Successful Treatment with Mepolizumab for Coronary Spastic Angina Associated with Eosinophilic Granulomatosis with Polyangiitis

Abstract

A 46-year-old man with a history of bronchial asthma and chronic sinusitis presented to our hospital with chest pain. We suspected angina evoked by epicardial coronary spasm and performed an ergonovine provocation test to diagnose coronary spastic angina (CSA). The patient also met the diagnostic criteria for eosinophilic granulomatosis with polyangiitis (EGPA) and was treated with 60 mg prednisolone (PSL) for EGPA-associated CSA. After PSL administration, eosinophils decreased, and angina attacks disappeared. However, when PSL was tapered to 12.5 mg, chest pain recurred. We administered mepolizumab subcutaneously and chest pain disappeared. Additional mepolizumab may be effective for EGPA with CSA.

Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a rare autoimmune condition characterized by inflammation of small- and medium-sized blood vessels, extravascular granulomas, eosinophilia, and tissue infiltration of eosinophils (1). The prognosis of EGPA is generally considered to be favorable; however, cardiac complications, such as pericarditis, myocarditis, and myocardial infarction, worsen the mortality rate. In particular, cardiac complications are common in antineutrophil cytoplasmic antibody (ANCA)-negative cases, and the mortality rate has been reported to be high (2).

Mepolizumab is an anti-interleukin (IL)-5 receptor monoclonal antibody that blocks the binding of IL-5 to eosinophils, inhibits the action of IL-5, and decreases the number of eosinophils in the blood and sputum (3). The indication was originally approved for severe eosinophilic asthma, and an additional indication was approved for EGPA in February 2020 in Japan. Mepolizumab is presently available for treating EGPA with an inadequate response to corticosteroids. However, the efficacy of mepolizumab treatment for cardiac involvement as a complication of EGPA has not been reported.

We herein report a rare case of EGPA complicated with coronary spastic angina (CSA) that was well-controlled with mepolizumab and prednisolone.

Case Report

A 46-year-old man had been diagnosed with bronchial asthma and chronic sinusitis and received steroid therapy because of frequent admission for asthma attack 10 years ago. At that time, his eosinophil count and total serum IgE levels had been elevated (342 /μL and 512.0 IU/mL, respectively), and allergen-specific IgE had been positive for cedar pollen. He also had a history of nasal polyps, eosinophilic sinusitis, eosinophilic otitis media, aspirin-induced asthma, gastric ulcer, and contrast media allergy. The patient continued to receive 0.25 mg of oral betamethasone from an otolaryngologist from 2012 to February 2020. After oral corticosteroids were discontinued, he noticed nausea, abdominal pain, diarrhea, and anorexia. Consequently, he was referred to our hospital. Gastrointestinal endoscopy showed eosinophilic esophagitis in late March 2020.

In early April 2020, he noted chest pain, progressive cough, dyspnea, nasal congestion, and anosmia. He also noticed persistent chest pain attacks for 10-15 minutes every day. He was referred to our hospital three days prior to emergency hospitalization. On suspicion of CSA, treatment with benidipine hydrochloride and isosorbide dinitrate tape was initiated. However, there was little improvement in his symptoms, and the chest pain radiated to his left shoulder and was associated with nausea, so he was transported to our hospital in April, 2020 (day 1). The electrocardiogram (ECG) in the emergency room showed ST-segment elevation in aVR, and ST-segment depression in I, II, aVL, and aVF (Fig. 1). Echocardiography showed hypokinesis and asynergy in the inferior base-apex. Chest computed tomography (CT) also showed multiple tiny lung infiltrates and a ground-glass appearance consistent with vasculitis processes at the bilateral lower lobe (Fig. 2). Laboratory data showed an elevated eosinophil count (980 /μL), and myeloperoxidase- and proteinase 3-ANCA tests were both negative (Table). On admission, the forced vital capacity, forced expiratory volume in 1 second, and peak expiratory flow were 3.56 L, 74.9%, and 8.16 L/s, respectively. The fractional nitric oxide concentration in exhaled breath was 46 ppb under budesonide/formoterol fumarate hydrate inhalation.

Figure 1.

Twelve-lead electrocardiogram (ECG) findings during chest pain attack. The ECG showed ST-segment elevation in aVR and ST-segment depression in I, II, aVL, and aVF.

Figure 2.

Imaging studies on admission. A: Computed tomography (CT) of the paranasal sinus showed sinusitis (arrows). B: Chest CT on admission showed reticular shadows around broncho-vascular bundles in the bilateral lower lobes and bronchial wall thickening (arrows).

