1.       Introduction 

Sarcoidosis is a multi-system inflammatory disorder of unknown etiology resulting in formation of non-caseating granulomas. In patients with sarcoidosis, a cardiac involvement has been reported in 3 to 40% of cases in clinical series according to diagnostic criteria and procedures [1-4], and in up to 30% of cases in pathology series [5,6]. Cardiac Sarcoidosis (CS) is a potentially life threatening condition as it is reported to account for 13 to 25% of sarcoidosis-related deaths in North America and up to 85% in Japan [7,8]. Main clinical manifestations reported in CS include conduction abnormalities, ventricular arrhythmias, congestive heart failure, and sudden death [9-11]. There is no controlled clinical trial to define the best strategy of CS treatment. Usually, corticosteroid therapy is given at 0.5 to 1.0 mg/kg/day for a prolonged duration [12-13]. Other immunosuppressive therapies have been used including methotrexate, azathioprine, cyclophosphamide and mycophenolate mofetyl [14]. The Place of TNF Alfa Inhibitor (TNFI) in the treatment of idiopathic chronic heart failure is debated. On one hand, the use of high doses of TNFI has been reported to adversely affect the clinical condition of patients with moderate-to-severe chronic heart failure [15,16]. On the other hand, case series and small cohorts have reported efficacy of infliximab and adalimumab in patients with chronic heart failure, although these drugs are not considered as current standard therapy [17-20]. There is a lack of data about the efficacy of TNFI in CS. The objective of this study was to evaluate effectiveness and tolerance of TNFI in the treatment of CS.

2.       Methods 

From a large French multicenter cohort of 132 patients with extra-thoracic sarcoidosis (cohort STAT, Sarcoidose Traitée par Anti-TNF alpha) [21], we retrospectively analyzed patients who fulfilled following inclusion criteria 1) a definite histologically proven extra-thoracic sarcoidosis, 2) a diagnosis of CS based on the 2011-Heart Rhythm Society consensus [22] (Online supplementary Table 1, Table 2), and 3) who received at least one course of TNFI. Other data collected at diagnosis and during the follow-up included main extra-cardiac sarcoidosis manifestations and treatments. No patient had comorbid conditions known to induce cardiac disease or pulmonary hypertension. For all patients, following cardiac diseases have been excluded: ischemic, valvular and alcohol cardiomyopathy, as well as Lyme disease, amyloidosis, dermato-polymyositis, granulomatosis with polyangiitis, Takayasu arteritis, rheumatoid arthritis and myocarditis.

2.1.  Anti-TNF Alpha Treatment 

After starting TNFI, patients have been evaluated every 3 ± 0.5 months for 6 months, at 12 months, at the end of TNFI, and at the last visit. The response to TNFI treatment was analyzed on multiple criteria including (i) cardiac clinical symptoms/signs i.e. New York Heart Association (NYHA) class for dyspnea, presence versus absence of signs of heart failure (right, left or both), and presence vs. absence of cardiac rhythm or conduction disturbances (auricular, ventricular or both), and (ii) presence versus absence of cardiac imaging abnormalities on echography, thallium scintigraphy, MRI, or 18 FDG PET scan. Patients were classified as complete responders when they showed a complete normalization of all abnormal exams at baseline (clinical and imaging). Non responders were defined by the absence of improvement of all abnormal baseline exams or an aggravation on at least one exam. All other cases were defined as partial responders. For complete/ partial responders, we analyzed at baseline and at the end of follow up/end of TNFI the daily dose of corticosteroids and other immunosuppressant received. 

The tolerance of TNFI treatment was analyzed for infections (tuberculosis, fungal infection, hepatitis B virus reactivation…), episodes of hypersensitivity or allergy, demyelinating lesions (multiple sclerosis), autoimmune diseases, malignant tumors and cytopenia with a clinical impact. The clinical impact was defined for thrombocytopenia as a major bleeding (requiring red cell transfusion or hospitalization), and for neutropenia and leucopenia as a proved episode of infection (requiring antibiotics, antivirals or hospitalization). The authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

3.       Results

3.1.  Baseline Characteristics 

The median age at sarcoidosis diagnosis was 39.5 years [range 20-73], with a female/male ratio of 0.32 (Table 1). Patients were mainly Caucasian (53%), originating from Sub-Saharan Africa (16%), Caribbean (16%) and Maghrebian (5%) (Table 1). None had had cancer. Main classical cardiovascular risk factors were arterial hypertension (1 patient), type 2 diabetes mellitus (5 patients) and dyslipidaemia (1 patient) but they were not associated to ischemic heart disease. The mean body mass index was 28.9 kg/m² [range 21.7-45.1]. At baseline, 8/19 (42%) patients had chest pain and/or heart failure signs [NYHA class 3 (n=5), class 4 (n=1), class 2 (n=2) and class 1 (n=11)], and abnormal test on EKG (13/18, 72%), cardiac MRI (11/15, 73%), thallium scintigraphy (9/13, 69%), 18 FDG PET scan (4/9, 44%), and echocardiography (10/17, 59%). No patient presented CS as the first sarcoidosis manifestation. Of note, 16/19 (84%) patients had a multivisceral extra-thoracic sarcoidosis and 6/19 (32%) more than four organs (heart excluded) involved by sarcoidosis (Table 1).

