Combination therapy of rituximab and mycophenolate in patients with systemic sclerosis and primary cardiac involvement refractory to cyclophosphamide: a retrospective exploratory analysis of 10 cases

Abstract

Despite the high mortality risk, no specific treatment options for cardiac manifestations in systemic sclerosis (SSc) currently exist. We performed a retrospective medical records analysis at our centre to explore the therapeutic effects of a combination therapy with rituximab (RTX) and mycophenolate (MMF) in 10 patients with SSc-related primary cardiac involvement refractory to previous primary treatment with cyclophosphamide (CP).SSc-related primary cardiac involvement was defined as the presence of troponin T elevation and of at least one of the following cardiac manifestations: right or left ventricular systolic or diastolic dysfunction, myocarditis, pericarditis, heart blocks or ventricular arrhythmias. Patients who had worsening or persistence of cardiac involvement after CP pulse therapy received a combination therapy of RTX (1000 mg every 3-6 months) and MMF (up to 3000 mg/day). Cardiac outcomes were evaluated during a 6-12-month follow-up period.Following the initiation of the combination therapy, consistent decreases in plasma levels of troponin T were observed in all patients (p=0.0020). Corresponding to this, left ventricular ejection fraction (LVEF) improved between 3% and 23% in five of the six patients with reduced LVEF, the rate of ventricular extrasystoles declined in all assessable patients (n=6, p=0.0313) and N-terminal pro hormone of brain natriuretic peptide decreased in six of the nine patients with elevated levels. Significant reductions in modified Rodnan skin score were also observed (p=0.0020). RTX/MMF combination was generally well tolerated. In the long-term follow-up period of up to 6 years, seven serious adverse events consisting of five infections and two fatal events were recorded.Our findings suggest that combination therapy with RTX and MMF may be an effective approach for improving refractory cardiac manifestations in patients with SSc. Controlled and prospective studies are required to further substantiate these encouraging observations and to prove the long-term safety of RTX/MMF combination.

Keywords: Cardiovascular Diseases; DMARD; Rituximab; Scleroderma, Systemic; Treatment.

Figure 1. Cardiac parameters before cyclophosphamide (CP) pulse therapy (T1), after CP pulse therapy and before the initiation of the rituximab (RTX)/mycophenolate (MMF) regimen (T2), and 6–12 months (12–24 months for mRSS) after initiation of the RTX/MMF regimen (T3). (A) Changes of plasma levels of troponin T (n=10 for T1, T2 and T3), (B) plasma levels of N-terminal pro hormone of brain natriuretic peptide (NTproBNP) (n=8 for T1; n=10 for T2 and T3), (C) the rate of ventricular extrasystoles (VES) per 24 hours (n=6 for T1, T2 and T3), (D) left ventricular ejection fraction (LVEF) (n=10 for T1, T2 and T3), (E) modified Rodnan skin scores (mRSS) (n=9 for T1; n=10 for T2 and T3) and (F) forced vital capacities (FVC) in % of predicted (n=9 for T1; n=10 for T2 and T3). Data show medians and IQRs. Wilcoxon test was used for paired comparison of changes between time points (p-values are indicated for changes between time points).