Interleukin-1 Blockade in Cardiac Sarcoidosis: A Pilot Study

Interest in cardiac sarcoidosis has recently intensified, including creation of the Cardiac Sarcoidosis Consortium¹ and 2014 Heart Rhythm Society Expert Consensus Statement.² Collaborative research efforts into this poorly-understood disease highlight the key unmet need for targeted immunologic therapies. We demonstrated activation of the inflammasome in hearts of patients with active cardiac sarcoidosis.³ The inflammasome is an essential part of the innate immune system activated in response to injury or danger signals, leading to interleukin-1(IL-1) release and inflammatory response amplification. C-reactive protein(CRP) is the preferred systemic inflammatory biomarker for cardiovascular risk stratification and surrogate for IL-1 activity, which predicts not only atherothrombotic events but also cardiac arrhythmias. Anakinra(Kineret^®) is recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes and recurrent pericarditis. We hypothesize that IL-1 blockade with anakinra is feasible and can safely modulate systemic inflammation in cardiac sarcoidosis.

The Multi-modality Assessment of Granulomas in Cardiac Sarcoidosis–Anakinra Randomized Trial (MAGiC-ART) is a randomized, open-label, controlled pilot clinical trial of patients with active cardiac sarcoidosis at Virginia Commonwealth University and University of Michigan who meet 3 criteria: (1) Heart Rhythm or Japanese Diagnostic criteria⁴ (2) myocardial inflammation on cardiac fluorodeoxyglucose positron emission tomography(FDG-PET), and (3)high-sensitivity(hs)-CRP≥2 mg/dL within 2 months. Key exclusion criteria include active infection, cancer, or treatment with TNF blockers. A detailed trial design has been published.⁴ Local IRBs approved this research and all subjects provided written informed consent. A simplified fully de-identified database will be available to share within 3 years of study completion. The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

Patients are randomized to anakinra 100 mg subcutaneous daily plus standard of care (SOC) or SOC for 28 days. The study design sample size was 28 patients, and one interim analysis of 16 patients(57%) is presented. The primary endpoint, interval change in hs-CRP between baseline and day 28, is a measure for systemic inflammation, and surrogate for IL-1 activity. Data are presented as N and % or median (interquartile range), and compared between groups using Chi-square, or Fisher’s test, for discrete variable or Mann-Whitney for continuous variables.

Sixteen patients were enrolled between September 24, 2020, and September 26, 2022; 12 females (75%) and 9 self-identified Black/African-American (56%), with median age 61 (54–65) years(Table). Time from sarcoidoidosis diagnosis to randomization was 160 months (68–216) and from cardiac sarcoidosis diagnosis to randomization was 31 months (18–90). Baseline therapy included methotrexate (n=8; 15 [15–25] mg weekly), prednisone (n=3; 2.5, 4, and 5 mg daily), azathioprine (n=3;50 mg twice daily), hydroxychloroquine (n=1,400 mg daily), and mycophenolic acid (n=1,1500 mg twice daily).

Table.

Primary and secondary data including biomarkers, FDG PET scans, cardiac MRI, and holter data comparing anakinra plus standard of care with standard of care at baseline and 28 days.

Clinical Data (N=16)
Female	12 (75%)
Black/African American	9 (56%)
Age	61 [54–65]
Time from sarcoidosis diagnosis to randomization (months)	160 [68–216]
Time from cardiac sarcoidosis diagnosis to randomization (months)	31 [18–90]
Clinical presentation (patient can have more than one)
Cardiomyopathy/myocarditis	9 (56%)
Heart block/syncope	6 (38%)
VT/cardiac arrest	4 (25%)
Biopsy proven	n=9
Lymph node biopsy	5 (56%)
Lung biopsy	2 (22%)
Skin biopsy	1 (11%)
Other biopsy	1 (11%)
Medications
Prednisone	3 (19%)
Methotrexate	8 (50%)
Azathioprine	3 (19%)
Hydroxychloroquine	1 (6%)
Mycophenolate	1 (6%)
Biomarker Data
	Anakinra+SOC (N=6)	SOC (N=9)	P-value
At Baseline
hs-CRP	8.14 [4.35–13.67]	4.62 [3.02–8.30]	0.39
White blood cell, 10⁹/L	5.40 [2.90–10.30]	5.60 [5.15–8.65]	0.78
Absolute neutrophil count, 10⁹/L	3.20 [1.98–8.13]	3.80 [2.30–5.85]	0.49
Creatinine, mg/dL	1.09 [0.87–1.49]	0.94 [0.80–1.05]	0.15
Platelet Count	254.50 [177.00–289.00]	237.00 [160.50–269.50]	0.69
At 28 days
hs-CRP	2.55 [1.79–6.32]	4.24 [3.70–7.34]
% Change from baseline	−63% [−73 to −4]	+4% [−29 to +47]	0.04
White blood cell, 10⁹/L	4.95 [2.20–9.48]	6.60 [5.50–8.55]
% Change from baseline	−15% [−24 to −2]	0% [−4 to +18]	0.04
Absolute neutrophil count, 10⁹/L	2.45 [1.13–6.50]	3.50 [2.60–6.30]
% Change from baseline	−31% [−43 to −17]	+6% [−12 to +28]	0.003
Platelet Count	226.50 [145.25–264.25]	235.00 [145.50–266.00]
% Change from baseline	−10% [−19 to −8]	−1% [−6 to +2]	0.01
FDG PET Data
	Anakinra+SOC (N=6)	SOC (N=5)	P-value
Mean LV SUV baseline	4.88 [2.80–7.7]	2.40 [2.25–10.15]
Mean LV SUV 28 days	3.90 [2.4–5.08]	2.05 [1.62–10.98]
% Change LV SUV from baseline	−17% [−35 to 0]	−14% [−38 to −13]	0.54
Ejection fraction baseline	58.50 [51.75–68.50]	60 [45–61.5]
Ejection fraction 28 days	62.5 [53.75–69.25]	55 [39.0–60.5]
% change LV ejection fraction from baseline	4.98% [−3.39 to 14.69]	−1.67% [−20.35 to 4.55]	0.247
Holter
	Anakinra+SOC (N=7)	SOC (N=9)	P-value
% PVCs baseline	2.17 [1.00–4.00]	1.00 [1.00–1.90]	0.174
% PVCs 28 days	2.00 [1.00–15.00]	3.00 [1.00–8.00]	1
% change % PVCs	0% [0 to +95]	+150% [+50 to +425]	0.101
# ventricular runs baseline	1 [0–3]	0 [0–0]	0.142
# ventricular runs 28 days	0 [0–19]	0 [0–1]	0.535
% change # ventricular runs	12% [−75 to +406]	0 [0–0]	0.400