3.2.  Treatment by TNF Alpha Inhibitor, Response Rates and Tolerance 

The mean sarcoidosis duration before starting TNFI was 156.7 months [19- 420]. TNFI treatment was indicated for cardiac involvement alone [4/19 (21.1%) patients] or associated with other sarcoidosis organ involvement [i.e. neurological 6/19 (31.6%), pulmonary 6/19 (31.6%), skin 5/19 (26.3%), ocular 1/19 (5.3%) and ear-nose-throat 1/19 (5.3%)]. Most patients were resistant or intolerant to one to four previous non-steroid immunosuppressive therapy i.e. methotrexate (14/19), cyclophosphamide (10/19), azathioprine (7/19), and mycophenolate mofetyl (3/19) (Table 1). Nineteen patients received Infliximab infusion (5 mg/kg) at baseline, week 2, and then every 4 to 8 weeks based on physician in charge decision. Only one patient received firstly etanercept (25 mg twice per week) for 10 days, and received thereafter infliximab. 

After a mean follow up of 36.6 months [3; 104] after starting TNFI, 5/19 (26.3%) patients were complete responders, 9/19 (47.4%) partial responders and 5/19 (26.3%) non-responders (Table 2). Two out of 19 (10.5%) patients developed a CS relapse during the TNFI treatment while they were receiving infliximab every 6 weeks. These patients returned to Infliximab infusion every 3 to 4 weeks with a complete response for one and a partial response for the other. Nine (47.4%) patients had had at least one infection (viral, fungal or bacterial). After a mean follow-up of 53.5 months [8; 111], four patients had to withdraw definitely TNFI treatment because of infection at 1 month (one patient), 8 months (two patients) and 38 months (one patient) after starting TNFI. Of these, three patients were partial responders and one non-responder. Two others had to withdraw TNFI because of pain chest and repolarization disturbance on EKG during the infusion at 10 and 16 months, with one non-responder and one partial responder. There was no episode of hypersensitivity or allergy. Three patients died, from cardiac failure (1), lung cancer (1) and respiratory failure of infectious origin (1). One patient developed a lung cancer. No case of lymphoma, auto-immune or demyelinating disease was noted.

All patients received corticosteroids during TNFI treatment. The mean daily dose of prednisone-equivalent was 21.4 mg [0; 60] at baseline versus 10.9 mg [0; 40] at the end of follow-up or the end of TNFI (P<0.0001) (Table 3). Forty-six percent of patients (7/15) have a cardiac treatment at the end of TNFI/end of the follow up. Before starting TNFI treatment, eighteen patients had received immunosuppressant (except corticosteroids). During TNFI treatment, most patients were receiving immunosuppressant therapy i.e. methotrexate (n=13 patients), mycophenolate mofetil (n=1), and azathioprine (n=1). Three patients had a cardiac defibrillator and one a pacemaker. 

4.       Discussion

Cardiac sarcoidosis remains a life-threatening condition with major difficulties in patient’s refractory to corticosteroids and immunosuppressant. In the present series of 19 patients with a definite CS refractory to corticosteroid plus immunosuppressive therapy, TNFI showed a complete/partial response in 74% of patients, with a significant corticosteroid-sparring effect. Of note, TNFI had to be withdrawn in 21% of patients because of infectious side effects. In previous reports, infliximab and adalimumab have showed a good efficacy in patients with refractory extra-cardiac sarcoidosis i.e. involvement of lungs, eyes, bone, and central nervous system [23-26]. Our results in patients with CS are in agreement with such results as well as with recommendations. Infliximab is recommended in CS when sarcoidosis activity is the only cause of heart failure [18,27,28]. We did not find new adverse events of TNFIs. 

There was no cardiac function degradation after the use of TNFI in CS patients as described in patients with severe idiopathic heart failure [16]. In the present series, no case of vasculitis or exacerbation as interstitial pneumonia was noted [29]. The most frequent adverse event was infection in patients who all received previously corticosteroids and immunosuppressant [19]. One patient died from respiratory failure of infectious origin. Two other patients died, one from cardiac failure and one from a lung cancer. However, cardiac sarcoidosis is known to have a very poor prognosis, with an estimated mortality rate of up to 50% [7]. The 5-year survival rate was reported to be 60 to 90% in patients who received steroids alone or combined with immunosuppressive therapy [8,13,14]. In the present series, one patient had an initial improvement of cardiac function under TNFI, but died after 30 months of a cardiac failure. TNFI had to be stopped because of chest pain and repolarization disturbance during the infusion in one non-responder and one partial responder.

We acknowledge some limitations of the present study. The gold standard for the diagnosis of CS has long been considered to be the endomyocardial biopsy. However, this invasive method showed a lack of sensitivity due to the heterogeneous distribution of granuloma within the heart [30,31]. The retrospective nature of this study is a well-known limitation e.g. the number of missing data for imaging in the present study. Controlled randomized studies are needed to better define investigation and treatment strategies. Corticosteroid treatment was a possible bias of confusion of the efficacy of TNFI although the latter permitted a steroid-sparing effect. Finally, the small number of patients should be analyzed considering the rarity of CS. In conclusion, despite the risk of infection, TNFI appear to be an effective treatment in patients with refractory cardiac sarcoidosis. Further studies are needed to confirm these results in larger population and to identify predictors of response to TNFI in patients with cardiac sarcoidosis.

5.       Conflict of Interest

There is no personal or financial support or author involvement with organization with financial interest in the subject.

Online supplementary Table 1: Summary of Heart Rhythm Society consensus statement of cardiac sarcoidosis.

Online supplementary Table 2: Main features of sarcoidosis and type of immunosuppressive therapy at baseline.

Table 1: Baseline characteristics of patients with cardiac sarcoidosis.

Table 2: Main cardiac features in patients with cardiac sarcoidosis at baseline and at the end of TNFI.

Table 3: Corticosteroids, immunosuppressive therapy and cardiac treatment for each patient with cardiac sarcoidosis, at baseline and at the end of TNF inhibitor (TNFI)/end of follow-up.

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