Mixed connective tissue disease (MCTD) is an overlap syndrome characterized by clinical features of systemic lupus erythematosus (SLE), scleroderma, and polymyositis. Patients typically have high titers of circulating anti–U1 RNP antibodies. During the course of this disease, many organ systems can be involved (1). Two separate studies were published in 1983 describing the nature and extent of cardiac abnormalities associated with MCTD (2, 3). Pericardial disorders are common in all connective tissue diseases and may present with a wide spectrum of disease manifestations ranging from acute pericarditis to cardiac tamponade. Although pericarditis is the most frequent cardiac abnormality in patients with MCTD, cardiac tamponade is rarely seen (4). We describe a case report of cardiac tamponade in a patient with long-standing MCTD. The clinical features, diagnostic approach, and treatment options are presented along with a literature review of the 5 previously reported cases.
A 35-year-old woman had a long-standing history of MCTD manifested by pleurisy, gastroesophageal reflux disease, Raynaud's phenomenon, arthralgias, sclerodactyly, digital ulcers, and positive antinuclear antibody (ANA) with an elevated RNP titer of 1:256 dilution. She had no previous history of cardiac symptoms. An echocardiogram from 6 months prior was normal. She presented with reports of fever, substernal chest pain, dyspnea, and nausea. She also had a 2-week history of progressively worsening arthralgias and Raynaud's symptoms. Urgent care evaluation detected a possible infiltrate on chest radiograph for which she received azithromycin; however, persistent symptoms prompted her referral to the rheumatology clinic. Her medications included aspirin, esomeprazole, celecoxib, and long-term use of a combination oral contraceptive, ethinyl estradiol/levonorgestrel. She had discontinued all of her medications 10 days prior to her rheumatology evaluation because of her acute illness.
Examination revealed an acutely ill-appearing woman who was afebrile with blood pressure of 98/67 mm Hg, heart rate of 106, and respiratory rate of 18. Jugular venous pressure was elevated to the angle of the jaw at 45 degrees. Pulsus paradoxus with a gradient of 20 mm Hg was noted. Pulmonary examination revealed the lungs to be clear on auscultation. Cardiac examination revealed tachycardia and a pericardial friction rub. Her skin examination disclosed tightness of the face with loss of wrinkling and decreased oral aperture, as well as sclerodactyly and Raynaud's changes with healing digital ulcers (Table 1). The electrocardiogram showed low voltage complexes with sinus tachycardia. Her chest radiograph revealed cardiomegaly without pleural or interstitial abnormalities. The echocardiogram demonstrated a moderate posterior and small anterior pericardial effusion (Figure 1A).
Initially, the patient was aggressively hydrated. Because of rapid deterioration of her hemodynamic status, she was taken to the cardiac catheterization lab for right heart catheterization. Tamponade physiology was demonstrated. There was equalization of diastolic pressures in all cardiac chambers with elevated pressure readings of 20 mm Hg. Using pericardiocentesis, 320 cc of serosanguineous fluid was removed. Pericardial fluid analysis revealed neutrophilia and an ANA titer of 1:5,120 dilution. The pericardial catheter was left in place for 24 hours and then removed. A repeat echocardiogram showed no pericardial fluid reaccumulation (Figure 1B). She received 25 mg of intravenous methylprednisolone every 12 hours for 24 hours and then 30 mg of oral prednisone twice daily. Colchicine 0.6 mg daily was initiated but discontinued secondary to myalgias and elevated creatinine kinase levels after 1 week. Her myalgias resolved and creatinine kinase levels normalized. The patient has been on a slow prednisone taper and currently takes 10 mg/day, with no recurrent symptoms or pericardial fluid reaccumulation by echocardiogram at 3- and 6-month followup.
