In patients with cardiac sarcoidosis (CS), whether reduced abnormal 18F-fluorodeoxygenase (FDG) uptake in the myocardium using steroids is associated with prognosis is unclear. We performed a sub-analysis of the ILLUMINATE-CS registry. Our results suggest the potential utility of serial changes in FDG uptake in patients with CS for predicting outcome.
.jpg)
Introduction
Sarcoidosis is a multisystemic inflammatory disorder of unknown aetiology involving non-necrotizing granulomas (1). The prevalence of sarcoidosis shows significant regional variation across the world. Ethnicity plays a crucial role in determining the prevalence rates of sarcoidosis (1). The prognosis in systemic sarcoidosis is determined by cardiac imvolvement. Cardiac sarcoidosis (CS) is frequent and occurs in approximately a quarter of patients with systemic sarcoidosis (2). The gold standard for diagnosing CS is endomyocardial biopsy; however, the diagnostic yield is low. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) provides information on whole-heart imaging and myocardial inflammation. Necrotizing granulomas in sarcoidosis contain epithelial cells, macrophages, multinucleated giant cells, and CD4+ lymphocytes. FDG is incorporated into these leukocytes through the glucose transporters in their membrane (1). Therefore, FDG-PET is a clinically useful tool for detecting inflammation of the myocardium, including in CS.
The mainstay of treatments for CS are immunosuppressive therapy and heart failure medication based on ejection fraction. Device therapy may also be necessary for patients with CS and ventricular arrhythmia. Initiation of immunosuppression before the progression of ventricular impairment may improve clinical outcomes in patients with CS (3). Additionally, the European Association of Cardiovascular Imaging and the American Society of Nuclear Cardiology proposed conducting FDG-PET/computed tomography (CT) at the time of diagnosis to provide prognostic information and to assess the therapeutic response of immunosuppressive agents in CS (4); however, the association between resolution of abnormal myocardial FDG uptake and prognosis in patients with CS has not been well evaluated. The purpose of our study was to determine the prognostic value of resolution of abnormal FDG uptake in patients with CS who received conventional treatment. The ILLUstration of the Management and prognosIs of JapaNese PATiEnts with Cardiac Sarcoidosis (ILLUMINATE-CS) was a retrospective registry used to assess the clinical characteristics and outcomes of patients with CS diagnosed from 2001 to 2017; the main findings have been published previously (5). Patients were enrolled from 33 participating hospitals (21 university hospitals, and 12 non-university teaching hospitals) in Japan.
We performed a sub-analysis of the ILLUMINATE-CS registry (6). We included patients who underwent FDG-PET before starting immunosuppressive treatment and at least one further scan after achieving the maintenance dose of steroid. If a PET scan was performed several times in the same patient after achieving the maintenance dose of steroid, the most recently acquired image was used. The American Heart Association 17-segment model was used to evaluate the distribution and semi-quantify the segments of the myocardium showing FDG uptake on PET/CT. Although the method of scanning and uptake was determined by each institution’s criteria, 18F-FDG (185MBq) was injected intravenously after at least 12 hours of fasting to minimize physiological myocardial FDG uptake in all participating institutions. Segments with abnormal FDG uptake on PET scans were counted, and the improvement in uptake in the heart (PETIMP) was defined as follows: Patients with myocardial segments with abnormal FDG uptake at baseline that decreased to ≤1 at follow-up scanning. The study population was divided based on the occurrence of PETIMP in order to investigate its impact on clinical outcomes. Patients without any myocardial FDG uptake at baseline and follow-up were excluded. The primary endpoint was all-cause death. Exploratory endpoints were hospitalization for heart failure and fatal ventricular arrhythmia events.