Abbreviations: SOC, standard of care; hs-CRP, high sensitivity C-reactive protein; LV, left ventricle; SUV, standardized uptake value; PVC, premature ventricular contractions

Seven patients (44%) were randomized to anakinra+SOC and 9 (56%) to SOC. No unexpected treatment-related adverse events occurred. All patients were compliant with investigational treatment. Three patients (43%) treated with anakinra had self-limited injection site reactions not requiring treatment cessation. One patient (14%) on anakinra had transient neutropenia (900/mm3) without any signs of infection. One patient in the anakinra group had a self-limited upper respiratory infection during treatment and was excluded from biomarker analysis.

Treatment with anakinra was associated with a significant reduction in neutrophil (−31%) and platelet counts (−10%)(Table). The primary endpoint, interval change in hs-CRP at 28 days, was significantly decreased in the anakinra+SOC group at −63% (−73% to −3%) vs SOC +4% (−29% to +47%, p=0.04).

On FDG-PET scan, % change left ventricular (LV) standardized uptake value (SUV) from baseline to 28 days was −17% (−35 to 0) in treatment group vs −14% (−38 to −13) in control group, p=0.54. Percent change in LV ejection fraction (EF) was +4.98% (−3.39 to +14.69) in the anakinra group vs. −1.67% (−20.35 to +4.55) in SOC, p=0.25. Secondary ECG Holter endpoints are shown(Table).

The MAGiC-ART study demonstrates feasibility of recruiting and enrolling a diverse patient population with cardiac sarcoidosis from two geographically distant academic centers, addressing a critical need in a disease that disproportionately affects females and African-American patients in the US.^{1, 4} This pilot study confirms the known safety profile of anakinra, with only mild side-effects and no unexpected treatment-related adverse events, and provides a biological signal for enhanced IL-1 signaling in cardiac sarcoidosis.^{3, 5} Reduction in hs-CRP levels with treatment suggests systemic inflammatory response modification with treatment, often associated with favorable outcomes in cardiovascular trials⁵, however the observed effects may or may not correlate with better clinical outcomes.

There is a critical knowledge gap regarding how to optimally treat cardiac sarcoidosis.² Corticosteroids remain the mainstay of initial treatment followed by the addition of steroid-sparing agents. The efficacy of different drugs in improving outcomes in cardiac sarcoidosis is unknown. Targeted immunomodulating therapies are being explored in sarcoidosis and IL-1 is one of the novel targets.^{3, 5} Future studies including more patients treated for longer duration with anakinra or other targeted therapies against IL-1, the inflammasome, or other related mediators, are necessary to further investigate the role this fundamental pathway plays in cardiac sarcoidosis.

Nonstandard Abbreviations and Acronyms

CRP

C-reactive protein

EF

ejection

FDG-PET

cardiac fluorodeoxyglucose positron emission tomography

hs-CRP

high sensitivity C-reactive protein

IL-1

Interleukin-1

LV

left ventricle

MAGiC-ART

Multi-modality Assessment of Granulomas in Cardiac Sarcoidosis–Anakinra Randomized Trial

PVC

premature ventricular contractions

SOC

standard of care

SUV

standardized uptake value