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To the Editor: Myocarditis associated with messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly affects male adolescents and young male adults (14 to <30 years of age) and typically occurs after receipt of the second vaccine dose.1,2 In adults with critical coronavirus disease 2019 (Covid-19) and in cases of multisystem inflammatory syndrome in children (MIS-C), we recently discovered neutralizing autoantibodies targeting the endogenous interleukin-1 receptor antagonist (IL-1RA), which inhibits interleukin-1 signaling and inflammation.3,4 In this study, we evaluated the prevalence of antibodies neutralizing IL-1RA and progranulin, which inhibits tumor necrosis factor signaling, in 69 patients (14 to 79 years of age) who had clinically suspected myocarditis after SARS-CoV-2 vaccination. A total of 61 patients underwent endomyocardial biopsy.

To the Editor: Myocarditis associated with messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly affects male adolescents and young male adults (14 to <30 years of age) and typically occurs after receipt of the second vaccine dose.1,2 In adults with critical coronavirus disease 2019 (Covid-19) and in cases of multisystem inflammatory syndrome in children (MIS-C), we recently discovered neutralizing autoantibodies targeting the endogenous interleukin-1 receptor antagonist (IL-1RA), which inhibits interleukin-1 signaling and inflammation.3,4 In this study, we evaluated the prevalence of antibodies neutralizing IL-1RA and progranulin, which inhibits tumor necrosis factor signaling, in 69 patients (14 to 79 years of age) who had clinically suspected myocarditis after SARS-CoV-2 vaccination. A total of 61 patients underwent endomyocardial biopsy. Myocarditis was confirmed by biopsy in 40 of 61 patients (Figure 1A). Among patients with histologically confirmed myocarditis, anti–IL-1RA antibodies were found in 9 of 12 patients (75%) younger than 21 years of age, as compared with 3 of 28 patients (11%) 21 years of age or older. Anti–IL-1RA antibodies were not detectable in the 21 patients in whom biopsy ruled out the diagnosis of myocarditis (Figure 1B and 1C). IL-1RA antibody–positive patients with biopsy-confirmed myocarditis had an early onset of symptoms, which occurred mostly after receipt of the second vaccine dose, and a milder course of myocarditis than patients with biopsy-confirmed myocarditis but without anti–IL-1RA autoantibodies (Tables S1 through S6 and Figs. S1 through S6 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).1,2

ch occurred mostly after receipt of the second vaccine dose, and a milder course of myocarditis than patients with biopsy-confirmed myocarditis but without anti–IL-1RA autoantibodies (Tables S1 through S6 and Figs. S1 through S6 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).1,2 IL-1RA antibodies were observed in 2 of 214 vaccinated control participants (1%) and in 2 of 125 participants (2%) who had histologically proven myocarditis that had been diagnosed before the Covid-19 pandemic. Previous data that had been obtained from patients with critical Covid-19 did not support the cross-reactivity of purified IL-1RA antibodies with structural proteins of SARS-CoV-2, including the spike protein,3 which argues against virus- or vaccine-driven molecular mimicry.

been diagnosed before the Covid-19 pandemic. Previous data that had been obtained from patients with critical Covid-19 did not support the cross-reactivity of purified IL-1RA antibodies with structural proteins of SARS-CoV-2, including the spike protein,3 which argues against virus- or vaccine-driven molecular mimicry. Current evidence points toward a transient hyperphosphorylation of IL-1RA preceding a breakdown of peripheral immune tolerance.3,4 In Western blots of total plasma protein, antibodies to IL-1RA coincided with weaker bands of free IL-1RA, but prominent immune (IgM or IgG)–complexed protein with an atypical IL-1RA isoform occurred exclusively in patients who were seropositive for anti–IL-1RA antibodies (Figure 1D). This additional IL-1RA isoform was hyperphosphorylated at threonine position 111, which had been observed previously in adult patients with critical Covid-19 and in patients with MIS-C.3,4 In contrast to our observations in patients with myocarditis after SARS-CoV-2 vaccination, IL-1RA was not hyperphosphorylated in any of the samples that had been obtained from control participants.

e position 111, which had been observed previously in adult patients with critical Covid-19 and in patients with MIS-C.3,4 In contrast to our observations in patients with myocarditis after SARS-CoV-2 vaccination, IL-1RA was not hyperphosphorylated in any of the samples that had been obtained from control participants. At the time of acute myocarditis, the mean (±SD) free IL-1RA plasma level in 15 patients who were seropositive for anti–IL-1RA antibodies was 236±82 pg per milliliter, whereas the level was 1736±312 pg per milliliter in 33 patients without anti–IL-1RA antibodies and 1599±277 pg per milliliter in 21 patients in whom histologic testing ruled out the diagnosis of myocarditis (Figure 1F). IL-1RA plasma levels correlated with markers of cardiac damage (troponin T, creatine kinase, creatine kinase MB, or pro–B-type natriuretic peptide), cardiac-tissue infiltration of CD3+ T cells and CD68+ macrophages, and systemic inflammation (C-reactive protein). There was a negative correlation between markers of cardiac damage and IL-1RA plasma levels in patients with anti–IL-1RA antibodies (Figure 1E). Interleukin-1 signaling reporter assay experiments showed direct impairment of IL-1RA bioactivity after the addition of anti–IL-1RA antibodies from patients’ plasma (Figure 1G).

ere was a negative correlation between markers of cardiac damage and IL-1RA plasma levels in patients with anti–IL-1RA antibodies (Figure 1E). Interleukin-1 signaling reporter assay experiments showed direct impairment of IL-1RA bioactivity after the addition of anti–IL-1RA antibodies from patients’ plasma (Figure 1G). Our study of SARS-CoV-2 vaccination–associated myocarditis and anti–IL-1RA antibodies should be interpreted within the context that the transiency of hyperphosphorylation (as previously reported in patients with critical Covid-19 or MIS-C3,4) and patients’ HLA haplotypes were not known. In our study, neutralizing antibodies against IL-1RA and a hyperphosphorylated IL-1RA isoform were observed in young male patients with biopsy-confirmed myocarditis after the receipt of SARS-CoV-2 mRNA vaccine. These antibodies impaired IL-1RA bioactivity in vitro, were associated with low circulating levels of IL-1RA, and were found in patients with biomarker evidence of cardiac damage and inflammation.