Rheumatology International

, Volume 28, Issue 3, pp 275–280

Clinical characteristics of lupus myocarditis in Korea

Authors

  • Jae-Wook Chung
    • Department of Allergy and RheumatologyAjou University School of Medicine
  • Dai-Yeol Joe
    • Department of Allergy and RheumatologyAjou University School of Medicine
  • Han-Jung Park
    • Department of Allergy and RheumatologyAjou University School of Medicine
  • Hyoun-Ah Kim
    • Department of Allergy and RheumatologyAjou University School of Medicine
  • Hae-Sim Park
    • Department of Allergy and RheumatologyAjou University School of Medicine
    • Department of Allergy and RheumatologyAjou University School of Medicine
Case Report

DOI: 10.1007/s00296-007-0414-6

Cite this article as:
Chung, J., Joe, D., Park, H. et al. Rheumatol Int (2008) 28: 275. doi:10.1007/s00296-007-0414-6

Abstract

Clinically important myocarditis is an unusual feature in systemic lupus erythematosus (SLE). We describe the clinical characteristics, management and outcomes of five SLE patients who developed severe left ventricular dysfunction. Four patients were female with mean age of 36.4 years. Three patients had both lupus myocarditis and lupus nephritis. Four patients had raised anti-dsDNA antibody titer and low complement level and two patients had positive IgG anticardiolipin antibody. Three patients were treated by high-dose corticosteroids, one patient by intravenous pulse methylprednisolone, and one patient by intravenous immunoglobulin and pulse cyclophosphamide with high dose corticosteroids. Left ventricular function improved markedly in four patients and all of them had no recurrence of lupus myocarditis up to follow-up of 33 months. However, one patient, who showed no improvement of left ventricular function, was expired due to sudden cardiac arrest. Lupus myocarditis should be treated by immunosuppressive therapy with high-dose corticosteroids and mostly the prognosis might be good with early treatment.

Keywords

Systemic lupus erythematosusMyocarditisImmunosuppressive therapy

Introduction

The heart is frequently involved in systemic lupus erythematosus (SLE). Cardiovascular investigations have found the prevalence of cardiac involvement in SLE to be higher than 50% [13]. Cardiac manifestation can involve all the cardiac structures, including the pericardium, the myocardium, and the endocardium. The prevalence of myocarditis from necropsy studies had been reported to be 40–70%. However, symptomatic lupus myocarditis is reported to occur in only 5–10%, suggesting that subclinical cardiac involvement is common [4, 5]. A prospective echocardiographic study of 70 patients found myocardial abnormalities in 14 cases (20%) but only one patient had clinical symptoms [6]. Myocarditis may manifest itself as an acute illness or have a chronic course with the development of a cardiomyopathy due to small vessel vasculitis and thrombosis [7]. Myocarditis may rarely be the initial presentation but a potentially fatal complication of SLE. There is a little information available on clinical manifestation and outcome of myocarditis in SLE.

We describe the clinical characteristics of five patients with SLE seen over a 33 month period, who presented with severe left ventricular dysfunction.

Case reports

We describe the clinical courses of three patients and all the clinical data and echocardiographic findings of five patients are shown in Tables 1, 2, and 3.
Table 1

Clinical and laboratory data of the five patients at admission

 

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Age (years)

44

26

28

63

23

Sex (M/F)

M

F

F

F

F

Initial symptoms

Dyspnea, generalized edema

Fever, anuria, dyspnea, generalized edema

DOE, palpitation

Chest pain, dyspnea

Dyspnea, blurred vision

WBC (/μl)

4,850

4,720

4,930

6,540

3,420

Platelet (/μl)

121,000

204,000

198,000

338,000

430,000

ESR (mm/h)

CRP (mg/dl)

97

2.85

92

3.9

22

4.9

51

4.7

53

0.82

C3/C4 (mg/dl)

33/6

19/3

17/3

61/16

177/29

CK (U/l)

CK-MB (μg/l)

103/4.2

262/3

20/0.8

15/2.0

253/7.78

Creatinine (mg/dl)

1.2

0.9

1.0

1.0

0.9

Albumin (g/dl)

