Long-term efficacy of tailored prolonged immunosuppressive therapy in biopsy-proven virus- negative myocarditis: a single center propensity weighted study

Abstract Background The efficacy of immunosuppressive therapy (IT) in biopsy-proven (BP) myocarditis was proved by small trials in lymphocytic myocarditis with heart failure (HF) presentation. Aim To evaluate the efficacy of IT in a single center cohort of BP myocarditis patients, irrespective of histological type and clinical presentation. Methods Consecutive BP myocarditis patients were included and, in the absence of contraindications, were treated with IT according to current guidelines on top of standard care. IT patients were compared with a propensity score-weighted control group of non-IT patients, considering age, gender, ejection fraction (EF), NYHA class and histological type (Fig. 1A). The primary outcome was a composite of death or heart transplant (HTx), and the secondary outcome a composite of variation of biventricular function, NYHA class and myocarditis relapse. Results 87 IT patients were compared with 265 without IT. IT patients were older (44 vs 39 years, p=0.035), and more frequently had a systemic immune-mediated disease (34% vs 10%, p<0.001), and HF (59% vs 46%, p=0.048) or fulminant presentation (9% vs 2 %, p=0.002). IT patients had lower baseline left ventricular (LV) EF both on echocardiography (35±15% vs 43±15%, p=0.001) and cardiac magnetic resonance (26±16 % vs 45.5±15 %, p=0.0013), lower right ventricular (RV) fractional area change (FAC: 34±11 % vs 41±11 %, p<0.001) and higher frequency of lymphocytic, eosinophilic and giant cell myocarditis (71% vs 58%, 11% vs 1 %, and 7% vs 2%, p<0.001 respectively) compared to non IT patients. IT was indicated because of unremitting HF (62%) and recurrent chest pain (14%), and mainly involved prednisone (PDN) and azathioprine as first-line (61%) and PDN and mycophenolate mofetil as second-line therapy (62%). IT lasted on average 24 months. No difference was observed in the primary outcome between the two groups (5 years survival 88% in IT vs 91% in non-IT patients, p=0.8, Fig. 1B), while relapse incidence was higher in IT patients (p<0.001, Fig.2B). At long-term follow up (54 months, IQR 21.4-96.45), LVEF and RV FAC were within the normal range in both groups, and propensity score weighting analysis showed that IT patients presented LVEF values of only 3% lower than non-IT (p=0.013, Fig. 2). In addition, IT patients had a similar probability of presenting the same NYHA class as non-IT patients at last follow up (p=0.46). Conclusions Our study shows for the first time the efficacy of prolonged tailored IT in BP lymphocytic and non lymphocytic autoimmune myocarditis, with or without HF and with or without RV dysfunction. IT patients, despite having lower biventricular function and a higher risk profile at baseline as well as a higher frequency of relapses, at long-term follow up showed normalized biventricular function and a similar survival compared to their propensity-score weighted controls. Thus, autoimmune myocarditis responds to IT, even when the disease relapses.Figure 1.Figure 2.