From a total of 512 patients registered in the ILLUMINATE-CS registry, we extracted the data of 192 patients who underwent FDG-PET/CT at baseline and at least once after the achievement of maintenance dose of steroid. At baseline, 186 patients (96.9%) showed FDG uptake in at least one segment. Of these, 113 patients were identified as being in the PETIMP group. Complete resolution of FDG uptake was observed in 97 patients (85.8%) in the PETIMP group. Follow-up PET was performed at a median of 488 days after the baseline scan (IQR 216–1090 days). The percentage of steroid use was similar in both groups (94.7% vs. 98.6%, P=0.14). The prednisolone equivalent steroid maintenance dose did not differ significantly between groups (7.5 ± 3.7 mg vs. 7.3 ± 3.3 mg, P=0.76). During a median follow-up period of 884 (IQR, 485–1563) days, the primary endpoint was observed in 11 patients; one patient with PETIMP (one non-cardiovascular death) and 10 patients without PETIMP died (0.9% vs. 13.7%). Kaplan–Meier curves for all-cause mortality showed that all-cause mortality was significantly lower in patients with PETIMP than in those without PETIMP (log-rank P=0.001). Kaplan–Meier curves for exploratory endpoints did not differ significantly between patients with and without PETIMP. In the unadjusted Cox hazard model (HR, 0.06, 95% CI, 0.01–0.49, P=0.008) and adjusted Cox hazard models (HR, 0.08, 95% CI, 0.01–0.70, P=0.02), PETIMP was a protective factor for all-cause mortality. In the LASSO regression analysis, PETIMP was also one of the predictors for all-cause death.
Our study was a post-hoc analysis of data obtained from the ILLUMINATE-CS registry, which is the largest retrospective cohort of patients with CS. This sub-analysis resulted in two main findings. First, of the 186 patients with CS who received conventional therapy, 113 patients had resolution of FDG uptake (60.8%). Complete resolution of abnormal FDG uptake was observed in 97 patients in the PETIMP group. Steroids were used in the majority of cases, with an administration rate of over 90%. Considering the paucity of data regarding serial FDG changes in patients with CS, our findings provide valuable information on the association between the conventional management of patients with CS and the resolution of myocardial FDG uptake. Second, all-cause mortality was significantly lower in patients with PETIMP than in those without PETIMP (log-rank P=0.001). Based on our findings, the resolution of myocardium FDG uptake after achieving the maintenance steroid dose may predict the prognosis in patients with CS. FDG-PET may be useful for detecting myocardial inflammation and evaluating the response to immunosuppressive treatment (4). However, there is no robust evidence about whether serial FDG-PET is suitable for monitoring the efficacy of immunosuppressive treatment. Our study provided substantial data to assess the association between resolution of FDG uptake and prognosis in patients with CS. Although death was rare in this cohort, all-cause mortality was significantly lower among CS patients with PETIMP.
According to previous studies, the prognostic value of FDG uptake in patients with CS is controversial. A previous study showed that one-fifth of patients without FDG uptake had ventricular arrhythmias, and that FDG-PET/CT findings may not be useful for ruling out ventricular arrhythmias in patients with CS (7). By contrast, Blankstein et al. reported that patients with CS who had FDG uptake had a higher rate of ventricular tachycardia and death (8). In addition, most studies of FDG-PET and CS used a single FDG-PET/CT scan. To our knowledge, only one study with a limited number of patients evaluated the association between changes in FDG-PET and prognosis (9). A strength of our study is that it evaluated the serial changes in FDG-PET findings before and after immunosuppressive therapy with a sizable number of patients with CS diagnosed according to the current guidelines. Our results suggest the possible prognostic usefulness of serial FDG uptake changes in patients with CS. An accurate quantitative evaluation of FDG uptake has not been well established for patients with CS, which may explain the inconsistent association between FDG findings and prognosis in patients with CS. The maximum standardized uptake value (SUV) may modify the accuracy of the prognostic value of PET/CT; however, this is also controversial (7).
