Case Analysis

The clinical history and the autopsy findings illustrate the potential life-threatening complications of long-term high dose steroid use, but also the cardiac manifestations of this patient's underlying disease, SLE.

Systemic Lupus Erythematosus (SLE) is a chronic, systemic disease associated with abnormalities of the immune system. The cause of this disorder is unknown, but its basis is the production of autoantibodies, particularly antibodies against nuclear proteins, DNA, and RNA. The deposition of antigen-antibody complexes in different organs accounts for most of the pathological and clinical manifestations of the disease.

The hallmark of the therapeutic approach to SLE in the past decades has been the use of corticosteroids, and recently adjuvant cytotoxic and antimetabolite drugs have been added successfully. Therefore, the cardiovascular manifestations in patients with SLE are a combination of the inflammatory processes characteristic of the disease itself, and the secondary effects of corticosteroid/immunosuppressive therapy. In the heart, the most affected sites are the pericardium and endocardium. Patients with SLE often present with pericarditis (approximately 80%), and it can be acute (fibrinous pericarditis) or chronic. Recurrent or persistent inflammation of the mesothelial lining of the pericardium may lead to mesothelial hyperplasia and fibrosis with the development of adhesions and subsequent obliteration of the pericardial cavity (fibrous pericarditis). Occasionally, examination of pleural fluid can reveal the presence of lupus erythematosus (LE) cells. These are macrophages or neutrophils that have phagocytized nuclei denatured by circulating antinuclear antibodies (ANA). Similar cells, known as LE or hematoxylin bodies can also be identified in tissue samples (Figure 81). Less commonly, myocarditis with a non-specific mononuclear infiltrate can occur. It is usually subtle, causing spotty myocardial necrosis, and is diagnosed when there is a high level of suspicion leading to an endomyocardial biopsy. The clinical presentation varies from tachycardia to complete heart block. Moreover, inflammation with subsequent scarring may affect the sinus and atrioventricular nodes as well as the bundle of His. Newborns of mothers with SLE and anti-Ro (Sjögren Syndrome A or SS-A) antibodies may develop heart block secondary to transient myocarditis. The latter are anti-nuclear antibodies directed against 52 and 60 kilo-Dalton (kDa) proteins, and are present in approximately 35% of patients with SLE and in patients with Sjögren syndrome. Anti-Ro IgG can cross the placenta and may cause a neonatal lupus-like syndrome. These maternal autoantibodies disappear within a 6-month period; however, long lasting conduction abnormalities in the offspring have been reported.

Valvular endocardial damage was more dramatic in the pre-steroid era. The classic valvular lesion of SLE is known as Libman-Sacks endocarditis (described in a necropsy series by Drs. Libman and Sacks from Mount Sinai Hospital, New York in 1924). It is a non-infective endocarditis manifested by the presence of small verrucous lesions on any valvular surface of the heart. The vegetations are composed of a mixture of immune complexes, inflammatory cells and fibrinoid necrosis. Significant valve dysfunction requiring valvular replacement is rare unless superimposed bacterial infection ensues. Aortic and mitral valvulitis are common in SLE, particularly in patients with antiphospholipid antibodies. The clinical manifestations in patients with the antiphospholipid syndrome (e. g. phospholipid or cardiolipin antibodies), which include venous and arterial thrombosis, recurrent miscarriages and thrombocytopenia, are secondary to a hypercoagulable state, and to the cellular damage caused by the antibodies.

In our patient, the valvular abnormalities were most likely the result of her independent, high-dose steroid abuse rather than her positive anticardiolipin status. Recently, prolonged use of corticosteroids has been linked to the development of a serious form of valvular pathology characterized by rigid and thickened valvular leaflets. The patient had fibrosis of the mitral valve leaflets with fusion of the valve commissure and chordae tendineae similar to that seen in patients with rheumatic heart disease (RHD). Could these changes be the result of chronic rheumatic heart disease? They could, but the clinical history and presence of other elements of cardiac involvement favor SLE and steroid use as etiologic factors for her valvulopathy. The vegetations present on the tricuspid valve were more consistent with non-bacterial thrombotic (marantic) endocarditis than with Libman-Sacks endocarditis. Marantic endocarditis occurs in chronically ill or debilitated patients and is manifested by the presence of small, brown vegetations situated close to the line of closure of the leaflets. Microscopically, they consist of non-infectious and non-inflammatory fibrin aggregates. These small thrombi may detach and embolize causing infarcts in the brain or other organs. They differ from Libman-Sacks vegetations by their location, and absence of inflammation and valvular damage. However, in some cases, they may be indistinguishable from each other.

