. 2021 Apr 29;34:100782. doi: 10.1016/j.ijcha.2021.100782

Table 2.

Cardiac effects of non-steroidal treatments in cardiac sarcoidosis.

Author, year	Non-steroidal treatment studied	Other prior/concurrent treatments	Study size (n)	Follow-up (months)	Cardiac outcomes
Synthetic disease-modifying antirheumatic drugs (sDMARD)
Yazaki et al, 2014 [19]	MTX	[Concurrent]: maintenance corticosteroids	7	N/A	• PET: Improvement in myocardial perfusion or decreased myocardial uptake of ⁶⁷Ga was observed in 2 patients (28.6%). • Metabolic: HbA1c decreased from 7.6 ± 1.9 to 7.2 ± 2.0% (P < 0.05) and triglycerides from 226 ± 124 to 167 ± 118 mg/dl (P < 0.05).
Yokomatsu et al, 2018 [20]	MTX	[Concurrent]: prednisolone taper	6	mean: 17.3	• PET: Reduction of ¹⁸F-FDG uptake area in all cases (6, 100%) with almost complete disappearance in 3 (50%) cases. SUVmax also decreased in all cases, the average index significantly reduced from 11.70 to 5.08 (p = 0.002). • LVEF: Mean LVEF increased from 41.8% to 45.4%.
Nagai et al, 2014 [21]	MTX	[Concurrent]: prednisolone	10 (7 steroid-only)	12, 36, 60	• LVEF: (Steroid-only vs MTX group) Baseline: 52.3 ± 6.07 vs 49.7 ± 6.9 (P = 0.46); 3 years: 44.5 ± 13.8 vs 60.7 ± 14.3 (P = 0.04); 5 years: 45.7 ± 15.5 vs 53.6 ± 13.3 (P = 0.350). • NT-proBNP: (Steroid-only vs MTX group) Baseline: 955.5 ± 551.9 vs 621.4 ± 444.9 pg/mL (p = 0.16); 5 years: 2,839.5 ± 3,953.3 vs 494.5 ± 609.8 (p = 0.04).
Ballul et al, 2019 [23]	MTX (5, 41.7%), AZA (5, 41.7%), CP (2, 16.7)	[Concurrent]: corticosteroids	12 (24 steroid-only)	median: 3.6 [range: 1–15.2] months	• Clinical relapse (defined as reduced LVEF, 3rd degree atrioventricular block, atrial/ventricular tachycardia, sudden cardiac death) was 6.7% (2/12) in the combined non-steroidal/steroidal group versus 45.8% (11/24) in the steroid-only group (p = 0.048)
Chapelon-Abric et al, 2017 [24]	CP (20, 57.1%), MTX (12, 34.3%), MMF (2, 5.7%), cyclosporine A (1, 2.9% - transplant)	[Concurrent]: corticosteroid taper	59 (35 treated with steroid-sparing)	median: 60 (95% CI: 42–86)	• Clinical relapse (reappearance of abnormalities on EKG, echocardiography and one other imaging method on previously healed lesions): The recovery rate was 75% (18/24) for patients who received steroids alone versus 82.9% (29/35) for those who received steroids plus non-steroidal treatment (11/12 cases with MTX and 17/20 cases with CP).
Fussner et al, 2016 [25]	MMF	[Concurrent]: prednisone (32, 97%), TNFi (2, 6%), cyclosporine (1, 3%)	33	median: 22 [IQR: 13–104]	• Median time to worsening cardiomyopathy (clinical and/or 10% decrease in LVEF): 28 months. • Median time to ventricular arrhythmia: 11.5 months. • Median time to the composite endpoint of VAD, heart transplant, or death: 79 months. Three (9%) patients not receiving VAD or transplant changed therapy for apparent disease progression.
Griffin et al, 2018 [26]	MMF	[Concurrent]: prednisone	25 (MMF), 12 prednisone only	12 months (n = 21, 84%)	• PET: Follow-up ¹⁸F-FDG PET in 19 patients in the MMF group showed complete resolution of inflammation in 6 (31.6%) and improvement in 8 (42.1%). • LVEF: mean delta[LVEF] was 6.95% in the MMF group versus −2.2% in the steroid group (p < 0.05). • Arrhythmia: In the MMF group, 6 (24%) patients had ventricular tachycardia and 6 patients had persistent advanced atrioventricular block.

