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ORIGINAL ARTICLE
Ahead of print publication  

Clinical Outcomes in Patients with Cardiac Lupus: A Retrospective Study


1 Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India

Correspondence Address:
Vijay Prakash Turaka,
Department of Medicine, Unit 2, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_127_19

  Abstract 


Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect every organ system. The study aimed to analyze the clinical manifestations, laboratory findings, antibody associations, and clinical outcomes of patients with cardiac lupus.
Materials and Methods: Biomedical records of patients admitted during 2014–2017 who had a diagnosis of SLE were reviewed. Using predetermined inclusion criteria patients with cardiac lupus were identified. Disease manifestations, antibody associations, and clinical outcomes were studied. The Cox proportional hazards model was used to study factors associated with mortality.
Results: Over a 3-year period, a total of 372 were admitted with a diagnosis of SLE, out of which 59 patients with cardiac lupus were identified. The patients were predominantly female (86.4%), fever and breathlessness were most common symptoms and the median SLE disease activity index score was 18. Myocardial disease (66.1%), pericardial disease (30.5%), and pulmonary artery hypertension (23.7%) were the most common cardiac manifestations. The mean ejection fraction was 46% ±11.4% with left ventricular systolic dysfunction present in 65.5% (n = 36). The inpatient mortality rate was 22% (n = 13). An elevated serum creatinine, elevated creatine Kinase–muscle/brain, neutrophilic leukocytosis, left ventricular systolic dysfunction, noninitiation of hydroxychloroquine, and the presence of neuropsychiatric lupus predicted mortality. On follow-up, 12 of the 13 echocardiograms demonstrated normal findings.
Conclusion: Cardiac disease affects a significant proportion of patients with lupus. A high mortality rate as evident from this study, highlights the importance of recognizing the cardiac complications of SLE. Clinicians should diligently search for the same, as early interventions could reduce mortality and morbidity.

Keywords: Cardiac disease, myocardial disease, pericardial disease, systemic lupus erythematosus



How to cite this URL:
Koshy K M, George T, Das S, Punitha J V, Rajan SJ, Yadav B, Sudarsanam TD, Turaka VP. Clinical Outcomes in Patients with Cardiac Lupus: A Retrospective Study. Indian J Rheumatol [Epub ahead of print] [cited 2020 Apr 3]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=277421




  Introduction Top


Systemic lupus erythematosus (SLE) is a connective tissue disease of unknown etiology, characterized by the formation of autoantibodies and immune complexes.[1] Lupus frequently affects women of the childbearing age group, and virtually any organ system can be involved.[2] Cardiac manifestations are known to occur with SLE, with a lifetime prevalence of 50%. Cardiac lupus is associated with significant morbidity and mortality.[3]

SLE can affect all layers of the heart, including the pericardium, conduction system, myocardium, valves, and coronary vessels.[4] Pericardial disease is the most common cardiac manifestation with a prevalence of 12%–48%. It is often asymptomatic and can occur as a part of generalized serositis. Rarely, patients can present in cardiac tamponade.[5] Conduction system abnormalities are rare and are most often not directly attributable to the disease. Approximately one-third of infants born to mothers with anti-SS-A antibodies can have congenital heart block.[6] Myocardial involvement is seen in a small proportion of patients. While most cases of myocardial dysfunction are related to indirect factors such as hypertension, drugs and coronary artery disease (CAD), immune-mediated myocarditis can also occur. Immune-mediated myocarditis necessitates high dose immunosuppressive therapy.[7],[8] Valve involvement is in the form of nodules, thickening, regurgitation, and vegetations. Nonbacterial thrombotic endocarditis usually occurs in the presence of antiphospholipid antibodies.[9]

Cardiac lupus in the Indian context has not been well studied. This study aimed to review the cardiac manifestations of SLE, based on the experience of the medical units of a tertiary care teaching hospital. Clinical presentation, antibody associations, and outcomes of patients with cardiac lupus were studied.


  Materials and Methods Top


This study was undertaken at a tertiary care referral hospital in South India between January 2014 and January 2017. All adult patients, ≥18 years who had SLE with cardiac involvement, were included in the study. Data regarding patient demographics, clinical presentation, laboratory and immunological parameters, radiological parameters, electrocardiography (ECG), and echocardiography (ECHO) findings were retrieved from the electronic medical records. Complications and long-term outcomes were also studied.

