnosis predicted fivefold higher stroke risk, which was a somewhat surprising and interesting finding,” Dr. Garg noted. Renal disorder also predicted a twofold higher risk. However, neither of these was predictive of ischemic heart disease risk. For that, age was a strong predictor, and neurological and immunological disorders (including ones such as antiphospholipid syndrome) were less so.
The factors underlying these racial differences—whether derived from social factors, differences in treatment (such as duration of steroid use) or treatment access, cardiovascular risk factors, or other unknown physiological drivers—remain a topic of high interest.
“In future studies we will examine mechanisms that drive different timings and predictors of cardiovascular disease subtypes and disparities. We will also examine the impact of timely prevention in high risk [lupus] subsets,” Dr. Garg concluded.
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
- Gianfrancesco M, Hyrich KL, Al-Adely S, et al; COVID-19 Global Rheumatology Alliance. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: Data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020 Jul;79(7):859–866.