The efficacy of methotrexate for intolerance to prednisolone therapy in cardiac sarcoidosis
Authors: Morimoto R , Kuwayama T , Ooishi H , Kazama S , Kimura Y , Shibata N , Hiraiwa H , Kondo T , Okumura T , Unno K , Murohara T 
Published: November 2020

Abstract

Background and purpose
Fluorine-18-flurodeoxyglucose positron emission tomography (18FDG-PET) is a useful examination assessing active inflammatory myocardium noninvasively in patients with cardiac sarcoidosis (CS). Though immunosuppression like prednisolone (PSL) and Methotrexate (MTX) as alternative therapy is used to suppress the inflammation, little is known about the rate of response and efficacy of MTX for intolerance to PSL therapy.

Methods
From Aug 2016, we prospectively enrolled CS with positively accumulated of FDG in the heart. The initial dose of PSL was 30mg/day, wherefrom the dose was tapered down 5mg/month until 6 months. After 6 months, follow-up 18FDG-PET was performed. Using 18FDG-PET images, we calculated total lesion glycolysis (TLG; SUVmeam x metabolic volume) and calculated the reduction rate of TLG. In order to estimate the response rate to PSL therapy, responder group (R-group) was defined as TLG reduction rate ≥70% and poor-responder group (PR-group) was defined as TLG reduction rate &lt;70% after PSL therapy. After prescribed PSL, subjects with PR-group randomized to PSL (maximum dose 30mg daily and tapered down 5mg/month until 6 months) or to MTX (6mg weekly).

Results
In 64 CS patients, 55 patients had serial 18FDG-PET before and 6 months after PSL therapy. 18FDG-PET images were acquired following 7 day's carbohydrate limitation and after at least 18-h fasting (mean free fatty acid level right before 18FDG-PET acquisition was 1.05 mEq/L). The mean age was 63.4 years old and 42 (76.4%) patients were female. Because of 6 months PSL therapy, even though there were no significant difference in BNP (from 59.9 (26.2–137.6) to 60.4 (18.5–122.0) (P=0.593), LV-Dd (from 50.9 (44.5–59.5) to 49.7 (45.5–61.3) (P=0.666) and LV-EF (from 49.5 (34.4–62.5) to 49.9 (38.0–62.0) (P=0.792) at pre and post therapy, respectively, TLG were detected significant reduction from 216.4 (74.2–411.6) to 0.8 (0.0–8.2), (p&lt;0.001). In response to PSL therapy, 47 (85.5%) CS patients were classified to R-group and 8 (14.5%) were classified to PR-group. Furthermore, when performed block randomization and divide 8 PR-group patients into MTX (n=3) and re-increased PSL (n=5) for more 6 months, MTX group is prone to high rate of TLG reduction than re-increased PSL-group (89.4% vs 59.9%) and one patient belonged to re-increased PSL group showed that the further elevation of TLG level at additional 6-months PSL therapy (349⇒483) (Figure).

Conclusions
1) By immunosuppression therapy using PSL for CS, about 86% patients showed significant reduction of myocardial FDG accumulation. 2) When detected intolerance for PSL therapy, MTX might be effective for reduction of inflammation of sarcoidosis in the heart, which might be effective as an alternate therapy in CS.
The TLG level after randomization

Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): Grant-in-aid for scientific research