Regarding immunosuppressive treatment, in the guidelines of the Japanese Circulation Society proposed in 2016, a prednisolone-equivalent dose of 5–10 mg/day was recommended (10). From our finding that resolution of abnormal FDG uptake was observed in 113 patients (60.8%), steroid treatment with a prednisolone equivalent of approximately 7.5 mg may be inadequate to suppress inflammation in some patients with CS. Subramanian et al. found that FDG uptake before treatment was a predictor of clinical and echocardiographic response to immunosuppressive treatment in patients with CS (11). In other words, the inflammatory burden in the myocardium may be associated with the response to immunosuppressive treatment. Based on these studies and our findings, we consider one of the therapeutic challenges in patients with CS to be non-responsiveness to steroids. Generally, an increase in the steroid dose is associated with a higher risk of adverse side effects, such as osteoporosis, diabetes mellitus, and gastric ulcer formation. Hence, the combination of steroids and other immunosuppressive agents may be an option for achieving complete resolution of FDG uptake, which may be consistent with the suppression of inflammation. Further research on novel immunosuppressive therapies is required.
Another important challenge to address is determining the optimal timing of repeat PET/CT imaging. Further prospective research is needed to determine the optimal timing of FDG-PET/CT for evaluating the efficacy of immunosuppressive therapy. The combination of PET/CT and other imaging modalities, such as late gadolinium enhancement, and T1 mapping derived from cardiac magnetic resonance, may improve the accuracy of the prognosis and facilitate the monitoring and evaluation of treatment effects (12). These points should also be evaluated in future studies.
References
[1] Trivieri MG, Spagnolo P, Birnie D, et al. Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review. J Am Coll Cardiol 2020;76:1878-1901.
[2] Silverman KJ, Hutchins GM, Bulkley BH. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:1204-1211.
[3] Yazaki Y, Isobe M, Hiroe M, et al. Central Japan Heart Study Group. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001;88:1006-1010.
[4] Writing group; Document reading group; EACVI Reviewers: This document was reviewed by members of the EACVI Scientific Documents Committee for 2014–2016 and 2016–2018. A joint procedural position statement on imaging in cardiac sarcoidosis: from the Cardiovascular and Inflammation & Infection Committees of the European Association of Nuclear Medicine, the European Association of Cardiovascular Imaging, and the American Society of Nuclear Cardiology. Eur Heart J Cardiovasc Imaging 2017;18:1073-1089.
[5] Nabeta T, Kitai T, Naruse Y, et al. Risk stratification of patients with cardiac sarcoidosis: the ILLUMINATE-CS registry. Eur Heart J 2022;43:3450-3459.
[6] Okabe T, Nabeta T, Naruse Y, et al. Prognostic Implication of the Resolution of Myocardial FDG Uptake in Patients With Cardiac Sarcoidosis. JACC: Asia. Jun 27, 2023. Epublished DOI: 10.1016/j.jacasi.2023.04.007
[7] Sperry BW, Tamarappoo BK, Oldan JD, et al. Prognostic Impact of Extent, Severity, and Heterogeneity of Abnormalities on 18F-FDG PET Scans for Suspected Cardiac Sarcoidosis. JACC Cardiovasc Imaging 2018;11:336-345.
[8] Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol. 2014;63:329-36.
[9] Ning N, Guo HH, Iagaru A, Mittra E, Fowler M, Witteles R. Serial Cardiac FDG-PET for the Diagnosis and Therapeutic Guidance of Patients With Cardiac Sarcoidosis. J Card Fail 2019;25:307-311.
[10] Terasaki F, Azuma A, Anzai T, et al. Japanese Circulation Society Joint Working Group. JCS 2016 Guideline on Diagnosis and Treatment of Cardiac Sarcoidosis- Digest Version. Circ J 2019;83:2329-2388.
[11] Subramanian M, Swapna N, Ali AZ, et al. Pre-Treatment Myocardial 18FDG Uptake Predicts Response to Immunosuppression in Patients With Cardiac Sarcoidosis. JACC Cardiovasc Imaging 2021;14:2008-2016.
[12] Greulich S, Gatidis S, Gräni C, et al. Hybrid Cardiac Magnetic Resonance/Fluorodeoxyglucose Positron Emission Tomography to Differentiate Active From Chronic Cardiac Sarcoidosis. JACC Cardiovasc Imaging 2022;15:445-456.
.png)