2.5

3.1

3.2

2.9

3.4

Random urine

protein/creatinine

110.5/34.7

36.7/20.7

360.8/152.1

35.1/73.9

55.6/41.7

ANA titration

>1:2,560

>1:2,560

>1:2,560

>1:2,560

1:160

Anti-dsDNA (IU/ml) (N < 7)

24.1

23.5

>98

12.9

<5

Anticardiolipin Ab

IgG (GPL) (N: 0–15)

IgM (MPL) (N: 0–12.5)

25.3

9.5

<9.4

15.9

Not done

31.7

17.3

<9.4

11.0

Lupus anticoagulant

Positive

Not done

Positive

Negative

Negative

Anti-Ro antibody

Not done

Positive

Positive

Positive

Negative

Prednisolone (1 mg/kg)

+

+

+

+

+

Pulse IV methylprednisolone (1 g/day)

+

+

Immunosuppressive agents for lupus myocarditis

IV Cyclophosphamide, Intravenous immunoglobulin

Table 2

Two-dimensional echocardiographic and coronary angiographic findings at the diagnosis of lupus myocarditis

 

1

2

3

4

5

Wall motion

Global hypokinesia of left ventricle

Global hypokinesia of left ventricle

Severe global hypokinesia of left ventricle

Akinesia of midanterior segment, Akinesia of whole apex

Global hypokinesia of left ventricle

Ejection fraction (%)

40

30

22

38

35

Left atrium size (mm)

50

36

47

41

43

Left ventricle end-diastolic end-diastolic dimension (LVEDD) (mm) /left ventricle end-systolic dimension (LVESD) (mm)

58/42

58/48

54/49

51/37

51/39

Pericardial effusion

Anterior

0.6 cm

Small amount

Anterior

0.6 cm

Anterior

0.63 cm

No

Posterior 2.1 cm

 

Posterior 1.6 cm

Posterior

0.84 cm

 

Right ventricular systolic pressure (RVSP) (mmHg)

59

28

38

62

40

Coronary angiography

Not done

Not done

Normal

Normal

Not done

Table 3

Two-dimensional echocardiographic findings at the last follow-up

 

1

2

3

4

5

Wall motion

Normal

Normal

Normal

Akinesia of whole apex, Akinesia of anteroseptum from base to mid left ventricle

Normal

Ejection fraction (%)

60

72

54

38

58

Left atrium size (mm)

34

32

32

40

37

Left ventricle end-diastolic end-diastolic dimension (LVEDD) (mm) /left ventricle end-systolic dimension (LVESD) (mm)

44/30

47/27

51/35

55/44

48/32

Pericardial effusion

Anterior 0.5 cm

Small

No

Posterior

0.9 cm

No

Posterior 0.5 cm

    

Right ventricular systolic pressure (RVSP) (mmHg)

29

22

20

63

21

Patient 1

A 44-year-old man presented with fever, dyspnea, orthopnea for 2 weeks. Clinical examination revealed pulmonary bilateral rales and peripheral pitting edema. Laboratory values were remarkable for anemia, thrombocytopenia, low C3 and C4 level, positive ANA (>1:2,560), positive anti-dsDNA (24.1 IU/ml, normal: <7.0 IU/ml), positive lupus anticoagulant, positive IgG anticardiolipin antibodies (25.3 GPL, normal 0–15 GPL), proteinuria, but CPK and CK-MB was normal. Human immunodeficiency virus, hepatitis B and C, and other viral serologies were all negative. Chest radiography showed marked cardiomegaly and interstitial pulmonary edema. Echocardiogram revealed enlarged left atrium, global hypokinesia of left ventricle with a decreased left ventricular ejection fraction (LVEF 40%, normal 54–66%), moderate amount of pericardial effusion, and mild to moderate pulmonary hypertension (right ventricular systolic pressure (RVSP) 59 mmHg) (Fig. 1). SLE with acute lupus myocarditis was diagnosed and treatment with prednisolone (60 mg/day) was begun. Two weeks later, the patient was well with normal LVEF (71%). However, he still had proteinuria and renal biopsy disclosed diffuse proliferative lupus glomerulonephritis (WHO class IV). On account of lupus glomerulonephritis, the patient was started with intravenous (IV) cyclophosphamide with angiotensin-converting enzyme (ACE) inhibitor. After twelve courses of cyclophosphamide therapy, urinary protein was negative and urinary sediment was normal. Prednisolone was tapered to 5 mg/day and he remained well at 2 year follow-up.
https://static-content.springer.com/image/art%3A10.1007%2Fs00296-007-0414-6/MediaObjects/296_2007_414_Fig1_HTML.gif
Fig. 1

