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ObjectivesTo investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the initial Omicron wave.MethodsWe conducted a retrospective cohort study investigating COVID-19 outcomes among patientswith SARD systematically identified to have confirmed COVID-19 from 1 March 2020 to 31 January 2022 at Mass General Brigham. We tabulated COVID-19 counts of total and severe cases (hospitalisations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared with the early COVID-19 period (reference group).ResultsWe identified 1449 patients with SARD with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (28%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 46% of cases were severe in the early COVID-19 period (1 March 2020–30 June 2020) vs 15% in the initial Omicron wave (17 December 2021–31 January 2022; adjusted OR 0.29, 95% CI 0.19 to 0.43). A higher proportion of those unvaccinated were severe compared with not severe cases (78% vs 60%).ConclusionsThe proportion of patients with SARD with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the initial Omicron wave. Advances in prevention, diagnosis and treatment of COVID-19 may have improved outcomes among patients with SARD.

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To describe a novel microporous drug delivery system (DDS) for sustained antivascular endothelial growth factor (VEGF) delivery to the eye and to evaluate its efficacy in a corneal injury model. Methods: A macro-porous DDS (1.5 × 1.5 × 4 mm) loaded with 2 mg of bevacizumab was implanted subconjunctivally in three Dutch-belted pigmented rabbits after corneal alkali injury (2N NaOH). Three rabbits received sham DDS. Animals were followed for three months and assessed in vivo and ex vivo for corneal neovascularization (NV), epithelial defect, stromal scarring, endothelial cell loss, and expression of angiogenic and inflammatory markers in the cornea and retina. Results: Anti-VEGF DDS treatment led to complete inhibition of superior cornea NV and complete corneal re-epithelialization by day 58 whereas sham DDS resulted in severe cornea NV and persistent epithelial defect (9%∼12% of total cornea area) through the end of the study. Histologically, anti-VEGF DDS significantly reduced CD45 + and F4/80 CD11b + cell accumulation (79%, P < 0.05) in the cornea, ameliorated tumor necrosis factor-α expression (90%, P < 0.05), reduced corneal stromal scarring and prevented corneal endothelial cell loss, as compared to sham DDS. Moreover, anti-VEGF DDS achieved retinal penetration and reduction in retinal VEGF levels at 3 months. Conclusions: Use of subconjunctival anti-VEGF DDS suppresses cornea NV, inflammation, stromal scarring, prevents endothelial cell loss, and abrogates retinal VEGF upregulation in a rabbit corneal alkali burn model. Moreover, it delivers anti-VEGF antibodies to the retina for three months. This delivery platform could enable antibody therapy of other corneal and retinal vascular pathologies. Translational Relevance: We describe a method for sustained anti-VEGF delivery to the eye for the treatment of ocular injuries.

Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC. A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fc-receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.

Objective: To investigate temporal trends, severe outcomes, and rebound among systemic autoimmune rheumatic disease (SARD) patients according to outpatient SARS-CoV-2 treatment. Methods: We performed a retrospective cohort study investigating outpatient SARS-CoV-2 treatments among SARD patients at Mass General Brigham (23/Jan/2022-30/May/2022). We identified SARS-CoV-2 infection by positive PCR or antigen test (index date=first positive test) and SARDs using diagnosis codes and immunomodulator prescription. Outpatient treatments were confirmed by medical record review. The primary outcome was hospitalization or death within 30 days following the index date. COVID-19 rebound was defined as documentation of negative then newly-positive SARS-CoV-2 tests. The association of any vs. no outpatient treatment with hospitalization/death was assessed using multivariable logistic regression. Results: We analyzed 704 SARD patients with COVID-19 (mean age 58.4 years, 76% female, 49% with rheumatoid arthritis). Treatment as outpatient increased over calendar time (p<0.001). A total of 426(61%) received outpatient treatment: 307(44%) with nirmatrelvir/ritonavir, 105(15%) with monoclonal antibodies, 5(0.7%) with molnupiravir, 3(0.4%) with outpatient remdesivir, and 6(0.9%) with combinations. There were 9/426 (2.1%) hospitalizations/deaths among those treated as outpatient compared to 49/278 (17.6%) among those with no outpatient treatment (adjusted odds ratio [aOR] 0.12, 0.05 to 0.25). 25/318 (8%) of patients who received oral outpatient treatment had documented COVID-19 rebound. Conclusion: Outpatient treatment was strongly associated with lower odds of severe COVID-19 compared to no outpatient treatment. At least 8% of SARD patients experienced COVID-19 rebound. These findings highlight the importance of outpatient COVID-19 treatment for SARD patients and the need for further research on rebound.