Table.

Laboratory Findings.

Hematology			Biochemistry			Serology
WBC	7,000	/μL	AST	12	U/L	CRP	0.63	mg/dL
Seg	70	%	ALT	12	U/L	BNP	<5.8	pg/mL
Stab	0	%	LDH	233	U/L	CK	48	U/L
Mon	5	%	ALP	147	U/L	CK-MB	1	U/L
Lym	11	%	TP	6.1	g/dL	TnI	55.5	pg/mL
Eos	14	%	ALB	3.3	g/dL	IgG	1,046	mg/dL
Bas	0	%	CRE	0.58	mg/dL	IgE	145	mg/dL
RBC	380	×104/μL	BUN	7	mg/dL	IgG4	95.4	mg/dL
Hgb	12.2	g/dL	Na	140	mEq/L	sIL-2R	1,076	U/mL
Hct	34.3	%	K	3.1	mEq/L	KL-6	145	U/mL
PLT	39.6	×104/μL	Cl	105	mEq/L	RF	5	U/mL
			Ca	8.4	mg/dL	ANA	<×40
						PR3-ANCA	<1.0	U/mL
						MPO-ANCA	<1.0	U/mL

WBC: white blood cell, RBC: red blood cell, Hgb: hemoglobin, Hct: hematocrit, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, TP: total protein, ALB: albumin, CRE: creatinine, BUN: blood urea nitrogen, Na: sodium, K: potassium, Cl: chlorine, Ca: calcium, CRP: C-reactive protein, BNP: brain natriuretic peptide, CK: creatine kinase, CK-MB: creatine kinase-MB, TnI: I troponin I, IgG: immunoglobulin G, IgE: immunoglobulin E, sIL-2R: soluble interleukin-2 receptor, KL-6: krebs von den lungen-6, RF: rheumatoid factor, ANA: antinuclear antibody, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody

A coronary angiogram performed two days after admission showed no coronary artery stenosis. CSA was suspected and 20 μg of ergonovine was loaded to induce coronary artery spasm (Fig. 3). Furthermore, the ergonovine provocation test induced severe coronary artery spasm in the right coronary artery, associated with ST segment elevation in II, III, and aVF, which improved after 10 mg isosorbide was injected. Subsequently, a diagnosis of CSA was made.

Figure 3.

A coronary angiogram obtained during the ergonovine provocation test (A: control, B: ergnovine). A: Before the ergonovine provocation test of coronary artery spasm. No significant stenosis in the right coronary artery. B: After intra-coronary infusion of ergonovine (20 μg), a severe coronary artery spasm was provoked in the right coronary artery.

The patient was diagnosed with definite EGPA due to bronchial asthma, eosinophilia, and weight loss (10 kg within 6 months) as symptoms of vasculitis. The patient was started on high-dose prednisolone (PSL) therapy of 60 mg (1 mg/kg) 4 days after admission. Following the initiation of PSL, the patient had minimal chest pains, and gastrointestinal symptoms, such as diarrhea, disappeared; his appetite recovered on day 7. Continuous intravenous nicorandil was terminated on day 9, and there was no recurrence of chest pain or ECG abnormalities after day 10.

Twenty days after admission, systemic symptoms improved completely, and chest CT showed sinusitis improvement and ground-glass opacities around the bronchial vascular bundle in the lower lobe. The dose of PSL was tapered to 50 mg after 2 weeks and then tapered 10 mg every week. The patient was discharged from the hospital with a 30 mg dose of PSL. He began outpatient visits once a month, and over a period of 4 months, PSL was tapered to 12.5 mg; however, he occasionally experienced mild chest pain with an increase of the eosinophil count. Therefore, additional treatment was considered. In addition to PSL, we initiated treatment with 300 mg mepolizumab to safely taper the PSL dose (Fig. 4).

Figure 4.

The clinical course after late March 2020. The patient noticed persistent chest pain attacks for 10-15 minutes every day in early April 2020. Marked elevation of eosinophil count was observed, and the diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) with coronary spastic angina was made. He was started on high-dose prednisolone (PSL) therapy of 60 mg (1 mg/kg) and chest pains improved. Following PSL administration, the eosinophil count markedly decreased, and angina attacks disappeared. When PSL was tapered to 12.5 mg, he occasionally experienced mild chest pain with slight progression of eosinophilia. The administration of 300 mg mepolizumab kept the eosinophils count under 100 cells/μL. Two years after the onset of EGPA, PSL was tapered to 6 mg, but there was no recurrence of chest pain or discomfort.

