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Corresponding author at: Division of Severe Heart Failure, Tokyo Women's Medical University Graduate School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 1628666, Japan. Tel.: +81 3 3353 8111; fax: +81 3 3356 0441.
Management of cardiac sarcoidosis (CS) can be challenging. The first-line therapy for this condition is corticosteroids, but other immunosuppressive agents are sometimes co-administered to reduce the dosage of corticosteroid and to thereby avoid steroid-induced adverse effects or to increase its therapeutic efficacy. Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase that acts more selectively on T and B lymphocytes when compared with azathioprine. A 40-year-old man was diagnosed with CS after presenting with ventricular fibrillation. His left ventricular ejection fraction was severely reduced (30%), and cardiac positron emission tomography (PET) showed abnormal uptake of 18F-fluorodeoxyglucose. A cardioverter-defibrillator was implanted and prednisolone (30 mg/day) was administered. He was re-admitted with recurrent sustained ventricular tachycardia and a positive PET finding despite a 5-month course of prednisolone, and MMF (1000 mg/day) was administered. Six months later, he had not required re-hospitalization for heart failure or arrhythmia. We conclude that combination therapy with MMF and corticosteroids is useful for refractory CS.
<Learning objective: Management of cardiac sarcoidosis (CS) can be challenging. Although some immunosuppressive agents are co-administered to reduce the dosage of corticosteroids or to intensify the effect of corticosteroids, the optimal combination regimen has not yet been established. This case report shows that combination therapy with corticosteroid and mycophenolate mofetil was useful for CS that was refractory to corticosteroid monotherapy.>
While early diagnosis and early treatment of CS may improve outcomes, treatment can be challenging. The main goal of treatment for sarcoidosis is to control and suppress the inflammation and activity of the disease. Corticosteroids comprise the first line of therapy [
]. However, the use of corticosteroids is frequently accompanied by serious adverse effects, such as gastric ulcers, osteoporosis, diabetes, and infectious diseases. Other immunosuppressive agents (e.g. methotrexate, azathioprine, leflunomide) are sometimes added to reduce the dosage of corticosteroids or to intensify therapy, but some patients do not respond to or tolerate these agents [
]. However, data regarding the use of MMF in cardiac sarcoidosis are limited. The present report describes a case of steroid-resistant CS that was successfully treated with combination therapy of MMF and corticosteroids.
Case report
A 40-year-old man was admitted due to ventricular fibrillation. He was resuscitated using an automated external defibrillator. On admission, he was alert and his electrocardiogram showed ventricular tachycardia. His coronary angiography revealed neither stenosis nor occlusion, and his echocardiogram showed a left ventricular (LV) ejection fraction (EF) of 30% and LV dilation (LV end-diastolic diameter, 61 mm) (Fig. 1A ). Laboratory testing showed a serum angiotensin-converting enzyme (ACE) level of 12.5 U/L (normal range: 8.3–21.4 U/L). CMR showed a significantly enlarged left ventricle and severe diffuse hypokinesis. Late gadolinium enhancement (LGE) revealed extensive epicardial hyper-enhancement in the anterior, lateral, and inferior walls (Fig. 1B). An endomyocardial biopsy did not demonstrate granulomatous inflammation, but a trans-bronchial lung biopsy (Fig. 1C) showed sarcoidosis.
Fig. 1Images leading to the diagnosis of cardiac sarcoidosis. (A) Transthoracic echocardiography shows a left ventricle (LV) ejection fraction of 30% and LV dilation. (B) Cardiovascular magnetic resonance shows the presence of a late enhancement of gadolinium contrast involving the interventricular septum and LV anterior-inferior-lateral-posterior walls. The pattern of enhancement involves the mid-myocardium and epicardium. (C) Trans-bronchial lung biopsy shows non-caseating epithelioid granuloma.
An implantable cardioverter-defibrillator (ICD) was placed, and medical therapy (including 20 mg of carvedilol) was initiated. Cardiac 18F-fluorodeoxyglucose (FDG) PET was performed to evaluate for myocardial inflammation and showed significant FDG uptake in the wall that corresponded to the LGE area. The maximal standardized uptake value (SUV max) was 6.01 in the anterolateral wall (Fig. 2A and B ). No active inflammation was observed in other organs (Fig. 2A).