Parasternal short axis view of the left ventricle in two-dimensional and M-mode echocardiography at diagnosis of lupus myocarditis (a) and 3 months later (b) showing the improvement of left ventricular function in one of the patients

Patient 2

A 26-year-old woman was admitted with a 1 month history of anuria and malar rash. Laboratory tests revealed hemolytic anemia (Hg/Hct 7.2/21.4) and lymphopenia (lymphocyte count 425/μl), positive ANA (>1:2,560), positive anti-dsDNA (23.5 IU/ml), positive extractable nuclear antigen antibodies (anti-Sm, anti-RNP, anti-Ro, and anti-La), low complement level, and proteinuria, which is roughly estimated at 2.7 g/day. Two days after her admission, she developed fever of 38.8°C, disorientation for time, and regressed behavior. Blood culture revealed enterococcus facium at three of four bottles and abdomen computed tomography showed small bowel wall thickening with fluid filled distension at proximal jejunal loop. An electroencephalogram and spinal tapping results were normal, but a brain magnetic resonance imaging showed diffuse brain atrophy. Diagnoses of sepsis of small bowel origin (enterococcus facium), lupus enteritis, and neuropsychiatric lupus were made and she was treated with intravenous antibiotics and antipsychotics. She had a persistent fever with decreasing C-reactive protein (CRP) from 1.46 to 0.22 mg/dl after antibiotic treatment for 1 week. Based on proper antibiotics for enterococcus sepsis and normalized CRP, lupus flare was considered and she was treated with pulse IV methylprednisolone (1 g/day for 3 days) and following oral prednisolone (60 mg/day). However, her condition was deteriorated with tachypnea, tachycardia, and chest discomfort and chest X-ray revealed cardiomegaly with bilateral pulmonary edema. An echocardiography showed global hypokinesia and LVEF of 30%. She was transferred to an intensive care unit for mechanical ventilation and intravenous immunoglobulin (IVIG) treatment (0.4 g/kg for 5 days) was initiated with digoxin, diuretics, β-blocker, and ACE inhibitor. Within 3 days, she could be weaned from mechanical ventilation. Two days after IVIG treatment, fever was subsided but echocardiographic findings revealed no significant change. In spite of IVIG and pulse IV methylprednisolone therapy, neuropsychiatric lupus, hemolytic anemia, and lupus myocarditis was not resolved, so IV cyclophosphamide was added. One month after the first cycle of IV cyclophosphamide, the estimated LVEF was increased to 72%. After recovery of her general condition and heart failure, she took a renal biopsy, which disclosed membranous lupus glomerulonephritis (WHO class V). She was discharged with tapered prednisolone (40 mg/day). After 12 courses of IV cyclophosphamide, prednisolone was tapered to 5 mg/day and she remained well at 1 year follow-up.