Biological disease modifying antirheumatic drugs (bDMARD)

Rosenthal et al, 2019 [22]	MTX (25) ± ADA (19, if persistent symptoms or intolerance to MTX)	[Concurrent]: Prednisone taper	28	mean: 49.2 (±18)	• PET: MTX (+prednisone taper) led to reduction (88%) or elimination (60%) of ¹⁸F-FDG uptake. ADA resulted in improved (84%) or resolved (63%) ¹⁸F-FDG uptake. Radiologic relapse occurred in 8/9 of the patients that stopped immunosuppression, 4/25 of the patients on MTX, and 0/19 patients on ADA. • Arrhythmia: Three out of 19 patients who remained on uninterrupted immunosuppression developed VT, while 3/9 who discontinued immunosuppression developed VT after interruption of therapy.
Sethi et al, 2018 [38]	MTX (15, 100%), ADA (added in 8 [53%])	[Concurrent]: Corticosteroids (94%)	15	median: 24	• PET: All 53% patients who were started on ADA had normalization of perfusion defects which were still present when they were on MTX. Stopping MTX early for non-compliance or side effects led to recurrence of perfusion defects in three (20%) patients. • LVEF: The percentage change in LVEF was 45 ± 12.91%, 50.6 ± 11.4% and 50.9 ± 10.7% at the initial and follow-up scans.
Estephan et al, 2017 [27]	IFX (8, 53.3%), ADA (1, 6.7%), MMF (7, 46.7%), AZA (2, 13.3%)	[Concurrent]: Prednisone (14, 93.3%)	15 (9 [60%] with PET follow-up)	6–12 months	• PET: Marked improvement or resolution of the hypermetabolic activity (myocardial ¹⁸F-FDG uptake) in all 9 patients (100%)
Kandolin et al, 2017 [28]	IFX	[Prior]: Steroids (9, 100%), MTX or AZA (n = 8, 88.9%)	9	mean: 14.8 [range: 4–37]	• PET: In all three patients with a follow-up ¹⁸F-FDG-PET study there was no myocardial ¹⁸F-FDG activity. • LVEF: no change as measured by echocardiography (p = 1.00). • Arrhythmia: One patient (11.1%) had sustained VT during the treatment. • NT-pro-BNP: decreased from 1600 (53–8000) ng/L to 1165 (37–5500) ng/L (p = 0.042).
Kowlgi et al, 2019 [29]	IFX	[Prior]: steroids ± steroid-sparing agents: MTX (70%), AZA (25%) and HCQ (10%)	27	21 [12.5–35.5]	• PET: at 25 (14–33) months there was decreased uptake in 74% of the pts. • LVEF: Median baseline LVEF was 49 (35–55) versus 49 (44–55) at follow-up (p = 0.49). • Arrhythmia: Ten-fold reduction in VT after IFX initiation (37.0% to 3.7%; p = 0.03).
Chapelon-Abric et al, 2015 [30]	IFX	[Prior]: CP (13, 81.3%), MTX (11, 68.8%), MMF (5, 31.3%), AZA (1, 6.3%), ETN (1, 6.3%)	16 (4 with CS)	median: 57 [range: 2–91]	• MRI: Gadolinium-enhanced MRI demonstrated remission of cardiac involvement in 4/4 patients with cardiac involvement prior to initiation of IFX
Harper et al, 2019 [31]	IFX	[At IFX initiation] steroids (32, 88.9%), MTX (25, 69.4%), leflunomide (9, 25%), AZA (1, 2.8%), HCQ (2, 5.6%)	36	6 (in 35/36, 97.2%), 12 (in 29/38, 76.3%)	• LVEF: 41% [IQR: 32–55, n = 31] at baseline versus 41% [IQR: 35–54, n = 28] at 6 months (p = 0.43) • Arrhythmia: VT from 32% (8/25) at baseline to 21.7% (5/23) at 6 months (p = 0.07), high-degree heart block from 28% (7/25) at baseline to 26.1% (6/23) (p = 0.37).
Cundiff et al, 2019 [32]	IFX (8, 88.9%), ADA (1, 11.1%)	[Prior]: steroids (8, 88.9%)	9	mean: 7	• PET: Number of LV myocardial segments with active CS decreased from 8.6 ± 3.6 to 1.9 ± 3.5 (p = 0.001) - Complete resolution of active CS in 6 (66.7%), partial in 2 (22.2%). • LVEF: no significant change (45 ± 15% to 50 ± 11% after therapy, p = NS).