This patient presented with clinical features characteristic of early tamponade in the setting of well-established MCTD, demonstrating a rare and potentially serious manifestation of MCTD. Pericardial disorders are a common occurrence in connective tissue disease and pericarditis is the most common cardiac manifestation in patients with MCTD. One series reported the frequency of pericardial involvement as follows: scleroderma 59%, SLE 44%, MCTD 30%, rheumatoid arthritis 24%, and polymyositis/dermatomyositis 11% (4). In a study by Oetgen et al, 25% of patients with MCTD had evidence of pericarditis by history, physical examination, or noninvasive cardiac evaluation (3). In an echocardiogram study, Alpert et al noted 29% of patients to have pericardial abnormalities (2). Singsen et al reported a 43% incidence of pericardial abnormalities in children (5). Pericardial disease has been noted in 56% of autopsy subjects with MCTD (6). Also, 24–38% of patients with MCTD have an asymptomatic pericardial effusion detected only by echocardiography (2, 3). Indeed, pericardial disease is often silent in MCTD, with only 10% of affected patients being symptomatic.
Interestingly, despite the high frequency of pericarditis and pericardial effusions, the incidence of cardiac tamponade in MCTD is rare. This infrequency is also observed in other connective tissue diseases (4). Longitudinal echocardiogram studies have demonstrated that in patients with MCTD with small nonconstrictive pericardial effusions, the majority of effusions last for years without severe symptoms (2). The much higher frequency of pericardial disease noted on autopsy and echocardiography compared with the low percentage of symptomatic patients may be related to corticosteroids or nonsteroidal drugs that may be controlling both pericardial inflammation and pain.
Cardiac tamponade is rare in patients with established MCTD and is even rarer as a presenting feature, with only 1 case reported in the literature. Clinically, patients frequently present with fever, tachycardia, progressive dyspnea, tachypnea, and characteristic chest pain. The substernal pleuritic-like chest pain is typically worse with inspiration and improves with leaning forward. A pericardial friction rub can sometimes be heard. Dyspnea is the most common symptom noted in the previously reported cases. Symptoms can be acute in onset with rapid deterioration and life-threatening consequences or subacute with mild, slowly progressive symptoms (7).
Our patient fit the diagnostic criteria of MCTD established by Sharp et al (1) and presented with cardiac tamponade due to a moderate-sized pericardial effusion. Features included a pericardial friction rub, pulsus paradoxus, chest radiograph demonstrating cardiomegaly, electrocardiogram with low voltage and tachycardia, positive echocardiogram findings, and right heart catheterization demonstrating elevation and equalization of pressures in all 4 cardiac chambers.
Although the previously reported 5 cases along with our case appear to be related to MCTD serositis (Table 2), other causes of pericarditis must also be considered in the differential diagnosis such as sepsis and uremia, although serious renal disease is relatively rare. Pericardiocentesis and pericardial fluid analysis provide useful information. Guidelines are not well established for transudate versus exudate, but it is reasonable to use pleural and pericardial fluid parameters used for patients with SLE. Cytology and culture are straightforward diagnostic tests. Pericardial fluid of patients with SLE has been evaluated for ANA titers, complement levels, and lupus erythematosus cells (8). Pericardial fluid results have not been reported in other cases of MCTD, but our findings are compatible with those seen in patients with SLE, probably reflecting a similar pathophysiology.
Table 2. Summary of patients with MCTD and cardiac tamponade reported in the literature*
Pulsus paradoxus, CXR, EKG, echo, right heart catheterization, pericardiocentesis with fluid analysis
Pericardiocentesis, corticosteroids, colchicine
Asymptomatic at 9 months on corticosteroid taper
Of the previously described patients with MCTD and cardiac tamponade, 4 patients underwent pericardiocentesis or pericardiostomy. The procedure was performed for diagnostic purposes in 2 cases and as a part of the therapeutic regimen in the other 2 cases (2, 4, 9, 10). Our patient similarly underwent pericardiocentesis for both diagnostic and therapeutic reasons.
