International Journal of Cardiology 171 (2014) 326–330
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Review
Cardiac involvement in mixed connective tissue disease: A systematic review Patompong Ungprasert a,⁎, Thapat Wannarong b, Theppharit Panichsillapakit b, Wisit Cheungpasitporn c, Charat Thongprayoon c, Saeed Ahmed a, Donald A. Raddatz a a b c
Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
a r t i c l e
i n f o
Article history: Received 22 October 2013 Accepted 23 December 2013 Available online 29 December 2013 Keywords: Mixed connective tissue disease Systematic review Cardiac involvement Pericarditis Myocarditis Pericardial effusion
a b s t r a c t Objective: To report the clinical characteristic of cardiac disease in patients with mixed connective tissue disease (MCTD). Method: We identified published case series that reported cardiac manifestations of patients with MCTD by searching the PubMed database using the search terms “mixed connective tissue disease”. We identified 11 case series that met our eligibility criteria. Result: 616 patients were included. Prevalence of cardiac involvement varied from 13% to 65% depending on patient selection and method used for detection. Pericarditis was the most common cardiac diagnosis with a prevalence of 30% and 43% in two prospective studies. Non-invasive cardiac tests, including electrocardiogram and echocardiogram, detected subclinical cardiac abnormalities in 6%–38% of patients. These abnormalities included conduction abnormalities, pericardial effusion and mitral valve prolapse. Diastolic dysfunction and accelerated atherosclerosis were well-documented in a case–control study. Three prospective studies revealed an overall mortality of 10.4% over the period of follow-up of 13–15 years. 20% of the mortality was directly attributable to cardiac cause. Conclusion: Cardiac involvement was common among patients with MCTD though the involvement was often clinically inapparent. Non-invasive cardiac tests might have a role for subclinical disease screening for early diagnosis and timely treatment as cardiac involvement was one of the leading causes of mortality. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Mixed connective tissue disease (MCTD) is an autoimmune disorder that was first described in 1972 as a new entity with mixed features of several connective tissue disorders, including systemic lupus erythematosus, systemic sclerosis, polymyositis and rheumatoid arthritis, in association with the presence of high titer of autoantibody to U1 ribonucleoprotein (RNP) [1]. A number of reports showed that the heart and its surrounding structure were frequently affected in patients with MCTD, as in other connective tissue disorders [2]. However, the true prevalence and nature of cardiac manifestation remain unclear as the results from previous reports varied according to patient selection and method of detection used and most of the studies emphasized only on pulmonary hypertension. This study aims to systematically review case series of patients with MCTD to better characterize the clinical
⁎ Corresponding author. E-mail address:
[email protected] (P. Ungprasert). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.079
characteristics of cardiac involvement, apart from pulmonary hypertension, of this disease. 2. Material and methodology We identified published case series that reported cardiac manifestations of patients with MCTD that met Sharp, Alarcon-Segovia, Kasukawa or Kahn criteria [3] (Table 1) by searching the PubMed database (until May 2013). We used the search terms “mixed connective tissue disease” and restricted our search to human studies. We included only article published in English. We also manually searched the references of all initially included articles. We excluded case series that reported on fewer than five patients to minimize the potential bias of reporting non-representative cases.
3. Data assessment Our search strategy yielded 73 potentially relevant articles. 39 articles were excluded as they were case reports or review article. 34 articles underwent full-length article review; 23 of them were excluded since they did not provide any data on cardiac involvement. 11 case series met our inclusion criteria and were included for data analysis [4–14]. Fig. 1 outlines our search methodology and selection process.