Sinokrot et al, 2019 [33]	IFX	[Prior]: prednisone (5, 100%), MTX (4, 80%), HCQ (1, 20%)	5	mean: 12 (±6)	• PET/MRI: Cardiac involvement decreased from 37.9% ± 10.7% to 28.7% ± 8.7% (p = 0.001) • LVEF: increased from 25 ± 10% to 35 ± 10.5% (p = 0.3).
Devraj et al, 2020 [34]	ADA (7, 58.3%) IFX (4, 33.3%) and RXM (1, 8.3%%)	[Prior]: prednisone (12)	12	N/A	• PET: Myocardial uptake on PET decreased in 9/12 (83%) 3 are awaiting imaging
Puyraimond-Zemmour et al, 2017 [35]	IFX (24, 96%), ETN (1, 4%)	[Prior]: MTX (24, 96%), CP (12, 48%), AZA (8, 32%), and MMF (6, 24%)	25	50.7	• Clinical response (complete and partial response defined in improvement in all three or one-two of the following: a) clinical symptoms; b) BNP levels; c) cardiac imaging findings): nine (36%) patients were complete responders, 12 (48%) partial responders and four (16%) non-responders. Two (8%) had a CS relapse and were treated by a second course of TNFi with good response.
Jamilloux et al, 2017 [15]	IFX (120, 91%), ADA (8, 6%), ETN (3, 2%), CZP (1, 1%)	[Prior]: Steroids (n = 113, 85.6%), MTX (n = 81, 61.4%), AZA (n = 10, 7.6%), MMF (n = 6, 4.5%)	132 (28 with CS)	20.5 [IQR 8–48] months	• ePOST [40]: for cardiac involvement (n = 28): Decrease in ePOST from 2.52 to 2.02 (p = 0.015)
Krause et al, 2016 [41]	RXM	[Concurrent]: prednisone (all), MTX (20%)	5	Median: 9.6 (range 2.4–22.8)	• PET: Decreased ¹⁸F-FDG uptake seen in all 5 patients (100%). • LVEF: Three patients (60%) had improvement in LVEF (from 26% to 54%, 33% to 47%, and 32% to 40%), one (20%) had stable LVEF and in one (20%) LVEF fell from 45% to 28%.
Baker et al, 2019 [37]	IFX (20, 26%)ADA 10 (13%)Golimumab 1(1%)	[Concurrent/prior prednisone (69), MTX alone (2) , [Concurrent} MTX 55(71%), AZA 8(10%), HCQ 5 (7%), MMF 4 (5%), Leflunomide 2 (3%)	77 (20 of these used TNF alfa inhibitors	Mean 4.8 years	• Imaging: Resolution of disease activity within 12 months
Gilotra et al, 2020 [39]	IFX (30, 79%)ADA (8, 21%)	[Prior]: steroids (38, 100%), SSA (37, 99%)	38	486 (IQR 405 days)	• PET: 30/38 had a pre and post FDG scan. 16/30 (53%) had complete resolution of FDG uptake. 6/30 (20%) had improvement, 6/30 (20%) were stable, 2/30 (6.7%) were worse • LVEF: no significant change before and after treatment. 7/38 (18%)had an absolute increase in LVEF of 10% or greater. 1/38 (2.6%) had a decrease in absolute LVEF of more than 105) • Arrythmias: 3/38 (7.9%) had new events after treatment
Injean et al, 2019 [36]	IFX (3,21%)MMF (1,7%)Steroids (10, 78%)AZA (5, 36%)MTX (3, 14%)HCQ (1, 7%)Tacrolimus (1, 7%)	N/A	14	N/A	• LVEF: Thirteen patients (93%) demonstrated improvement in LVEF or stability.

ADA: adalimumab; AZA: azathioprine; (NT-pro)-BNP: N-terminal pro-brain natriuretic peptide; CP: cyclophosphamide; CS: cardiac sarcoidosis; CZP: certolizumab pegol; EKG: electrocardiogram; ePOST: extrapulmonary physician organ severity tool; ETN: etanercept; FDG: fluorodeoxyglucose; HCQ: hydroxychloroquine; IFX: infliximab; IQR: interquartile range; MMF: mycophenolate mofetil; MRI: magnetic resonance imaging; MTX: methotrexate; N/A: not available; PET: positron emission tomography; RXM: rituximab; TNF(i): tumor necrosis factor (inhibitor); VAD: ventricular assist device.