To evaluate disease flare and postvaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases (RMDs) following 2-dose SARS-CoV-2 messenger RNA (mRNA) vaccination.Methods. RMD patients (n = 1,377) who received 2-dose SARS-CoV-2 mRNA vaccination between December 16, 2020 and April 15, 2021 completed questionnaires detailing local and systemic reactions experienced within 7 days of each vaccine dose (dose 1 and dose 2), and 1 month after dose 2, detailing any flares of RMD. Associations between demographic/clinical characteristics and flares requiring treatment were evaluated using modified Poisson regression.Results. Among the patients, 11% reported flares requiring treatment; there were no reports of severe flares. Flares were associated with prior SARS-CoV-2 infection (incidence rate ratio [IRR] 2.09, P = 0.02), flares in the 6 months preceding vaccination (IRR 2.36, P < 0.001), and the use of combination immunomodulatory therapy (IRR 1.95, P < 0.001). The most frequently reported local and systemic reactions included injection site pain (87% after dose 1, 86% after dose 2) and fatigue (60% after dose 1, 80% after dose 2). Reactogenicity increased after dose 2, particularly for systemic reactions. No allergic reactions or SARS-CoV-2 diagnoses were reported.Conclusion. Flares of underlying RMD following SARS-CoV-2 vaccination were uncommon. There were no reports of severe flares. Local and systemic reactions typically did not interfere with daily activity. These early safety data can help address vaccine hesitancy in RMD patients.The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Functional interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) in the arterial wall are necessary for controlling vasoreactivity that underlies vascular resistance and tone. Key signaling pathways converge on the phosphorylation of myosin light chain (P-MLC), the molecular signature of force production in SMCs, through coordinating the relative activities of myosin light chain kinase (MLCK) and myosin phosphatase (MP). Notch signaling in the vessel wall serves critical roles in arterial formation and maturation and has been implicated in arterial vasoregulation. In this report, we hypothesized that Notch signaling through ligands Jagged1 (in SMC) and Dll4 (in ECs) regulates vasoreactivity via homotypic (SMC-SMC) and heterotypic (EC-SMC) cell interactions. Using ligand induction assays, we demonstrated Jagged1 selectively induced smooth muscle MLCK gene expression and P-MLC content while inhibiting MP function (i.e. increased Ca sensitization) in a ROCKII dependent manner. Likewise, selective deficiency of smooth muscle Jagged1 in mice resulted in MLCK and P-MLC loss, reduced Ca sensitization, and impaired arterial force generation measured by myography. In contrast, smooth muscle Notch signaling triggered by Dll4 increased expression of myosin phosphatase targeting subunit-1 (MYPT1, the MP regulatory subunit) while arteries from endothelial Dll4 deficient mice featured reduced MYPT1 levels, enhanced force production and impaired relaxation independent of endothelial derived nitric oxide (NO) signaling. Taken together, this study identifies novel opposing vasoregulatory functions for ligand-specific Notch signaling in the vessel wall, underscoring instructional signaling between endothelial and smooth muscle cells and suggesting Notch signals might behave as a "rheostat" in arterial tone control.

Background Cardiac sarcoidosis is an increasingly common indication for a heart transplant, but there is a paucity of knowledge with regard to long‐term outcomes following transplant. Methods We utilized the Organ Procurement and Transplantation Network database to retrospectively analyze adult patients undergoing first‐time, single‐organ heart transplant between January 1999 and March 2020. Results Of the 41,447 patients that underwent heart transplant during the study period, 289 (0.7%) were transplanted for a primary diagnosis of restrictive cardiomyopathy due to cardiac sarcoidosis (RCM‐Sarcoidosis). RCM‐Sarcoidosis was associated with 33% reduced risk of mortality over 10 years compared to non‐RCM indications in a multivariable Cox proportional hazards model (p = .03). Ten‐year survival functions were improved among RCM‐Sarcoidosis compared to this reference group (73.4% [64.2%–80.6%] vs. 59.5% [58.8%–60.1%], p = .002). Among patients transplanted after 1999 who had at least 10 years of follow‐up (n = 19,489), median survival of RCM‐Sarcoidosis patients was 11.9 [8.3–14.6] years while that of non‐RCM patients was 9.9 [4.0–13.1] years. RCM‐Sarcoidosis was not associated with an increased risk of secondary outcomes such as graft failure, rejection, or infection. The incidence of retransplant was comparable between RCM‐Sarcoidosis and non‐RCM patients (1.38% vs. 1.50%, p = .93). Conclusions These data suggest that long‐term outcomes following transplant for cardiac sarcoidosis are favorable compared to heart transplant for other indications.