At 2 years from the onset of EGPA, PSL was tapered to 6 mg, but there was no recurrence of chest pain or discomfort. In addition, 300 mg mepolizumab administered subcutaneously every 4 weeks induced no adverse events.

Discussion

We herein report a case of EGPA with CSA diagnosed after a 10-year history of bronchial asthma accompanying type 2 inflammation. The patient also had vasculitis-associated symptoms, but these were relieved by betamethasone and were thought to have worsened after discontinuation of oral corticosteroids. This case appeared to be one of steroid-dependent refractory EGPA, and mepolizumab was effective for relieving angina attacks. To our knowledge, this is the first report indicating that mepolizumab is effective against EGPA-associated CSA.

The diagnosis of EGPA in the setting of acute coronary syndromes is very rare but has been previously reported. In a case series reported by Wong et al. in 2008, among 19 cases of CSA due to eosinophilia, 5 were diagnosed as EGPA (Churg-Strauss syndrome) (4). To our knowledge, there were another eight cases of EGPA complicated with CSA reported from 2009-2021 (5-12). All cases were reported to be negative for ANCA. Cardiac complications are particularly common in ANCA-negative cases, and the mortality rate is high (2). In approximately half of these cases, PSL alone was inadequate to control EGPA symptoms. Wong et al. suggested that sudden death and cardiac arrest could occur due to tapering or discontinuation of corticosteroids (4). Our case is consistent with these previous reports, and it was expected to have a poor prognosis and with difficulty controlling the symptoms.

CSA can be well-treated with nitric acid, nicorandil, and calcium channel blockers. However, when the treatment is ineffective, it is diagnosed as refractory CSA. Coronary artery vasospasm in EGPA is considered to be due to eosinophilic infiltration of the coronary artery wall. Eosinophilic basic proteins or vasoactive cytokines are suggested to directly stimulate the constriction of vascular smooth muscle (4), resulting in a condition that is refractory to vasodilators. In the present case, chest pain attacks with ST-T changes were frequent despite the use of vasodilators. Therefore, we need to check the eosinophil count and make differential diagnoses of the cause of refractory CSA as well as determine whether or not the condition is related to hyper-eosinophilia, such as EGPA. In addition, our patient experienced occasional slight chest pain despite oral corticosteroid treatment, which was tapered to 12.5 mg PSL, suggesting that corticosteroids alone are insufficient for managing EGPA-associated CSA.

In moderate-to-severe EGPA, cyclophosphamide is generally recommended as an induction remission therapy (1). In fact, there have been several reports of similar cases of EGPA with CSA treated with cyclophosphamide (5-7). Chai et al. described a 42-year-old man with acute ST-elevation myocardial infarction complicated with EGPA, who was successfully treated with the prompt initiation of intravenous cyclophosphamide and remained well and asymptomatic on maintenance immunosuppressants using azathioprine at 1-year follow-up (5). Many patients require long-term therapy. Steroid-sparing immunosuppressants, such as cyclophosphamide and azathioprine, can reduce the required doses of steroids, diminishing the side effects. Additional agents should be considered for the reduction of the corticosteroid dose in the treatment of EGPA.

In relapsing or refractory EGPA, the remission induction rate was significantly better in the mepolizumab group than in the placebo group (3). Therefore, mepolizumab is considered to be a viable alternative drug for severe EGPA and is presently commercially available in Japan. Considering the presence of various allergic symptoms, such as sinusitis and aspirin-induced asthma, in our patient, we suspected that mepolizumab would be beneficial. The patient was relatively young and concerned about the side effects of cyclophosphamide, such as myelosuppression and a decreased reproductive function; therefore, he selected mepolizumab. As a result, the patient remained asymptomatic for 2 years, and PSL was able to be safely reduced to 6 mg. Our patient experienced no adverse events caused by mepolizumab. Additional mepolizumab administration may be a promising optional strategy for treating severe EGPA, especially in cases with cardiac involvement.

In conclusion, we experienced a rare case of refractory CSA associated with ANCA-negative EGPA successfully treated with mepolizumab. Mepolizumab combined with oral steroid treatment seems to be useful for EGPA complicated with cardiac involvement. Further investigations are warranted to confirm the usefulness of mepolizumab for such patients.

The authors state that they have no Conflict of Interest (COI).