A 37-year-old white woman presented to our clinic with symptoms, including reduced physical capacity (NYHA II), strong recurrent dizziness (i.e. near-syncope), fatigue, and diffuse arthralgias as well as myalgias, which commenced approximately 4 years prior. Besides recurrent episodes of depression, treated with 60 mg/day fluoxetine p.o., her past medical history was unremarkable. The patient denied consumption of alcohol, tobacco or drugs. Her family history revealed that her grandfather received a pacemaker at the age of 50, for reasons that could not be further specified. Other familial diseases, including relevant genetic aberrations, were unknown.
Preceding admission to our clinic, an electrocardiogram performed by her cardiologist revealed complex conduction abnormalities, including a right bundle branch block, left anterior hemi-block, and atrioventricular block 1 (Figure 1A and B). While echocardiographic left ventricular (LV) volume appeared normal, LV-function was mildly impaired (LVEF 51%). Therefore, treatment with 1.25 mg/day Ramipril p.o. was initiated. Additionally, the interventricular septum was thickened (IVSd 13 mm; LVPWd 10 mm; LVIDd 50 mm). Consecutive cardiac magnetic resonance imaging (CMR), performed due to suspicion of cardiac amyloidosis, unveiled focal septal scarring as possible aetiology of the combined conduction defect, with no signs of active inflammation. Our patient then underwent cardiac catheterization with extraction of four endomyocardial biopsies (EMB) for further diagnostic workup. Histology of those EMBs demonstrated signs of inflammatory cardiomyopathy. In the meantime, negative results for IgG- and IgM-antibodies against Borrelia burgdorferi excluded concerns about potential Lyme-disease, following a tick bite 10 years prior.
Upon admission to our clinic, thorough physical examination of our patient revealed no abnormalities. Blood analyses showed elevated NT-proBNP (157 ng/L) but normal levels of high-sensitivity Troponin T (6 ng/L) and Myoglobin (<21 mug/L). Relative (18.3%) and absolute (0.99/nL) lymphocyte count were also abnormally low, implying a possible viral aetiology of the patient's myocardial inflammation. However, a consecutive PCR-screening for cardiotropic viruses proved inconclusive. Biomarkers of rheumatic diseases, suspected due to the patient's diffuse joint and muscular pain, were also inconspicuous (ANA negative; c-ANCA <0.5; P-ANCA 1.0). Moreover, levels of soluble Interleukin-2 Receptor (sIL-2R) and serum angiotensin-converting enzyme (ACE), both established biomarkers of sarcoidosis, were normal (383.0 IU/mL and 23.7 U/L, respectively). Additionally, genetic analysis for variants of the alpha-galactosidase gene, which may cause conduction defects and thickened left ventricular walls by predisposing to Morbus Fabry, were negative.
Despite negative biomarker results, sarcoidosis remained our working diagnosis due to the prevalence of complicated conduction abnormalities in a young patient, histological evidence of inflammatory cardiomyopathy and typical septal scarring in the absence of signs for acute myocarditis on CMR.
Based on strong suspicion of CS with long-standing complex conduction abnormalities as the most probable cause for our patients recurrent near-syncopes, she underwent implantation of a dual-chamber pacemaker-defibrillator (DDD-ICD) given the risk of ventricular arrhythmias and sudden cardiac death in CS. This decision was reached in accordance with indications for device therapy in CS outlined in the HRS expert consensus statement for the management of arrythmias associated with CS published by Birnie et al. in 2014 (i.e. 'unexplained near-syncope, felt to be arrhythmic in nature'; Class IIa) and our patient's wish.
Subsequently, positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography (18F-FDG-PET-CT) was performed to screen for hypermetabolic lesions, which indicate active inflammation (Figure 2A, D, G, and J). Our patient followed a special high-fat low-carbohydrate diet to suppress physiological myocardial 18F-FDG uptake. Intense hypermetabolic myocardial lesions were found in the septum, anterior wall, and proximal pulmonary trunk:a pattern indicative of active cardiac sarcoidosis. Moreover, multiple pulmonary, hepatic, splenic, and spinal lesions were found along with various hypermetabolic peripheral lymph nodes.
