Treating Myocardial Inflammation in Cardiac Sarcoidosis

Recognition of cardiac sarcoidosis as an entity that can cause heart failure, ventricular arrhythmias, conduction disease, or sudden cardiac death has increased over time.^1,2 However, once it is diagnosed, management of cardiac sarcoidosis varies considerably, reflecting the fact that evidence-based guidelines and recommendations are lacking. Some of the key questions in the field include the following: Who should undergo placement of a cardiac implantable electronic device? Which patients with myocardial inflammation should be treated? What immunosuppressive regimens should be used? How should treatment response be followed up?³

In this issue of JACC: Cardiovascular Imaging, Rojulpote et al⁴ retrospectively studied the response to immunosuppressive therapy in 83 patients with suspected cardiac sarcoidosis (all were treatment naive) who underwent baseline fluorodeoxyglucose (FDG) positron emission tomography (PET) between 2008 and 2020 at the University of Pennsylvania (Philadelphia, Pennsylvania). All patients also underwent follow-up FDG PET imaging after initiation of immunosuppressive therapy. The objective of the study by Rojulpote et al⁴ was to identify potential patient- or therapy-specific markers associated with complete, partial, or no treatment response by FDG PET.

A total of 59 patients (71%) achieved complete (n = 25; 30%) or partial (n = 34; 41%) treatment response at the time of follow-up FDG PET (median 6.7 months [IQR: 4.9–8.5 months] after baseline FDG PET). These patients were more likely to have biopsy-proven sarcoidosis (n = 51; 61%: endomyocardial, n = 9; and extracardiac disease, n = 42) and therefore meet the Heart Rhythm Society (HRS) diagnostic criteria for cardiac sarcoidosis⁵ when compared with patients who did not achieve treatment response. Patients with complete or partial treatment response also had more myocardial FDG uptake and a higher likelihood of having extracardiac FDG-avid disease at baseline when compared with patients with no treatment response. Among patients receiving prednisone monotherapy as their immunosuppressive regimen, the highest rates of complete or partial response were present in patients who were started on moderate-dose (≥30 and <50 mg/d) or high-dose (≥50 mg/d) therapy. Over a median follow-up period of 4.7 years (IQR: 3.1–7.8 years) after the baseline FDG PET, 52 patients (62.6%) had an adverse event, consisting of death (n = 6), admission for heart failure (n = 38), or a ventricular tachycardia or ventricular fibrillation episode (n = 36). There was no statistically significant difference in adverse event rate in patients who achieved complete treatment response when compared with patients who achieved no treatment response or in patients who achieved complete or partial treatment response when compared with patients who achieved no treatment response. Cardiovascular event–free survival was more favorable in patients with biopsy-proven sarcoidosis.

This study has several important findings. First, the data emphasize that response to immunosuppressive therapy in cardiac sarcoidosis highly variable. Therefore, the study underscores the importance of using imaging to assess response to therapy when treating patients with cardiac sarcoidosis. Moreover, these results reinforce the need prospectively to evaluate changes in myocardial inflammation over time in response to different treatment regimens and the impact of treatment on clinical outcomes. Second, the study points out that although the optimal dose of prednisone therapy in cardiac sarcoidosis is unknown, an initial high or moderate dose may be preferable to a low dose. Third, confirming a diagnosis of cardiac sarcoidosis remains a challenge,⁶ but doing so may be important. Although all patients in the study were clinically managed as having cardiac sarcoidosis with immunosuppressive therapy and referred for follow-up FDG PET to assess response to therapy, only 51 patients (61%) met the HRS diagnostic criteria. Patients meeting HRS diagnostic criteria had better cardiovascular event–free survival than patients who did not. It is possible that patients who did not meet the HRS criteria had a worse prognosis because some of them had isolated cardiac sarcoidosis, an entity that is more challenging to diagnose and that may have a worse prognosis. Alternatively, these patients may have had a diagnosis other than cardiac sarcoidosis.⁷ Regardless, these results reflect the uncertainty that exists when making a diagnosis in and treating patients with suspected cardiac sarcoidosis.

A common yet perplexing question in cardiac sarcoidosis is: How soon after starting treatment should FDG PET imaging be performed to assess response to therapy? The study by Rojulpote et al⁴ provides some insight into the association between follow-up scan interval and treatment response. Although Rojulpote et al⁴ showed that a shorter time interval may be associated with better treatment response, this finding was limited by the observational nature of this study. For instance, it is possible that patients who had follow-up with a shorter time interval had more concerning disease and were treated more aggressively. Nevertheless, the results of this study support the fact that treatment response may occur early (eg, ≤6 months), and thus it may be reasonable to image patients early if this information will affect the treatment strategy. However, the benefits of early imaging, which may provide information on response to the initial dose of therapy and early in a taper regimen, should be balanced against the opportunity to image patients later during a taper, thus providing an opportunity to observe response at a lower dose of immunosuppression at the time of imaging.