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Table 1 Proposed diagnostic criteria for mixed connective tissue disease. Major criteria
Minor criteria
Diagnosis
Sharp (1987)
1. Myositis 2. Pulmonary involvement: a. Diffuse capacity b 70% of normal values b. Pulmonary hypertension c. Proliferative vascular lesions on lung biopsy 3. Raynaud's phenomenon or esophageal hypomotility 4. Swollen hands 5. Anti-ENA Ab N 1:10,000 and anti-U1 RNP Ab positive and anti-Sm negative
1. Alopecia 2. Leukopenia 3. Anemia 4. Pleuritis 5. Pericarditis 6. Arthritis 7. Trigeminal neuropathy 8. Malar rash 9. Thrombocytopenia 10. Mild myositis 11. History of swollen hands
At least 4 major criteria plus anti-U1-RNP Ab titer of at least 1:4000 or two major criteria from among criteria 1, 2 and 3 plus 2 minor criteria plus anti-U1-RNP Ab titer of at least 1:1000 Exclusion criteria: positivity for anti-Sm Ab
Serological criteria
Clinical criteria
Diagnosis
AlarconSegovia (1987)
Anti-RNP Ab titer N 1:1000
1. Edema in hands 2. Synovitis 3. Myositis, 4. Raynaud's phenomenon 5. Acrosclerosis
Serological criteria plus at least 3 clinical criteria included either synovitis or myositis
Common symptoms
Mixed symptoms
Diagnosis
1. Raynaud's phenomenon 2. Swollen fingers or hands Anti-RNP Ab positive
1. SLE-like symptoms: a. Polyarthritis b. Lymphadenopathy c. Facial erythema d. Pericarditis or pleuritis e. Leukopenia or thrombocytopenia. 2. SSc-like findings: a. Sclerodactyly b. Pulmonary fibrosis, restrictive changes of lung, or reduced diffusion capacity c. Hypomotility or dilatation of esophagus. 3. PM-like findings: a. Muscle weakness b. Elevated serum levels of muscle enzymes (CPK) c. Myogenic pattern on EMG
At least one of common symptoms plus positivity for anti-RNP Ab plus one or more signs/symptoms of the mixed symptoms in at least two of the three disease categories
Serological criteria
Clinical criteria
Diagnosis
Presence of high titer anti-RNP Ab corresponding to speckled ANA at titer ≥ 1:2000
1. Raynaud's phenomenon 2. Synovitis 3. Myositis 4. Swollen fingers
Serological criteria plus Raynaud's phenomenon and at least two of the three following signs (synovitis, myositis and swollen fingers)
Kasukawa (1987)
Kahn (1991)
Abbreviation: RNP = ribonucleoprotein, ENA = extractable nuclear antigen, Sm = Smith, SLE = systemic lupus erythematosus, SSc = systemic sclerosis, PM = polymyositis, CPK = creatine phosphokinase, EMG = electromyography, ANA = anti-nuclear antigen.
4. Results
4.2. Subclinical cardiac involvement
Table 2 summarizes the result of the eleven case series that met our inclusion criteria. Five studies were conducted in North America, four studies were done in Asia and two studies were from Europe. These case series comprised a total of 616 patients. The largest study contributed about one-third of patients [14]. The studies varied in term of definitions and methods used to detect cardiac abnormalities.
Non-invasive cardiac tests, including electrocardiogram (ECG), Holter monitor and echocardiogram, detected subclinical cardiac abnormality in 6%–38% of patients. The most common ECG abnormality was conduction disturbance (hemiblock, bundle branch block and atrioventricular block) that was seen in 20% of patients in the largest series [12]. Echocardiogram detected subclinical cardiac involvement in 12%– 38% of patients. Pericardial effusion was the most common echocardiographic abnormality which was consistently seen in about one-fourth of patients. Valvulopathy, particularly mitral valve prolapse (MVP), was also common in these patients. The prevalence of MVP was noted to be as high as 25–32% in two studies [4,6].
4.1. Prevalence of cardiac involvement Prevalence of cardiac involvement varied from 13% to 65% depending on patient selection and method used for detection. Three studies reported the prevalence of symptomatic cardiac disease which ranged from 24% to 63% (mean of 32%) [4,5,7]. Common symptoms were chest pain, dyspnea and palpitation. Pericarditis was the most common cardiac diagnosis with the prevalence of 30% and 43% in two prospective studies [10,14] while impaired diastolic function in this group of patients was well-documented in two case–control studies [5,10].
4.3. Mortality 3 prospective studies were included in this systematic review. 2.1% of patients in these cohorts died of direct cardiac cause (excluding pulmonary hypertension and cor pulmonale) over the period of follow-up
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Table 2 Summary of 11 included studies. Methodology
Alpert et al. [4] (1983)
– Prospective cohort study (authors did not mention about the duration of follow-up)
Oetgen at al. [5] (1983)
Prevalence
Conclusion
38
24% had symptoms attributable to cardiac origin
– Cross-sectional study
16
63% had symptoms attributable to cardiac origin
Comens et al. [6] (1989)
– Cross-sectional study
38
32% had MVP
Leung et al. [7] (1990) and Leung et al. [8] (1990)
– Cross-sectional and case–control study
17
24% had symptoms attributable to cardiac origin
Murata et al. [9] (1992)
– Cross-sectional study
Burdt et al. [10] (1999)
– Prospective cohort study with duration of followup of 15+/−8 years
Nedumaran et al. [11] (2000) Rebollar-Gonzalez et al. [12] (2001) Vegh et al. [13] (2007)
– Retrospective chart review – Cross-sectional study
Hajas et al. [14] (2013)
– Prospective cohort study with duration of followup of 13+/−8 years