Although these findings were highly suggestive of systemic sarcoidosis in light of the patient's clinical presentation, co-existent disseminated malignancies (i.e. lymphoma) could not be excluded securely until the diagnosis would be confirmed through biopsy of an easily accessible lesion. Therefore, bronchoscopy with real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed. No signs of malignancy were observed. Two samples of suspicious pulmonary tissue and three samples of 18F-FDG-PET-responsive mediastinal lymph nodes were obtained and sent for histopathological assessment. Additionally, 150 mL of bronchoalveolar lavage (BAL) specimen was extracted and sent for microbiological and cytological examination.
Infections with Mycobacterium tuberculosis, other mycobacteria or fungi could be excluded through negative QuantiFERON-tests, cultivation, MOTT-PCR, as well as PAS-stains of the BAL and tissue samples, respectively. Cytological analysis revealed an elevated CD4/CD8 T-cell ratio (4.3), indicative of sarcoidosis. Histopathological evaluation identified characteristic infiltrates with non-caseating epithelioid granulomas in one of the obtained tissue samples. Given the exclusion of other granulomatous diseases, that finding provided sufficient proof of sarcoidosis. Due to the lack of associated symptoms and limited inflammatory activity observed in pulmonary tissue samples, it was concluded that pulmonary sarcoidosis is currently inactive in our patient, while CS prevails. Supporting this conclusion, spirometry results indicated sustained lung function regarding VC (103%), TLC (112%), FEV1 (80%), FVC (89%), and FEV1/FVC (91%) with no signs of restriction or obstruction.
Confirmation of sarcoidosis was followed by prompt initiation of immunosuppressive treatment with 50 mg/day prednisolone p.o.. A tapering strategy, reducing daily prednisolone doses by 10 mg/week until a dose of 20 mg/day was reached and further reductions of 2.5 mg/week after that, was followed to a maintenance dose of 5 mg/day. Additionally, our patient was advised to substitute vitamin D3 (1000 IE/day) and take pantoprazole (40 mg/day) to reduce the prednisolone-related risk of osteoporosis and gastric ulcer.
In consideration of our patient's extensive organ involvement and data indicating significantly reduced relapse rates for combined steroid and immunosuppressive therapy, prednisolone therapy was augmented with 1000 mg cyclophosphamide i.v., which was administered once a month for a duration of 6 months in an inpatient setting under gonadal protection through subcutaneous administration of gonadotropin-releasing hormone analogues.Cyclophosphamide was chosen over the more widely used corticosteroid-sparing agent methotrexate, based on data from patients with neurosarcoidosis and clinical observations made by the treating team in previous CS patients, indicating superior long-term outcomes. A benefit of cyclophosphamide was later also reported by Cacoub and colleagues, who demonstrated significantly lower relapse rates for intravenous cyclophosphamide than for methotrexate in CS.
The combined immunosuppressive therapy was well-tolerated and induced significant improvements in subjective physical capacity and quality of life within three months of initiation. In contrast, a control 18F-FDG-PET-CT indicated that most sarcoid lesions remained morphologically and metabolically unchanged at that time point (Figure 2B, E, H, and K). Yet, the therapeutic scheme was retained, as one of the pulmonary lesions appeared to be metabolically normalized, indicating partial response to treatment.
Following six cyclophosphamide cycles with a cumulative dose of 6000 mg, a maintenance regimen featuring weekly subcutaneous injections of 15 mg methotrexate, which would facilitate relatively uncomplicated outpatient treatment, was initiated. Methotrexate was chosen for therapeutic maintenance to reduce the risk of sterility posed by the well-established cumulative dose-dependent gonadotoxicity of cyclophosphamide, since our patient still had a strong wish to have children, as outlined above. Treatment duration could not be finally defined at the time of initiation, as it depends on the course of the disease. Specifically, an approach where the methotrexate dose is maintained for at least 6 months upon achievement of remission, followed by a tapering attempt reducing the weekly methotrexate dose by 2.5-5 mg every three months, was applied.
Eventually, a second control 18F-FDG-PET-CT performed 9 months after treatment initiation (Figure 2C, F, I, and L) indicated good overall response with full regression of lymph node and osseous lesions and slight residual activity at most in anteroseptal regions of the heart and in the liver. Solely the splenic lesions remained clearly hypermetabolic. The rate of ventricular stimulation recorded at a pacemaker interrogation approximately 9 months after treatment initiation was still 86%. However, partial recovery of our patient's conduction abnormalities, including the  1 AV-block and left anterior hemi-block, could be noted in an electrocardiographic follow-up approximately one year after initiation of treatment (Figure 1C and D).
Both pulmonary and cardiac function remained stable throughout the course of treatment, as assessed by serial spirometry and echocardiographic examinations.