Researchers examine latest evidence for COVID-19 risks in lupus patients
BY WALTER ALEXANDER
The latest evidence on SARS-CoV-2 infection risk in patients with systemic lupus erythematosus (SLE), as well as the risk for a more severe course of COVID-19 among such patients, does not point to any greater concerns overall for such patients but does raise worries about adverse outcomes with the use of systemic glucocorticoids, according to the most up-to-date review article on the topic. Multiple factors, including the considerable variation in outcomes following COVID-19 infection, underscored a need to assess COVID-19’s impact in patients with SLE. Also, a 20% increase over the average expected number of deaths in United States mortality between March 1 and Aug. 1, 2020, pointed to a likely underestimation of COVID-19 deaths, according to the authors of the review in Translational Research. Heightened susceptibility?Potentially heightened susceptibility in SLE patients to infection and more severe outcomes, the authors noted, may arise from use of systemic glucocorticoids and immunosuppressants, as well as from underlying SLE-related organ damage. High type I interferon (IFN) activity is also evident in most SLE patients, which in theory may provide either a line of antiviral defense or may contribute to harmful hyperinflammatory COVID-19 responses. Beyond type I IFN dysregulation, SLE is characterized by defective immune tolerance mechanisms. Furthermore, there is an overlap between prevalence and severity of SLE and poor COVID-19 outcomes in individuals of African and Hispanic ancestry, although it is unclear whether social determinants of health or biologic factors are at play. Overall mortality in SLE patients is estimated to be two to five times greater than that of the general population, and the bacterial, viral, and opportunistic infections common to SLE are the second leading cause of death in SLE patients in developed countries. Infection mortality ranges from 25% to 50%, with infections more frequent in the first 5 years after diagnosis, reflecting either underlying disease pathogenesis or early aggressive immunosuppressive therapy. SLE’s effects on immune cells, in both number and function, may be reflected in lymphopenia and neutropenia, with active inflammation or immunosuppressants leading to apoptosis. Also, the CD8 T-cell responses in SLE patients are marked by defects in phagocytosis and chemotaxis. |
COVID-19 hospitalizationsOne of the most common causes behind SLE hospitalizations (and early death) is respiratory infections. In particular, patients aged 65 years and older with rheumatic conditions have higher risk for influenza and influenza-related complications, and bacterial infections often follow influenza pneumonia, frequently leading to prolonged hospitalizations and overall worse outcomes. Furthermore, viral infections can trigger SLE flares after the virus is cleared. Annual flu vaccinations have been shown to reduce hospital and ICU admissions in SLE populations, and are highly recommended, according to the review’s first author, Ruth Fernandez-Ruiz, MD, and coauthors at New York University. |
![]() Dr. Ruth Fernandez-Ruiz |
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Conflicting evidence on antiphospholipid antibodiesWhile various initial studies may indicate that antiphospholipid antibodies in the setting of clinically significant thrombotic episodes are mere “innocent bystanders,” a recent cross-sectional study suggested a potential pathogenic role in severe COVID-19. Half of hospitalized COVID-19 patients in the study had antiphospholipid antibodies, with elevated circulating neutrophil extracellular trap markers and a more severe COVID-19 course associated with higher titers.Dysregulated complement systemComplement dysregulation, with hypocomplementemia as a marker of disease activity, is a classic SLE feature. The excessive inflammatory response seen in severe COVID-19 has been associated with complement activation and a complement-mediated microvascular injury syndrome. The overactive complement system associated with age-related macular degeneration is also associated with worse COVID-19 outcomes, and genetic variants associated with age-related macular degeneration have been identified as predisposing factors for COVID-19 hospitalization. A role for complement inhibitors targeting thromboinflammation in COVID-19 has been proposed, with clinical trials investigating that possibility ongoing, the authors said.SLE and COVID-19In initial case study reports from the most heavily affected regions, hydroxychloroquine has failed to protect SLE patients from contracting COVID-19. In the same reports, baseline immunosuppressant therapy and the presence of rheumatic disease have not predisposed patients to COVID-19 infection. Systemic glucocorticoid use, however, has been significantly associated with COVID-19 hospitalization and positive reverse transcription–polymerase chain reaction (RT-PCR) tests. Male sex and previous lung disease have also conferred greater hospitalization risk. |
RegistriesAmong registries initiated in response to a paucity of data on COVID-19 in patients with immune-mediated diseases, the COVID-19 Global Rheumatology Alliance has published findings from the first 600 rheumatic disease patients entered. That group included 85 patients with SLE, of whom 55% were hospitalized. Prednisone doses of at least 10 mg/day were associated across all rheumatic diseases with higher odds of hospitalization. No association was found for immunosuppressant use and hospitalization for COVID-19, with the exception of lower odds of hospitalization with tumor necrosis factor inhibitor use. |
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Some conflicting findingsA large Italian study comparing more than 20,000 SARS-CoV-2 test–positive and nearly 35,000 test-negative subjects found no association between autoimmune disease (including SLE) and a positive COVID-19 test. On the other hand, a meta-analysis of seven case-control studies of autoimmune disease and COVID-19 showed doubled odds of COVID-19 infection, with systemic glucocorticoid use significantly associated with infection risk. In patients with SLE, Sjögren's syndrome, and systemic sclerosis (in aggregate with 60% systemic glucocorticoid use), hospitalization prevalence was higher. Dr. Fernandez-Ruiz and coauthors observed that, while studies overall suggest most patients with SLE are not at increased COVID-19 infection risk, they may as a group have feared worse outcomes and implemented more strict protective behaviors. Dr. Fernandez-Ruiz had no relevant conflicts of interest to disclose. One coauthor disclosed receiving grants from the Colton Center for Autoimmunity at NYU, the National Institutes of Health, the Lupus Research Foundation, and the Lupus Research Alliance, as well as research grants from EMD Serono and Janssen, and payments for serving as a consultant for Thermo Fisher and Inova. All are unrelated to the review article. |