Add-on rituximab for primary heart involvement associated with systemic sclerosis: A step forward in the tailored treatment of myocarditis?

The recently defined primary heart involvement (pHI) is a frequently underdiagnosed complication of systemic sclerosis (SSc), mostly representing a chronic condition but nonetheless associated with mortality.¹ No gold standard technique has been defined to diagnose SSc-pHI, with previous studies relying on heterogeneous criteria.¹ Cardiac magnetic resonance (CMR) with tissue mapping has become central in diagnosing SSc-pHI, as it can characterize myocardial inflammation, fibrosis, and microvascular perfusion – key elements in the pathogenesis.² The management of SSc-pHI remains an area of uncertainty due to the lack of evidence on how to define clinically relevant pHI, assess the risk of heart failure or fatal arrhythmias,¹ determine optimal treatment strategies, and establish appropriate follow-up to boost, change, or discontinue therapies. Limited data suggest efficacy of immunosuppressants commonly used in SSc, such as mycophenolate mofetil (MMF), which has shown efficacy also in autoimmune myocarditis,³ cyclophosphamide,⁴ and nintedanib.⁵ Rituximab (RTX), a B-cell depleting agent, is effective in treating SSc-related manifestations, particularly as a rescue strategy on top on MMF,⁶ but no data are available for SSc-pHI.

We present the results observed in a cohort of patients diagnosed with CMR-confirmed SSc-pHI while already receiving MMF therapy at a stable maximum tolerated dose (2–3 g/day). These patients (1–5) were subsequently treated with RTX (1 g i.v. 2 weeks apart, every 6 months) on top of MMF, and CMR was repeated after 12 months (i.e. two RTX courses). For comparison, we report data from five patients (6–10), matched by sex and autoantibody, who were treatment-naïve at the time of pHI diagnosis. Patients 6–10 were subsequently treated with MMF (3 g/day), and CMR was also repeated after 12 months.

Suspicion for pHI arose because of new-onset symptoms (dyspnoea, palpitation, angina, syncope), ventricular arrhythmia on 24-Holter electrocardiogram, and/or elevated serum myocardial enzymes during follow-up. In case of suspicion of pHI, patients were referred for CMR. CMR criteria defining pHI included increased native T1, T2 mapping times, extracellular volume (ECV), late gadolinium enhancement (LGE), or elevated T2 myocardial/skeletal muscle ratio.²

Within a cohort of 350 SSc patients followed between May 2016 and May 2023, 37 (11%) were diagnosed with pHI, 5 (14%, patients 1–5) of whom were already on stable MMF (2–3 g/day) for a median of 6 months (range 4–12). These patients were mostly early diffuse SSc with anti-topoisomerase-I antibodies and interstitial lung disease, and none had pulmonary arterial hypertension. Baseline CMR in patients 1–5 revealed increased native T1 (median 1047 ms [range 1009–1088]) and T2 mapping time (54 ms [50–56]) in four patients each, increased ECV in all five patients (35% [33–62]), and increased myocardial/skeletal muscle T2 ratio in two of five cases. No patient was reported having areas of LGE. Median left ventricular ejection fraction was 59% (range 47–65%), while right ventricular ejection fraction was 57% (range 45–60%) (Table 1).

Rituximab was initiated, but patient 5 developed anaphylaxis 20 min from the first infusion and was excluded from subsequent analysis. After 12 months, CMR revealed a decrease in T2 mapping time in all patients with elevated baseline values, normalization of myocardial/skeletal muscle T2 ratio in the two patients with abnormal baseline values, and no new areas of LGE. T1 mapping time decreased only in one patient with elevated baseline values. Overall, three patients (1–3) showed improvement in CMR parameters; no change was observed in patient 4, a woman with early diffuse SSc without features of active inflammatory myocarditis at baseline, but with increased T1 mapping time (1081 ms) and ECV (34%). Ventricular ejection fractions and volumes remained substantially unchanged after two courses of RTX, despite a trend towards improvement in patient 2, who had the most altered values at baseline. Serum troponin I normalized in all patients. Among the two patients with arrhythmic presentation, the burden of ventricular arrhythmias markedly decreased in patient 2, while remaining sustainedly elevated in patient 3, who required treatment with flecainide.

In the matched group (patients 6–10), similar SSc features were recorded, except for a higher prevalence of limited cutaneous disease and slightly longer disease duration. The clinical presentation and baseline CMR findings were comparable to those of patients 1–5. After 12 months of therapy, similar improvements in clinical, laboratory features, and CMR parameters were observed in patients 6–10 receiving first-line MMF, and patients 1–5 receiving RTX on top of MMF (Table 1).

By presenting five cases of SSc-pHI diagnosed during active and stable MMF treatment, we first report and highlight that pHI may occur de novo in patients whose other disease manifestations are satisfactorily controlled by ongoing immunosuppressive therapy. Inflammation and fibrosis are both involved in SSc-pHI pathogenesis, potentially justifying MMF as a first-line treatment due to its pleiotropic anti-fibrotic and anti-inflammatory actions.⁷ Previous attempts to define tailored immunosuppressive strategies did not show significant benefits in patients with biopsy-proven immune-mediated myocarditis.⁸ Our findings suggest that RTX may be an effective add-on therapy for patients diagnosed with SSc-pHI while already on MMF or, potentially, in case of worsening inflammatory component during MMF treatment. Remarkably, RTX appears to improve CMR parameters related to myocardial inflammation but not those associated with fibrosis, as indicated by the minimal change in T1 mapping time.

Some limitations need to be accounted for. First, caution should be exercised regarding the potential for anaphylaxis associated with RTX. Second, we are aware that, due to the small sample size, no statistical analysis could be conducted. Third, the immunological rationale behind our observations still needs to be demonstrated and cannot be speculated.

In conclusion, RTX could represent an effective and safe strategy for treating SSc-pHI in patients refractory to MMF. Moreover, we suggest that SSc-pHI can be considered an independent domain of SSc, and advocate for a deep profiling of the inflammatory and fibrotic pathways involved in its pathogenesis. This step will justify the adoption of drugs with different mechanisms of action in the therapeutic arsenal for SSc-pHI, in harmony with the principles of precision medicine.