Serum Organ-Specific Anti-Heart and Anti-Intercalated Disk Autoantibodies as New Autoimmune Markers of Cardiac Involvement in Systemic Sclerosis: Frequency, Clinical and Prognostic Correlates

Abstract

Background: Heart involvement (HInv) in systemic sclerosis (SSc) may relate to myocarditis and is associated with poor prognosis. Serum anti-heart (AHA) and anti-intercalated disk autoantibodies (AIDA) are organ and disease-specific markers of isolated autoimmune myocarditis. We assessed frequencies, clinical correlates, and prognostic impacts of AHA and AIDA in SSc.

Methods: The study included consecutive SSc patients (n = 116, aged 53 ± 13 years, 83.6% females, median disease duration 7 years) with clinically suspected heart involvement (symptoms, abnormal ECG, abnormal troponin I or natriuretic peptides, and abnormal echocardiography). All SSc patients underwent CMR. Serum AHA and AIDA were measured by indirect immunofluorescence in SSc and in control groups of non-inflammatory cardiac disease (NICD) (n = 160), ischemic heart failure (IHF) (n = 141), and normal blood donors (NBD) (n = 270). AHA and AIDA status in SSc was correlated with baseline clinical, diagnostic features, and outcome.

Results: The frequency of AHA was higher in SSc (57/116, 49%, p < 0.00001) than in NICD (2/160, 1%), IHF (2/141, 1%), or NBD (7/270, 2.5%). The frequency of AIDA was higher (65/116, 56%, p < 0.00001) in SSc than in NICD (6/160, 3.75%), IHF (3/141, 2%), or NBD (1/270, 0.37%). AHAs were associated with interstitial lung disease (p = 0.04), history of chest pain (p = 0.026), abnormal troponin (p = 0.006), AIDA (p = 0.000), and current immunosuppression (p = 0.01). AHAs were associated with death (p = 0.02) and overall cardiac events during follow-up (p = 0.017).

Conclusions: The high frequencies of AHA and AIDA suggest a high burden of underdiagnosed autoimmune HInv in SSc. In keeping with the negative prognostic impact of HInv in SSc, AHAs were associated with dismal prognosis.

Keywords: autoantibodies; autoimmunity; myocarditis; prognosis; systemic sclerosis.

Figure 1

Representative Anti-Heart Auto-antibodies (AHA) and Anti-Intercalated Disk Autoantibodies (AIDA) patterns by indirect immunofluorescence test. Negative AHA, AIDA, and ANA control serum pattern on human heart tissue (panel (a), ×200) and on human skeletal muscle (panel (b), ×400). Organ-specific AHA pattern: panel (A) on human heart tissue: strong diffuse cytoplasmic staining of cardiac myocytes (organ-specific AHA pattern) (×400); panel (B) (×400) on human skeletal muscle tissue: negative. Organ-specific AHA and AIDA pattern: panel (C) strong linear staining of the intercalated disks (AIDA pattern) (white arrows) and associated organ-specific AHA diffuse and fine striational pattern (×400); panel (D) (×400) on human skeletal muscle tissue: negative. Organ-specific AHA and ANA pattern: panel (E) on human heart tissue: strong diffuse cytoplasmic staining of cardiac myocytes (organ-specific AHA pattern) and associated antinuclear antibody (ANA) (white arrows) (×200); panel (F) (×200) on human skeletal muscle tissue: negative for AHA and positive for ANA (white arrows). Note the intracellular location of ANA on human heart and the peripheral location of ANA on skeletal muscle.

Figure 2

Survival curves according to auto-antibodies status. (A) Kaplan–Meier survival curves in systemic sclerosis (SSc) patients according to Anti-Heart Autoantibodies (AHA) status. AHA positive SSc patients have lower survival (p = 0.005). (B) Kaplan–Meier curves comparing survival in systemic sclerosis (SSc) patients as a function of Anti-Centromere Autoantibody (ACA); ACA positive SSc patients have better survival (p = 0.036). (C) Anti-Nuclear Autoantibody (ANA) status. ANA positive SSc patients have better survival (p = 0.002). Kaplan–Meier curves in systemic sclerosis (SSc) comparing time to cardiac worsening as a function of (D) Anti-Heart Autoantibodies (AHA), AHA positive SSc patients have lower survival free from cardiac worsening (p = 0.017); (E) Anti-Centromere Autoantibody (ACA), ACA positive SSc patients have higher survival free from cardiac worsening (p = 0.016); (F) Anti-Nuclear Autoantibody (ANA) status. ANA positive SSc patients have higher survival free from cardiac worsening (p = 0.010). In all curves, 0 = negative antibody status, 1 = positive antibody status.