Rojulpote et al⁴ dutifully discussed the limitations of their study. Two are worth highlighting here. First, perfusion imaging was not routinely obtained at the time of sarcoidosis FDG PET at their center. Several studies and consensus statements have highlighted the value of myocardial perfusion imaging in both the diagnosis of cardiac sarcoidosis and in its prognosis, particularly when there is corresponding FDG uptake (perfusion-metabolism mismatch).^8–13 Second, conclusions regarding optimal treatment dose, taper regimen, and timing of follow-up imaging are challenging to draw from a small, retrospective, observational study because of confounding. This study highlights the heterogeneity of immunosuppressive medication doses and taper regimens within 1 high-volume academic center, thus underscoring that heterogeneity almost certainly exists among centers as well.

Given the paucity of data on immunosuppressive therapy in cardiac sarcoidosis, 3 trials are either under way or about to start (Table 1). The CHASM-CS-RCT (Cardiac Sarcoidosis Randomized Trial) is a phase 3 study that is randomizing 194 immunosuppressive therapy treatment-naive patients with cardiac sarcoidosis to either standard-dose prednisone or prednisolone therapy or low-dose prednisone or prednisolone in combination with methotrexate.¹⁴ The primary endpoint of CHASM-CS-RCT is the 6-month summed perfusion rest score by PET, an endpoint that may be less likely to be affected by immunosuppressive therapy than FDG metabolism imaging.

TABLE 1.

Immunosuppressive Therapy Trials in Cardiac Sarcoidosis That Are Currently Under Way or About to Start Recruiting

Study	ClinicalTrials.gov Identifier	Phase	Arms	Primary Outcome Measure
CHASM-CS-RCT (Cardiac Sarcoidosis Randomized Trial)	NCT03593759	3	Active comparator:  Japan: prednisone or prednisolone 0.5 mg/kg orally (max dose, 30 mg) for 1 mo then reduce by 5 mg/mo for 5 mo  Everywhere except Japan: prednisone 0.5 mg kg/d orally for 6 mo (max dose, 30 mg) Experimental:  Japan: methotrexate 5–20 mg orally, subcutaneously, or intramuscularly once a wk for 6 mo + prednisone or prednisolone 20 mg orally daily for 1 mo, then 10 mg daily for 1 mo, then 5 mg daily for 1 month; subjects will also take folic acid 2 mg orally daily for 6 mo  Everywhere except Japan: methotrexate 15–20 mg orally, subcutaneously, or intramuscularly once a wk for 6 mo + prednisone 20 mg orally daily for 1 mo, then 10 mg daily for 1 mo, then 5 mg daily for 1 mo; subjects will also take folic acid 2 mg orally daily for 6 mo	Summed perfusion rest score by PET
MAGiC-ART (Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis)	NCT04017936	2	Experimental: anakinra 100 mg/d subcutaneously for 4 wks No intervention: standard of care	Change in plasma C-reactive protein
RESOLVE-Heart (A Study to Assess the Safety, Tolerability, and Efficacy of Namilumab in Participants With Active Cardiac Sarcoidosis)	NCT05351554	2	Cohort A: namilumab or placebo (subcutaneously every 4 wks through wk 30) + daily dose of prednisone or equivalent in addition to any other currently prescribed immunosuppressive therapy Cohort B: namilumab subcutaneously in an open label fashion, and patients must continue their currently prescribed immunosuppressive therapy	Incidence and severity of treatment emergency adverse events, serious adverse events, and adverse events leading to discontinuation

max = maximum; PET = positron emission tomography.

The MAGiC-ART (Interleukin-1 Blockade for Treatment of Cardiac Sarcoidosis) study is a phase 2 study that is randomizing 28 patients with cardiac sarcoidosis (defined using HRS diagnostic criteria) to treatment with anakinra (an interleukin-1 receptor antagonist), 100 mg daily by subcutaneous injection for 4 weeks, vs standard of care.¹⁵ The primary outcome measure in MAGiC-ART is change in plasma C-reactive protein.

The RESOLVE-Heart (Study to Assess the Safety, Tolerability, and Efficacy of Namilumab in Participants With Active Cardiac Sarcoidosis) is a phase 2 study involving namilumab (a monoclonal antibody that binds to granulocyte-macrophage colony-stimulating factor) that will enroll 30 subjects in 2 cohorts. Subjects in cohort A will be randomized to receive namilumab or placebo (subcutaneously every 4 weeks through week 30) and will also be treated with a daily dose of prednisone or equivalent, in addition to any other currently prescribed immunosuppressive therapy. Subjects in cohort B will receive namilumab subcutaneously in an open label fashion and must continue their currently prescribed immunosuppressive therapy. The primary outcome measures in RESOLVE-Heart are the incidence and severity of treatment emergency adverse events, serious adverse events, and adverse events leading to discontinuation. The secondary outcome measures include mean change from baseline in maximum standardized uptake value.

The important work by Rojulpote et al⁴ highlights the need to study different immunosuppressive regimens, therapy intensity, and taper regimens in cardiac sarcoidosis. Although we know from previous work that perfusion¹⁰ and metabolism^8,9 abnormalities on FDG PET are associated with worse outcomes in cardiac sarcoidosis, and that treating myocardial inflammation is associated with improvement in left ventricular systolic function,¹⁶ we do not know whether treating myocardial inflammation is associated with improved clinical outcomes. We also do not know the natural history of treated vs untreated myocardial inflammation in cardiac sarcoidosis. In this regard, Rojulpote et al⁴ have provided useful insights on the treatment of myocardial inflammation in cardiac sarcoidosis and have also shed light on the many questions and challenges that remain.