Fig. 218F-fluorodeoxyglucose-positron emission tomography (FDG-PET) findings before immunosuppressive therapy. (A) PET scan shows significant abnormal FDG uptake in the heart and no abnormal extra-cardiac findings. (B) Significant abnormal FDG uptake is found in the wall and corresponds with the late gadolinium enhancement positive region. Standardized uptake value max is 6.01 in anterolateral wall.
One month later, the patient was re-admitted to the hospital with frequent but appropriate discharges of his ICD. His laboratory data on admission demonstrated high brain natriuretic peptide (1000 pg/ml), and prednisone (30 mg/day) and amiodarone therapy was initiated. Four months after starting prednisone, he was readmitted with recurrent ventricular tachycardia (VT). His serum ACE level remained low (6–7 U/L). Follow-up FDG-PET study revealed positive findings (SUV max = 4.46) despite an 8-month course of prednisolone (Fig. 3).
Fig. 3Clinical course of the case. Despite corticosteroid therapy, the patient experienced refractory ventricular tachycardia and abnormal uptake on positron emission tomography (PET) remained. After the administration of mycophenolate mofetil with corticosteroid, he has not required re-hospitalization for ventricular arrhythmia and abnormal uptake on PET was decreased. VT, ventricular tachycardia; MMF, mycophenolate mofetil. * Using blood concentration monitoring, we adjusted the amount of MMF to a target of 2.0 μg/ml.
To intensify the therapy, we increased the amount of corticosteroid, but VT storm occurred again. MMF (1000 mg; CellCept®; Roche Laboratories, Basel, Switzerland) was added to corticosteroid in order to intensify the immunosuppressive effect. Using blood concentration monitoring, we adjusted the dosage of MMF to a target of 2.0 μg/ml, and the frequency of ICD discharges for VT gradually decreased. Obvious adverse effects of MMF, such as gastrointestinal symptoms and leukopenia, did not occur. At 6 months after the initiation of MMF, the patient has not required re-hospitalization for either heart failure or arrhythmia. The PET SUV value decreased slightly (SUV max = 3.93) (Fig. 3), and his cardiac function remained impaired (EF = 25%).
Discussion
The report describes the use of combination therapy of corticosteroids and MMF in a case of refractory CS. Brill et al. reported that the addition of MMF to corticosteroid in 10 patients with chronic pulmonary sarcoidosis allowed for a significant reduction in the dosage of corticosteroids while simultaneously maintaining lung function. They also reported that the addition of MMF was safe and well tolerated [
Corticosteroids comprise the first line of therapy for sarcoidosis. Other immunosuppressive agents, such as methotrexate and azathioprine, are sometimes co-administered either to reduce the dosage of corticosteroid (to decrease the risk of steroid-related adverse effects) or to intensify its efficacy [
], and the drug can be given orally or subcutaneously. Since methotrexate is cleared by the kidneys, monitoring of renal function is advised, and adjustment of the methotrexate dose is needed in patients with renal insufficiency (i.e. serum creatinine > 1.5 mg/dl). Azathioprine, which has been used with other medications to prevent transplant rejection, has recently been studied in the management of sarcoidosis. However, azathioprine increases the risk of infection [
]. On the other hand, MMF is a prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, and acts more selectively on T and B lymphocytes when compared with azathioprine [
]. Indeed, the use of MMF is thought to have more immunological efficacy and less severe adverse effects than methotrexate or azathioprine. Since the patient in the present case was at risk of renal dysfunction due to severely impaired cardiac function, we decided to use MMF in combination with corticosteroids as a second-line therapy for refractory CS.
The data regarding the use of MMF in sarcoidosis, especially in CS, are limited. The present report suggests that MMF may be safe and effective in suppressing CS disease activity and refractory VT, although it is difficult to perfectly prevent physiological FDG uptake in the normal and failing myocardium. More data with regard to MMF therapy for CS are needed to establish this strategy for refractory CS.
Conclusions
We report the efficacy of combination therapy with corticosteroids and MMF in a patient with sarcoidosis and refractory cardiac involvement. MMF, which has fewer adverse effects than methotrexate or azathioprine, should be considered as an alternative option for the treatment of corticosteroid-resistant sarcoidosis.
Conflicts of interest
The authors declare that they have no conflicts of interest.
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