Patient 3

A 63-year-old woman presented with polyarthralgias and chest pain. She had a history of hypertension for 13 years and been suffered from polyarthralgias for 3 years. She admitted 1 year ago with atypical chest pain. At that time, her heart evaluation was normal LVEF of 70% by echocardiography and normal coronary arteries by angiography. Clinical examination revealed audible rales on both lung fields. Laboratory data showed low C3 and C4 level, positive ANA (>1:2560), positive anti-dsDNA (12.9 IU/ml), positive anti-Ro antibody and positive IgG anti-cardiolipin antibody (31.7 GPL). CK and CK-MB was normal. Human immunodeficiency virus, hepatitis B and C, and other viral serologies were negative. The chest radiography showed marked cardiomegaly and interstitial pulmonary edema. An echocardiogram revealed enlarged left atrium, decreased left ventricular systolic function (LVEF of 38%), akinesia of whole apex, moderate amount of pericardial effusion and moderate pulmonary hypertension (RVSP 62 mmHg). Diagnoses of hypertension and lupus myocarditis were made and the patient was treated with high-dose corticosteroids (60 mg/day). She was started an anticoagulation and conventional therapy for heart failure. A follow-up echocardiogram 11 days later showed as same as previous result. However, her symptom was improving and she was discharged. She was followed at out patient clinic with digoxin, angiotensin receptor blocker, diuretics, coumadin, hydroxychloroquine, and prednisolone, which was tapered to 10 mg/day and she remained well at 5 months follow-up. Six months after her discharge, the patient returned with dyspnea, cramping abdominal pain, nausea, and generalized tonic-clonic seizure attack. Laboratory data were remarkable for low C3 and C4 level. Anti-dsDNA antibody was negative and serum potassium, magnesium, ionized calcium, CK, CK-MB, erythrocyte sedimentation rate and CRP were normal. Abdomen computed tomography showed small bowel wall edema. A brain magnetic resonance imaging and spinal tapping results were normal, but an electroencephalogram showed epileptic discharge waves at left parietal lobe. An echocardiography showed enlarged left atrium with decreased systolic function (LVEF of 38%), akinesia of whole apex and anteroseptum from base to mid LV, small amount of pericardial effusion. One day after her admission sudden ventricular tachycardia was developed, but she was recovered after the electro-cardioversion (200 J). She was transferred to an intensive care unit and intravenous amiodarone was started. Prednisolone was increased up to 20 mg/day with antiepileptics due to increased disease activity such as neuropsychiatric lupus and lupus enteritis. Two days later, sudden cardiac arrest was developed and she was expired in spite of the resuscitation. A postmortem examination was not carried out.

Discussion

Myocarditis is the most characteristic feature of myocardial involvement in SLE. In SLE patients, however, myocardial dysfunction may be the consequence of other features, particularly coronary artery disease due to premature atherosclerosis, hypertension, renal failure, valvular disease and toxicity from medications, such as cyclophosphamide and chlorquine [1, 2]. We report five cases of myocarditis with congestive heart failure, in the absence of coronary artery disease, characterized by their early occurrence in the course of the lupus disease. The common presenting symptoms are dyspnea, fever, chest pain. There are basal crackles on chest auscultation and cardiomegaly in chest X-ray in all patients.

The gold standard of diagnosing myocarditis remains endomyocardial biopsy [8]. However, endomyocardial biopsy is invasive with procedure-related risks and diagnostic yielding is low in 10–20%, so it is not powerful enough to confirm the diagnosis [9]. Lupus myocarditis could be diagnosed by clinical suspicion and echocardiographic evidence of impaired LVEF and wall motion abnormality, if other etiologies such as viral and ischemic cardiomyopathy were excluded [8, 10]. Our five patients met the American College of Rheumatology criteria for SLE and none of them had viral etiologies and ischemic heat diseases. Two patients performed coronary angiography, which showed normal findings. All patients had echocardiographic findings of impaired LVEF, wall motion abnormality with enlarged left atrium or left ventricular end-diastolic dimension (LVEDD), pericardial effusion, and pulmonary hypertension. Four of them (80%) returned to normal LVEF and wall motion after immunosuppressive therapy. Also, right ventricular pulmonary pressure was normalized and it suggests that the high prevalence of pulmonary hypertension may be due to active disease with symptomatic myocardial involvement.

In myocarditis, histologic findings show small foci of fibrinoid necrosis with infiltrates of plasma cells and lymphocytes. Immunofluorescence studies demonstrate fine granular immune complex and complement deposition in the walls and perivascular tissues of myocardial blood vessels supporting the hypothesis that lupus myocarditis is an immune complex-mediated vascular phenomenon [11]. Some reports demonstrate an association between anti-Ro and anticardiolipin antibodies with left ventricular dysfunction [12, 13]. Antiphospholipid antibodies such as anticardiolipin antibody, lupus anticoagulant, anti-β2 glycoprotein-I antibody could be an independent risk factor for coronary artery disease and myocardial infarction so it might be explained by intracoronary vessel thrombosis, even though the data is insufficient.

