Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity.

Evaluation of Immune Response and Disease Status in Systemic Lupus Erythematosus Patients Following SARS-CoV-2 Vaccination.

OBJECTIVE: To evaluate seroreactivity and disease flares after COVID-19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE). METHODS: Ninety SLE patients and 20 healthy controls receiving a complete COVID-19 vaccine regimen were included. IgG seroreactivity to the SARS-CoV-2 spike receptor-binding domain (RBD) and SARS-CoV-2 microneutralization were used to evaluate B cell responses; interferon-γ (IFNγ) production was measured by enzyme-linked immunospot (ELISpot) assay in order to assess T cell responses. Disease activity was measured by the hybrid SLE Disease Activity Index (SLEDAI), and flares were identified according to the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index. RESULTS: Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS-CoV-2 spike RBD compared to fully vaccinated controls. Twenty-six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti-double-stranded DNA antibody level prior to vaccination were associated with decreased vaccine responses. IgG seroreactivity to the SARS-CoV-2 spike RBD strongly correlated with the SARS-CoV-2 microneutralization titers and correlated with antigen-specific IFNγ production determined by ELISpot. In a subset of patients with poor antibody responses, IFNγ production was similarly diminished. Pre- and postvaccination SLEDAI scores were similar in both groups. Postvaccination flares occurred in 11.4% of patients; 1.3% of these were severe. CONCLUSION: In a multiethnic/multiracial study of SLE patients, 29% had a low response to the COVID-19 vaccine which was associated with receiving immunosuppressive therapy. Reassuringly, severe disease flares were rare. While minimal protective levels remain unknown, these data suggest that protocol development is needed to assess the efficacy of booster vaccination.

Evaluation of SARS-CoV-2 IgG antibody reactivity in a multi-racial/ethnic cohort of patients with systemic lupus erythematosus

1206 Figure 1SARS-CoV-2 IgG in SLE[Figure omitted. See PDF]ConclusionsMost patients with SLE and confirmed COVID-19 were able to produce a serologic response despite use of a variety of immunosuppressants. These findings provide reassurances regarding the efficacy of humoral immunity and possible reinfection protection in patients with SLE.AcknowledgmentsData presented on behalf of the NYU WARCOV investigators. We thank Leora Horwitz for her assistance with the ICD-10 query at NYU. We also acknowledge Tania Moin and Ranit Shriky for assistance in navigating regulatory matters.

Evaluation of SARS-CoV-2 IgG antibody reactivity in patients with systemic lupus erythematosus: analysis of a multi-racial and multi-ethnic cohort.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection. METHODS: For this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits. FINDINGS: 329 patients with SLE were included in this analysis, 146 from the WARCOV study and 183 from the NYU Lupus Cohort, and were tested for SARS-CoV-2 antibodies between April 29, 2020, and Feb 9, 2021. 309 (94%) were women and 91 (28%) were of Hispanic ethnicity. 51 (16%) of 329 patients had a positive SARS-CoV-2 IgG antibody test. Seropositive patients were more likely than seronegative patients to be Hispanic (24 [47%] of 51 vsz 67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset. INTERPRETATION: Most patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2. FUNDING: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

COVID-19 in patients with systemic lupus erythematosus: lessons learned from the inflammatory disease.

As the world navigates the coronavirus disease 2019 (COVID-19) pandemic, there is a growing need to assess its impact in patients with autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). Patients with SLE are a unique population when considering the risk of contracting COVID-19 and infection outcomes. The use of systemic glucocorticoids and immunosuppressants, and underlying organ damage from SLE are potential susceptibility factors. Most patients with SLE have evidence of high type I interferon activity, which may theoretically act as an antiviral line of defense or contribute to the development of a deleterious hyperinflammatory response in COVID-19. Other immunopathogenic mechanisms of SLE may overlap with those described in COVID-19, thus, studies in SLE could provide some insight into immune responses occurring in severe cases of the viral infection. We reviewed the literature to date on COVID-19 in patients with SLE and provide an in-depth review of current research in the area, including immune pathway activation, epidemiology, clinical features, outcomes, and the psychosocial impact of the pandemic in those with autoimmune disease.

Leveraging the United States Epicenter to Provide Insights on COVID-19 in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To characterize patients with systemic lupus erythematosus (SLE) affected by coronavirus disease 2019 (COVID-19) and to analyze associations of comorbidities and medications on infection outcomes. METHODS: Patients with SLE and reverse transcriptase-polymerase chain reaction-confirmed COVID-19 were identified through an established New York University lupus cohort, query of 2 hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Data on baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected on asymptomatic patients and those with COVID-19-like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID-19-positive patients. RESULTS: A total of 226 SLE patients were included: 41 with confirmed COVID-19, 19 who tested negative for COVID-19, 42 with COVID-19-like symptoms who did not get tested, and 124 who remained asymptomatic without testing. Of the SLE patients with confirmed COVID-19, hospitalization was required in 24 (59%) and intensive care unit-level of care in 4, and 4 died. Hospitalized patients tended to be older, nonwhite, Hispanic, have higher body mas index (BMI), history of nephritis, and at least 1 comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least 1 comorbidity, and BMI as independent predictors of hospitalization. CONCLUSION: In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE.

Acute respiratory viral adverse events during use of antirheumatic disease therapies: A scoping review.

INTRODUCTION: COVID-19 is an acute respiratory viral infection that threatens people worldwide, including people with rheumatic disease, although it remains unclear to what extent various antirheumatic disease therapies increase susceptibility to complications of viral respiratory infections. OBJECTIVE: The present study undertakes a scoping review of available evidence regarding the frequency and severity of acute respiratory viral adverse events related to antirheumatic disease therapies. METHODS: Online databases were used to identify, since database inception, studies reporting primary data on acute respiratory viral infections in patients utilizing antirheumatic disease therapies. Independent reviewer pairs charted data from eligible studies using a standardized data abstraction tool. RESULTS: A total of 180 studies were eligible for qualitative analysis. While acknowledging that the extant literature has a lack of specificity in reporting of acute viral infections or complications thereof, the data suggest that use of glucocorticoids, JAK inhibitors (especially high-dose), TNF inhibitors, and anti-IL-17 agents may be associated with an increased frequency of respiratory viral events. Available data suggest no increased frequency or risk of respiratory viral events with NSAIDs, hydroxychloroquine, sulfasalazine, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, or apremilast. One large cohort study demonstrated an association with leflunomide use and increased risk of acute viral respiratory events compared to non-use. CONCLUSION: This scoping review identified that some medication classes may confer increased risk of acute respiratory viral infections. However, definitive data are lacking and future studies should address this knowledge gap.