A long-term follow-up of necrobiotic xanthogranuloma with concomitant large-vessel vasculitis and heart failure with reduced ejection fraction: a case report

Abstract

Background

Necrobiotic xanthogranuloma (NXG) is a non-Langerhans cell histiocytosis and multisystem disorder. Low level of HDL cholesterol associated with a systemic inflammatory profile, which may result from the interaction of monoclonal immunoglobulin and lipoproteins, is a characteristic feature. There is no evidence of NXG-associated large-vessel vasculitis, nor are there any established treatments, although chemotherapy for comorbid multiple myeloma is most often administered.

Case summary

We describe a case of a 53-year-old male with a first history of heart failure with impaired systolic function. He presented with orbital xanthomas and multiple subcutaneous nodules, and laboratory examination showed elevated levels of C-reactive protein, low HDL, and paraproteinemia. A constellation of these clinical features and pathological findings of skin biopsy led to the diagnosis of NXG. ¹⁸F-Fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) confirmed increased uptake in the aorta and bilateral common carotid arteries. He began prednisolone treatment with reference to treatment for large-vessel vasculitis. After the treatment, C-reactive protein immediately decreased with markedly increased levels of apolipoprotein A1 (Apo-A1) and HDL. Systolic dysfunction was restored at 6-month follow-up. The patient has not experienced heart failure for 5 years after treatment, and the follow-up PET/CT demonstrated resolution of vascular inflammation.

Discussion

This is the first report of NXG-associated large-vessel vasculitis. Low-dose prednisolone may benefit for NXG-associated vasculitis and cardiomyopathy. HDL, Apo-A1, and C-reactive protein levels may be useful for monitoring the activity of NXG, and PET/CT was a valuable diagnostic tool for NXG-associated vasculitis.

Introduction

Necrobiotic xanthogranuloma (NXG) is a non-Langerhans cell histiocytosis and multisystem disorder first described by Kossard and Winkelmann in 1980.¹ Necrobiotic xanthogranuloma is characterized by low level of HDL and persistent paraproteinemia, yet the underlying mechanism remains elusive. We describe a case of NXG with large-vessel vasculitis and heart failure with reduced ejection fraction.

Summary figure

Case report

A 53-year-old Japanese male presented with worsening dyspnoea. Marked oedema was observed in the extremities, and chest radiography revealed pulmonary congestion. Transthoracic echocardiography showed a LVEF of 15%, biventricular diffuse hypokinesis, and left ventricular dilation with functional mitral regurgitation. He was hospitalized with a diagnosis of heart failure with reduced LVEF (HFrEF).

Ten years prior to the admission, he underwent liver biopsy for one hepatic mass, which showed a granulomatous lesion with Langerhans-type multinucleated giant cells and necrosis. Although Mycobacterium tuberculosis was not detected, he had been taking drugs against suspected tuberculosis. Eight years before the admission, he was diagnosed with multiple myeloma and treated with lenalidomide and prednisolone. The multiple myeloma subsequently settled down, and lenalidomide and prednisolone had been discontinued 4 years before admission. He had been followed up without hospitalization.

On admission, he presented with orbital xanthomas (Figure 1A) and subcutaneous nodules on the neck, trunk, and back (Figure 1B), which had been asymptomatic and uninvestigated since his childhood. Laboratory examination showed elevated levels of C-reactive protein, brain natriuretic peptide (BNP), high-sensitivity troponin I, and liver enzymes, and apolipoprotein A1 (Apo-A1) and HDL cholesterol were extremely low (see Supplementary material online, Table S1). Serum protein electrophoresis confirmed the presence of an IgGκ paraproteinemia. Urine immunoelectrophoresis indicated the presence of Bence Jones protein; however, bone marrow biopsy showed that plasma cells represented <10% of all nucleated cells, which did not meet the diagnostic criteria of multiple myeloma.

Computed tomography showed numerous plaques were accumulated from the aortic arch to the descending aorta (Figure 2A). Magnetic resonance angiography (MRA) showed prominent plaque formation, wall irregularities in bilateral common carotid arteries, and occlusion of left subclavian artery and left vertebral artery (Figure 2B). Coronary angiography demonstrated significant stenosis in the left anterior descending artery (LAD, Figure 2C), and the intravascular ultrasound confirmed diffuse hypoechoic plaques (Figure 2D). Right ventricular endomyocardial biopsy showed no obvious abnormalities. Cardiac MRI showed an inducible perfusion defect in extensive anterolateral region under adenosine triphosphate stress (Figure 2E and F). On the other hand, there was no evidence of myocardial oedema or late gadolinium enhancement (Figure 2G). Cardiac dysfunction was at least partly attributed to reduced blood flow in the coronary artery, and percutaneous coronary intervention was indicated for the LAD lesions; however, we prioritized optimal medical therapy due to the incidence of contrast-induced nephropathy after coronary angiography.