The diagnosis of SLE was based on the Systemic Lupus International Collaborating Clinics criteria. Patients had to fulfill ≥4 criteria including 1 clinical and 1 laboratory criterion or had biopsy-proven lupus nephritis in the presence of antinuclear antibody (ANA) or anti-double stranded DNA (dsDNA) antibodies.[10] SLE disease activity index (SLEDAI) and Sequential Organ Failure Assessment (SOFA) scores were calculated to assess disease severity.[11],[12] Cardiac involvement was defined as follows:

1. Pericardial disease: ECHO report showing moderate/severe pericardial effusion or effusion more than 10 mm posteriorly OR any significant anterior effusion OR features of cardiac tamponade

2. Myocardial disease:

Asymptomatic

Evidence of regional wall motion abnormality (RWMA)/low ejection fraction (EF) of <40%/moderate-to-severe regurgitant lesions OR ECG changes suggestive of myocardial involvement (Q waves, ST-T changes).

Symptomatic

Elevated cardiac biomarkers OR ECG features of myocardial involvement OR ECHO features of RWMA/reduced EF/or moderate to severe regurgitant lesions/chamber enlargement.

3. Conduction system abnormality: Symptomatic or asymptomatic patients with bundle branch blocks//prolonged QTc/atrial or ventricular bradyarrhythmia or tachyarrythmias OR Holter showing rhythm abnormalities

4. Valvular disease: Regurgitation was considered to be present if it was mild and associated with valvular thickening, moderate or severe, or a vegetation of the respective valve. Minimal or mild regurgitation of a structurally normal valve was not considered.

A valvular vegetation was defined as an abnormal localized echodensity with well-defined borders either part of or adjacent to valve leaflets, the subvalvular apparatus, or the great vessels.

Abnormal valvular thickening was considered to be present when a thickness of >3 mm (for the mitral and tricuspid valves) or >2 mm (for the aortic valve) was observed in at least two leaflets or in one leaflet with an associated vegetation, at least mild regurgitation, or both.

Libman Sacks endocarditis was defined as vegetations appearing as valve masses of varying size (≥2 mm in diameter) and shape with irregular borders and echodensity, firmly attached to the valve surface and exhibiting no independent motion-involving either the valve or the subvalvular apparatus.

5. Pulmonary artery hypertension: ECHO evidence of tricuspid regurgitant jet velocity more than 3.5 m/s.

Continuous variables were summarized using mean and standard deviation when normally distributed and median and inter-quartile range (IQR) when not normally distributed. Categorical variables were analyzed using proportions. The Cox proportional hazards model was used to study factors associated with mortality. Kaplan–Meier survival analysis was done using follow-up data. The study was approved by the Institutional Review Board and Ethics Committee. Data were analyzed using IBM SPSS Software, version 25.


  Results Top


Baseline characteristics

Over a 3-year period (2014–2016), 372 patients with SLE were admitted and managed in the general medical units. About 16% (n = 59) of the patients with SLE had cardiac involvement according to the above-defined criteria. The patients hailed from various Indian states and were predominantly female (n = 51, 86.4%) with a mean age of 29.4 ± 10.2 years. Patients were symptomatic for a median duration of 60 days (IQR: 30–180) with fever and breathlessness being the most common presenting symptoms. Majority of the patients were diagnosed with SLE during the same admission (n = 48, 81.3%). At admission, most patients were tachycardic and tachypneic. Elevated jugular venous pressure and basal crepitations were elicited in 54.2% (n = 32) and 57.6% (n = 34) patients, respectively.