– Mean age was 37 years – 9/38 (24%) had symptoms attributable to cardiac origin (chest pain, dyspnea, pedal edema, syncope and palpitation) – 6/28 (21%) had conduction disturbance, 8/28 (29%) had ST–T abnormalities on ECG – 8/32 (25%) had pericardial effusion, 8/32 (25%) had MVP, 4/32 (13%) had LVH seen on echocardiogram – 5/38 (13%) died during follow-up, 1 patient died of cardiac cause (cardiac temponade) – Mean age was 26 years – 10/16 (63%) had symptoms attributable to cardiac origin (chest pain, dyspnea, and palpitation) – 1/16 (6%) had conduction disturbance, 1/16 (6%) had ST–T abnormalities on ECG – 6/16 (38%) had pericardial effusion seen on echocardiogram – Mean age was 37 years – 12/38 (32%) had MVP seen on echocardiogram – Mean age was 44 years – 4/17 (24%) had symptoms attributable to cardiac origin (chest pain, dyspnea, and palpitation) – 1/17 (6%) had conduction disturbance, 3/17 (18%) had ST–T abnormalities on ECG – 2/17 (12%) had pericardial effusion, 2/17 (12%) had pericardial thickening, 2/17 (12%) had thickened anterior mitral valve leaflet seen on echocardiogram – Diastolic function was impaired while systolic function was intact in patients with MCTD compared with age & sex matched control – Mean age was 44 years – 2/8 (25%) had pericardial effusion, 1/8 (13%) had moderate MR – Mean age was 28 years – 20/47 (43%) patients had pericarditis at initial presentation or during follow-up – 11/47 (23%) died during follow-up. None of them was attributable to direct cardiac cause (though 5/11 were attributable to pulmonary hypertension) – 1/8 (13%) had pericarditis – 23/113 (20%) had conduction disturbance on ECG (hemiblock, bundle branch block, atrioventricular block) – Diastolic function was impaired while systolic function was intact in patients with MCTD compared with age & sex matched control – Mean age was 53 years – 181/280 (65%) had cardiac disease (pericarditis, valvulopathy, cardiomyopathy, arrhythmia or ischemic heart disease) – 22/280 (8%) died during follow-up. 7 of them died of direct cardiac cause (CAD, cardiomyopathy and ventricular arrhythmia)
– Case–control study
Number of patients
8 47
8 113 51 280
38% had abnormal echocardiogram (excluding pulmonary hypertension) 43% had pericarditis
13% had cardiac disease 20% had conduction disturbance on ECG NA 65% had cardiac disease
Abbreviation: ECG = electrocardiography, MVP = mitral valve prolapse, LVH = left ventricular hypertrophy, MCTD = mixed connective tissue disease, MR = mitral regurgitation, NA = not applicable, CAD = coronary artery disease.
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Potentially relevant article sidentified from search of MEDLINE database and screened for retrieval (n=73)
Detailed review of potentially relevant articles
39 articles were excluded (25 articles were case report and 14 article were review)
34 potentially relevant articles included for fulllength article review
23 articles were excluded since they did not provide any data on cardiac involvement
11 articles were included in systematic review
Fig. 1. Case series identification.
of 13–15 years compared with the overall mortality of 10.4%. The cardiac cause of death included cardiac temponade, coronary artery disease, cardiomyopathy and ventricular arrhythmia. 5. Discussion Mixed connective tissue disease is a systemic autoimmune disorder that can virtually affect any organ system including the heart. The prevalence of cardiac disease can be as high as 65% [14]. On the other hand, symptomatic disease was seen in only about one-fourth to one-third of patients. This emphasizes the subtle nature of cardiac disease in MCTD. The pathophysiology of cardiac involvement in MCTD is not wellunderstood but appears to resemble other connective tissue disorders. Myocarditis, as evident in two post-mortem studies [14,15], might be responsible for the conduction abnormalities and diastolic dysfunction. We hypothesize that myocarditis might be linked to myositis-liked spectrum of MCTD as studies in polymyositis/dermatomyositis showed similarities in pathologic changes between the myocardium and skeletal muscle [16,17]. Pericardial effusion/pericarditis was common and was seen in up to 43% of patients although cardiac temponade was exceedingly rare. We, again, hypothesize that the pathophysiology of this serositis might be related to rheumatoid arthritis-like and lupuslike spectrum of MCTD. Another common cardiac abnormality was MVP which might be due to focal alteration of the valve leaflets
resulting in reduced capacity to support systolic stress, as seen in systemic lupus erythematosus [18]. One study addressed the issue of accelerated atherosclerosis and confirmed a higher prevalence of premature atherosclerosis in this group of patients [14], as in other chronic inflammatory disorders. MCTD has been considered as a connective tissue disease with a relatively benign course. Our systematic review confirmed this view as the 3 prospective studies revealed mortality rate of only 10.4% over the period of follow-up of 13–15 years. However, interestingly, about onefifth of mortality was attributable to a direct cardiac cause (excluding pulmonary hypertension). This finding supports the role of direct cardiac injury from MCTD as well as accelerated atherosclerosis as two of the major causes of mortality. In conclusion, we conducted a systematic review of case series of patients with MCTD, focusing on cardiac manifestation. We found that cardiac involvement was common among these patients although the involvement was often clinically inapparent. Non-invasive cardiac tests, especially ECG and echocardiogram, might have a role for subclinical disease screening for the early diagnosis and timely treatment as cardiac involvement was one of the leading causes of mortality. Funding None.
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Authors' contributions All authors had access to the data and a role in writing the manuscript.
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