Including our reported case, 5 of the 6 patients received high-dose corticosteroid therapy, with favorable outcomes noted in 4 of these patients (2, 4, 9–11). One of these patients had complete reversal of cardiac tamponade with steroid therapy alone (11). Success with only nonsteroidal antiinflammatory drug (NSAID) therapy after a diagnostic pericardiocentesis was reported in the French literature (9). In 1 case, a patient with SLE and cardiac tamponade responded to indomethacin therapy alone (12).
The relative merit of different treatment approaches remains unclear due to the rarity of the condition. Treatment of pericardial disease in patients with MCTD appears to be guided by case reports and case series of other rheumatic diseases, such as SLE. The current literature on MCTD and cardiac tamponade demonstrates that corticosteroids seem to play an important role in controlling pericarditis and cardiac tamponade (2, 4, 9–11). There may also be a role for NSAID therapy in pericardial diseases. NSAIDs are used as first-line therapy for idiopathic pericarditis (13). Therefore, there may be a role for NSAID therapy in pericardial diseases in patients with MCTD and other connective tissue diseases. Our patient was previously taking aspirin and celecoxib, which may have been attenuating the underlying pericardial inflammation and pain. Her symptoms may have accelerated upon discontinuation of these antiinflammatory compounds and corresponded with the development of the large pericardial effusion and cardiac tamponade.
Due to the rarity of hemodynamic effects of pericarditis in patients with MCTD and good response to NSAIDs and corticosteroids, pericardiocentesis should be reserved for more severe cases, such as management of potentially life-threatening tamponade, persistent large pericardial effusion, or evaluation of possible septic pericarditis. The acute presentation and hemodynamic parameters of our patient prompted treatment with the combination of corticosteroids and pericardiocentesis, resulting in a favorable outcome. In 1 patient with SLE and tamponade, a pericardial window was placed at the time of initial presentation of cardiac tamponade to prevent a recurrence (14). However, not all patients respond to corticosteroids or even pericardiocentesis, and some require a pericardial window.
Colchicine, another possible therapeutic option, is effective as an adjunct for the treatment of recurrent idiopathic pericarditis and the prevention of further recurrences after conventional treatment failure (13). More recently, the Colchicine for acute Pericarditis trial demonstrated that colchicine in combination with aspirin or prednisone is efficacious in the treatment of acute idiopathic pericarditis and prevention of recurrences (15). Although colchicine has not been extensively studied in patients with connective tissue diseases, 2 case reports describe the effectiveness of colchicine therapy in rheumatoid pericarditis complicated with tamponade (16, 17). Because of colchicine's ability to inhibit various leukocyte functions, the finding of a neutrophil predominance in our patient's pericardial fluid supports a rationale for trying this drug in the setting of MCTD pericarditis complicated with tamponade.
Immunosuppressive therapy is another possible therapeutic option, although the literature on its use in pericardial diseases is sparse. One study reviewed the clinical outcome of patients with recurrent pericarditis treated with either azathioprine or cyclophosphamide (18). The authors recommend immunosuppressive therapy for those patients resistant to or intolerant of high-dose corticosteroids (18). Whether or not patients with underlying MCTD as the cause of their pericarditis will respond as well to immunosuppressants is unreported but likely, based upon experience in SLE (14).
In summary, the cardiac manifestations of MCTD include a wide range of pericardial disorders from acute pericarditis to cardiac tamponade. Although pericarditis is the most common manifestation in this group of patients, cardiac tamponade is very uncommon. The majority of cases reported the occurrence of tamponade in the setting of well-established MCTD. The low incidence of tamponade despite the high frequency of pericarditis in patients with MCTD may be related to both the disease predilection and widespread use of corticosteroids and NSAIDs. Our case report and a review of the current available literature highlight the need for clinicians to consider the diagnosis of tamponade in patients with MCTD and dyspnea or hemodynamic compromise. The favorable outcomes reported in 4 of the 6 patients indicate that patients with MCTD often respond to antiinflammatory therapy when cardiac involvement is diagnosed.