In the cohort, cardiac involvement was characterized by pericardial disease in 30.5% (n = 18), myocardial in 66.1% (n = 39), valve involvement in 8.5% (n = 5), conduction abnormalities in 6.8% (n = 4) and pulmonary artery hypertension in 23.7% (n = 14). Other organs of involvement included biopsy-proven lupus nephritis in 76.3% (n = 45), hematological involvement in 78% (n = 46), arthralgia/arthritis in 57.6% (n = 34), cutaneous lupus in 52.5% (n = 31) and neuropsychiatric lupus in 25.4% (n = 15). Baseline characteristics are summarized in [Table 1].
Table 1: Baseline characteristics and laboratory parameters of patients with cardiac lupus

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The median SLEDAI score was 18 (IQR: 12–26), and the admission SOFA score was 2 (IQR: 1–4). All patients had positive anti-nuclear antibodies. The median dsDNA titer was 767 (IQR: 429–1029). Laboratory parameters are summarized in [Table 1]. Twelve of the 59 patients fulfilled the criteria for antiphospholipid antibody syndrome (APS).

Electrocardiography, echocardiography, and radiographic findings

Seventy-three percent (n = 38) patients had tachycardia on ECG, with a mean rate of 112 ± 21 beats/min. Nearly 20% of patients (n = 12) had axis deviation (left axis deviation, n = 5 and right axis deviation, n = 7). ST-T changes were evident in 43.4% (n = 23) patients, and one patient had rhythm abnormality in the form of atrial fibrillation.

The mean EF was 46% ±11.4%. The left ventricular systolic dysfunction was present in 65.5% (n = 36) and 18.5% (n = 10) patients had regional wall motion abnormalities. Of the 18 patients with pericardial effusion, 12 had moderate effusion, three had massive effusion, and three patients had massive effusion precipitating cardiac tamponade. Mitral and tricuspid regurgitation was present in 10 and 7 patients, respectively. One patient had features of Libman–Sacks endocarditis. Pulmonary artery hypertension was evident in 23.7% (n = 14). Co-existing APS and systemic hypertension were was present in a fifth of the patients

Chest radiograph abnormalities included cardiomegaly (n = 39), pericardial effusion (n = 17), pleural effusion (n = 22), pulmonary edema (n = 2), and pulmonary artery hypertension (n = 5).

Treatment and outcomes

Nearly 50% (n = 31) patients received pulse steroid therapy while 96.6% (n = 57) received oral steroids. Other immunosuppressive therapy administered included cyclophosphamide (n = 16), mycophenolate mofetil (n = 14), and azathioprine (n = 10). The majority of the patients received hydroxychloroquine (88.1%). Anti-failure medication in the form of diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, and digoxin was administered, when deemed appropriate. Thirty percent (n = 18) patients required inotropic supports and 22% (n = 13) patients were mechanically ventilated. Seven patients required an interventional procedure in the form of therapeutic pericardiocentesis.

The case fatality rate was 22% (n = 13). Of the 46 patients who were discharged 44 patients had improved, while 2 clinically deteriorated. Four of the deaths were attributed to sepsis, while nine patients succumbed to refractory shock. Of the survivors, 76.1% (n = 35), 65.2% (n = 30) and 56.5% (n = 26) were followed up till 3, 6, and 12 months, respectively. At follow up, repeat ECHO was performed in 13 of the 46 survivors. Ninety two percent (n = 12) of the repeat ECHOs demonstrated normal findings.

On Cox proportional hazards regression analysis [Table 2], a raised serum creatinine and Creatine Kinase–muscle/brain (CK-MB) at admission, neutrophilic leukocytosis with relative lymphopenia, along with an elevated admission SOFA score significantly predicted mortality. The presence of left ventricular systolic dysfunction and neuropsychiatric lupus was also associated with mortality. A significant protective effect was seen in those initiated on Hydroxychloroquine. A Kaplan–Meier survival graph is shown in [Figure 1].
Table 2: Cox proportional hazards for mortality in cardiac lupus

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Figure 1: Kaplan–Meier survival graph of patients with cardiac lupus

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  Discussion Top


This study has highlighted that cardiac disease affects a considerable proportion (16%) of patients with lupus and contributes significantly to morbidity and mortality (22%). It affects all layers of the heart with myocardial disease the most frequent (66.1%, n = 39) followed by pericardial disease (30.5%, n = 18) and pulmonary artery hypertension (23.7%, n = 14). As expected, it predominantly affected young women in the reproductive age group. It is important to note that for a majority of patients, the current admission was the index presentation of the disease.

The high median SLEDAI score is an indication that most patients had a severe disease at the time of presentation. A significant proportion of patients required aggressive immunosuppressive therapy along with anti-failure medication when deemed appropriate. This immunosuppressive therapy could have contributed to mortality as some patients had died of sepsis and related complications.