Anti-Ro antibody is implicated in the pathogenesis of conduction abnormalities, which are rare in adults [14]. It is explained by inflammatory myocardial damage or a direct arrhythmogenic activity of anti-Ro antibody. However, the role of anti-Ro antibody in lupus myocarditis is not known so it could be further evaluated. There is a report that all patients had raised anti-dsDNA antibody, but the role of anti-dsDNA for lupus myocarditis was not mentioned [15]. In our cases four patients had increased anti-dsDNA level, but unlike the case of Law et al. in which only five patients (44%) had concomitant active nephritis, three patients (60%) had concomitant lupus nephritis with low complements and increased anti-dsDNA levels. Anti-dsDNA and complement have been found to be good markers of disease activity and predictors of outcome in lupus nephritis in some, but not all, studies. Increased anti-dsDNA levels in our case might reflect renal flares, but the possibility of the association between anti-dsDNA and lupus myocarditis could not rule out.

Treatment of myocarditis should include an angiotensin-converting enzyme inhibitor and β-adrenergic blocking agent in all patients and the selective use of an aldosterone antagonist in patients with persistent symptoms. The long-term sequelae of viral myocarditis appear to be related to abnormal cellular and humoral immunity, many clinicians believe that immunosuppression should be beneficial for myocarditis treatment, but has not shown to be effective as conventional treatment for acute myocarditis [16, 17]. Early trials of antiviral therapies, such as interferon, suggest a potential therapeutic role but require further investigation. However, immunosuppression is now essentially recommended for treatment of myocarditis associated with connective tissue disease [18]. Even though there is no report of randomized controlled trial, lupus myocarditis should be treated immediately with high-dose corticosteroids. In the most severe forms it is necessary to use pulse IV corticosteroids followed by high doses of oral corticosteroids. Immunosuppressives like cyclophosphamide [19] or azathioprine [20], combination of corticosteroids and pulse IV cyclophophamide [19] may be beneficial in the treatment of myocarditis. There are some case reports of the beneficial use of IVIG in myocardial dysfunction in SLE [21]. If treated with the corticosteroids with or without immunosuppressives, most patients had an improvement on follow-up echocardiography. The need to anticoagulation when anticardiolipin antibodies are positive, in the absence of coronary artery disease, remains controversial [22]. In our case, three patients who were treated initially with high-dose corticosteroids showed dramatic resolution of symptoms within 2 weeks of treatment and their echocardiography showed normalized hemodynamic findings. One patient was not improved after pulse IV methylprednisolone, so she was treated by IVIG and pulse IV cyclophosphamide. After that treatment, the clinical response was appeared slowly and her follow-up echocardiography showed improvement in 1 month later. Three patients had accompanying lupus nephritis (two: WHO class IV, one: WHO class V), which were treated with pulse IV cyclophosphamide.

In our cases, there was one death. When it compared to other cases, the patient, who was the oldest in our cases, had hypertension, positive anti-Ro antibody, positive IgG anticardiolipin antibody, normal coronary arteries documented by angiography, and persistent heart failure. Similar to myocarditis of other causes such as viral myocarditis, lupus myocarditis can progress to dilated cardiomyopathy and chronic heart failure [23]. In chronic heart failure, intraventricular conduction is depressed and sudden cardiac death due to ventricular arrhythmia is common. Recently, there is a report that anti-Ro antibody is associated with complete heart block and corrected QT interval prolongation in adult [24]. So anti-Ro antibodies might have a role in her arrhythmia. We assumed that the cause of death could be due to sudden onset arrhythmia associated with chronic heart failure during the lupus flare of neuropsychiatric lupus and lupus enteritis.

There is not much information available on the clinical characteristics, managements, and outcomes of lupus myocarditis. Our case series showed myocarditis would be as part of the acute initial presentation of SLE and early treatment of lupus myocarditis with corticosteroids with or without immunosuppressives could result in good outcomes.

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© Springer-Verlag 2007