Advanced atherosclerotic lesions for his age, wall thickening of the aorta, and persistently elevated C-reactive protein level were highly suggestive of vasculitis. ¹⁸F-Fluorodeoxyglucose PET/CT confirmed increased uptake in the aorta, bilateral common carotid arteries, and the skin area corresponding to the characteristic eruptions (Figure 3D–F).

He underwent skin biopsy of the eruption in the neck, which showed necrotic lesions from the dermis to the subcutaneous tissue, surrounded by inflammatory cell infiltration including foamy histiocytes (Figure 4). Cholesterin deposits and an infiltrate of foreign body-type polygonal giant cells that phagocytosed these deposits were also observed, and these were consistent findings with liver biopsy specimen 10 years ago.

He was finally diagnosed with NXG based on a constellation of his clinical and histopathological features. Necrobiotic xanthogranuloma is a non-Langerhans cell histiocytosis and multisystem disorder. Although the pathogenesis remains unknown, impaired macrophage lipid homeostasis associated with a systemic inflammatory profile, which may result from the interaction of monoclonal immunoglobulin and lipoproteins, and extremely low levels of HDL are characteristic features.² He began prednisolone treatment with at an initial dose of 0.5 mg/kg/day (30 mg/day) with reference to treatment for large-vessel vasculitis. After the treatment, skin yellow rashes became thinner (Figure 1C and D), and C-reactive protein immediately decreased with markedly increased levels of Apo-A1 and HDL (Figure 5). In addition to prednisolone, carvedilol, and enalapril as a guideline-directed medical therapy (GDMT) for HFrEF at the time, aspirin and rosuvastatin for ischaemic heart disease were introduced. Brain natriuretic peptide level also decreased promptly and ST-T abnormalities of electrocardiogram on admission gradually improved (see Supplementary material online, Figure S1). Left ventricular ejection fraction increased to 41% at 6-month follow-up.

Three years after the treatment, when prednisolone tapered to 5 mg/day, skin rashes relapsed with mild C-reactive protein elevation. Prednisolone dose was increased to 20 mg/day and tapered slowly to the maintenance dose of 8 mg/day. Thereafter, no relapse of skin rashes or C-reactive protein elevation was observed for 3 years. According to the updated GDMT, he is currently taking carvedilol 10 mg, sacubitril valsartan 100 mg, dapagliflozin 10 mg, and rosuvastatin 2.5 mg daily and receives 140 mg of evolocumab every 2 weeks as well. His HDL and Apo-A1 levels remain high despite the persistent paraproteinemia and M-proteinemia. Although LVEF has not recovered completely, his BNP level maintains low (Figure 5). The PET/CT obtained 5 years after treatment demonstrated decreased uptake in the aorta and cervical arteries, reflecting the resolution of vascular inflammation (Figure 3G–gI).

Discussion

We experienced a case of NXG with large-vessel vasculitis and HFrEF. Optimal medical therapy combined with low-dose prednisolone drastically restored cardiac function, and the inflammation in the large vessels was repressed. Cardiac manifestations of NXG have been reported; however, a limited number of studies have been reported on NXG-associated vasculitis, and there is no evidence to suggest direct involvement in large-vessel inflammation.^1,3–6 Treatment for NXG varies greatly depending on the clinical features and severity, and chemotherapy for haematological disorders including multiple myeloma is most often administered.^7,8 In the present case, low-dose prednisolone was administered in accordance with the treatment for large-vessel vasculitis because his paraproteinemia did not meet the treatment criteria for multiple myeloma. Low-dose prednisolone drastically restored the status of heart failure and improved lipid profile, which to the best of our knowledge have not been reported before. Additionally, HDL and Apo-A1 levels remained high despite the persistent paraproteinemia and M-proteinemia. This suggests that prednisolone cannot prevent production of monoclonal immunoglobulin by plasma cells nor the interaction with lipoproteins but curb the consumption of Apo-A1 by repressing inflammation. Apo-A1, HDL, and C-reactive protein would be useful for the management of NXG and NXG-associated vasculitis.

The PET/CT was sensitive for the detection of large-vessel vasculitis on admission, while aortic ¹⁸F-FDG uptake could be detected also 10 years before the diagnosis of NXG (Figure 3A–C); however, these findings had been left unexplored due to a lack of the apparent symptom until incidental heart failure. The present case might suggest NXG remains underinvestigated or underdiagnosed in many cases, and thus, further investigation is crucial to identify patients with vasculitis who may benefit from low-dose prednisolone; PET/CT evaluation should be an essential diagnostic tool in the imaging of cardiovascular inflammation.

Lead author biography

Naoto Setoguchi graduated from Yamaguchi University in 2016. In 2018, he completed his junior residency programme at the University of Tokyo Hospital. From 2018 to 2022, he worked as a senior resident at Mitsui Memorial Hospital. Currently, he is working as a graduate student at the Department of Cardiovascular Medicine, University of Tokyo Hospital.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Consent: Written informed consent in accordance with COPE guidelines was obtained from the patient.

Funding: This work was supported by Japan Society for the Promotion of Science (grant number 21K08122).

Data availability

The data underlying this article are available in the article and in its online Supplementary material.

References

Author notes