The presence of left ventricular dysfunction, elevated cardiac biomarkers (CK-MB), neutrophilic leukocytosis, neuropsychiatric lupus, and elevated creatinine at admission was associated with mortality.

Hydroxychloroquine is well known to have significant benefits on outcomes in SLE, and our study findings corroborate those benefits in those with cardiac lupus as well.

Although suboptimal, its interesting to note that on follow-up, 12 of the echocardiographies done on 13 patients demonstrated normal findings. On survival analysis, majority of the patients who survived the initial acute event did well [Figure 1]. These findings further underline the need for aggressive therapy for patients with cardiac lupus, to tide over the acute crisis and the promising outcomes at follow-up.

While the pericardial disease is the most commonly reported form of cardiac involvement, our study found a higher prevalence of myocardial disease. This could be because we excluded patients with mild pericardial effusion. Further, the contribution of medications, hypertension, and other factors to myocardial dysfunction was not explored in this study.[4],[7] While previous studies including a study from India, have demonstrated an association between antiphospholipid antibodies and cardiac disease, particularly valvular dysfunction, the same was not evident in our study.[9],[13] Comparison of data from other studies on cardiac lupus from India reveals wide differences in the incidence of involvement of different layers of the heart which could be attributed to varying criteria used for the diagnosis of cardiac lupus [Table 3].[13],[14] Our results are similar to a previous study in which the incidence of cardiac tamponade was found to be around 6%.[15] In contrast to our study, which looked mainly at inpatient mortality outcomes, studies with long-term follow-up showed that mortality in patients with lupus due to cardiovascular disease reaches nearly 25%. However, these studies focused more on the CAD aspect which was not evaluated in or study.[16],[17] A retrospective autopsy study of SLE patients showed that a significant proportion of them had cardiovascular involvement, only a minor proportion of them was suspected antemortem.[18]
Table 3: Comparison of data from other Indian studies on cardiac lupus

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This study of 59 patients from South Asia gives fresh insight into the nature of cardiac lupus. However, a few limitations merit mention, the most important being the retrospective nature of the study. Although patients were followed up to the extent possible, this was incomplete and consequently, repeat ECHO findings for all patients could not be obtained. Premature atherosclerotic disease contributes significantly to the cardiac burden of lupus with previous studies showing that 6%–15% of patients with SLE have symptomatic CAD and up to 8% may have nonfatal stroke. Unfortunately, this aspect was not examined in our study.[3],[19]


  Conclusion Top


Cardiac disease contributes significantly to the morbidity and mortality of SLE. However, the cardiac disease does not feature in classification criteria or disease severity indices. This study highlights the need for clinicians to have a high index of suspicion and diligently search for cardiac involvement in patients with active disease. Early intervention may greatly reduce mortality and morbidity outcome in patients with SLE.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Schattner A, Liang MH. The cardiovascular burden of lupus: A complex challenge. Arch Intern Med 2003;163:1507-10.  Back to cited text no. 3
    
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Apte M, McGwin G Jr, Vilá LM, Kaslow RA, Alarcón GS, Reveille JD, et al. Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort (LV). [corrected]. Rheumatology (Oxford) 2008;47:362-7.  Back to cited text no. 7
    
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Kini S, Vekhande C, Londhey V. A cross-sectional study of cardiovascular involvement in systemic lupus erythematosus in an Urban Indian tertiary care centre with emphasis on 2-D echocardiography. J Assoc Physicians India 2017;65:59-64.  Back to cited text no. 14
    
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Goswami RP, Sircar G, Ghosh A, Ghosh P. Cardiac tamponade in systemic lupus erythematosus. QJM 2018;111:83-7.  Back to cited text no. 15
    
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Abu-M AA, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. J Rheumatol 1995;22:1259-64.  Back to cited text no. 17
    
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Panchal L, Divate S, Vaideeswar P, Pandit SP. Cardiovascular involvement in systemic lupus erythematosus: An autopsy study of 27 patients in India. J Postgrad Med 2006;52:5-10.  Back to cited text no. 18
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19.
Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408-15.  Back to cited text no. 19
    


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