Other cardiovascular manifestations of SLE include coronary artery disease and acute necrotizing vasculitis. Patients with long-standing SLE, especially those diagnosed at a young age, are prone to develop accelerated coronary atherosclerosis. Risk factors for coronary artery disease and ischemia such as early onset hypertension, glucose intolerance, obesity and hyperlipidemia are strongly associated with long term glucocorticoid treatment (e.g. cushingoid features). Atherosclerosis is also more common in patients taking 10 mg or more of prednisone a day. Our patient had early atherosclerotic changes in the coronary arteries, and in the aorta near the ostia of the celiac and mesenteric vessels. Despite the fact that her cholesterol levels were not elevated, the presence of multiple abdominal lipomas, fatty infiltration of the myocardium and excessive epidural lipomatosis reflected the alterations of this young woman's lipid metabolism. The fat distribution affected by steroid treatment not only involves visceral organs and soft tissues, but bone as well. She had a history of avascular necrosis of the hips probably due to fat emboli involving osseous arterioles, and microvessel occlusion secondary to hypertrophy of bone marrow adipocytes.

Acute necrotizing vasculitis can occur in any tissue and involves small arterioles and capillaries. Histologically, it is characterized by inflammation of the vessel wall and fibrinoid necrosis (Figure 82). Endothelial damage causes extravasation of red blood cells, thrombosis and ischemia. The pathogenesis of vasculitis is complex and not completely understood. Potential causal mechanisms include deposition of immune complexes in the vessel wall as well as direct damage of the endothelium by antiendothelial cell antibodies.

In this case, the cause of death as well as the clinical signs and symptoms were the result of her dependence on corticosteroids. The cushingoid facies, cataracts, centripetal obesity, bilateral adrenal atrophy, myopathy and severe osteopenia were all adverse effects of steroid therapy. Corticosteroids cause osteopenia by inhibiting osteoblastic function and intestinal calcium absorption, and by increasing bone turnover and parathyroid activity. Steroid therapy is effective in suppressing the acute inflammatory manifestations of SLE, but carries a significant risk since it inhibits the host's response to infections. Infectious complications in an immunocompromised host, like this patient, can be due to the usual organisms affecting the normal general population. However, what makes these hosts unique is their susceptibility to infections caused by opportunistic pathogens (e.g. Pneumocystis carinii, Cryptococcus neoformans). The latter group of agents can be difficult to diagnose, since they would not normally pose a threat to the normal host. Therefore, the medical personnel taking care of immunosuppressed individuals must have a high index of suspicion when approaching acute, subacute or chronic infections in these patients. This woman died as a result of overwhelming infection with Pneumocystis carinii leading to adult respiratory distress syndrome, disseminated intravascular coagulation and fibrino lysis. Unfortunately, she attributed her back pain to her underlying disease when in fact it was caused by her self-prescribed treatment. Even though steroids and other immunosuppressive agents have proven to be very effective in controlling autoimmune diseases, the patients have to be carefully monitored to prevent or closely follow any significant deleterious effects that may arise as a consequence of these medications use or abuse.

Suggested Readings

1 . Roberts WC, High ST. The heart in systemic lupus erythematosus. Curr Probl Cardiol. 1999; 24:1-56.

2. Nesher G, Ilany J, Rosenmann D, Abraham AS. Valvular dysfunction in antiphospholipid syndrome: prevalence, clinical features, and treatment. Semin Arthritis Rheum. 1997; 27:27-35.

3. Moroni G, La Marchesina U, Banfi G, Nador F, Vigano E, Marconi M, Lotto A, Ponticelli C. Cardiologic abnormalities in patients with long-term lupus nephritis. Clin Nephrol. 1995; 43:20-8.

4. Ben-Chetrit E. The molecular basis of the SSA/Ro antigens and the clinical significance of their autoantibodies. Br J Rheumatol. 1993; 32:396-402.

5. Bruce IN; Gladman DD; Urowitz MB. Premature atherosclerosis in systemic lupus erythematosus. Rheum Dis Clin North Am. 2000; 26:25778.

6. Cunnane G; Lane NE. Steroid-induced osteoporosis in systemic lupus erythematosus. Rheum Dis Clin North Am. 2000; 26:311 -29.

7. Stuck A, Minder C, Frey F. Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis. 1989; 11:954-963.

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Figure 79. Chronic pericarditis. Fibrous adhesions are present between the epicardial surface and the pericardial sac (arrow).

Figure 79. Chronic pericarditis. Fibrous adhesions are present between the epicardial surface and the pericardial sac (arrow).

Figure 80. Libman-Sacks endocarditis. Small, friable vegetations are present on the tricuspid valve (arrow).

Figure 81. Libman-Sacks endocarditis with hematoxylin-like bodies (arrow) (Histologic section, Hematoxylin and Eosin stain, 40X).

Figure 82. Systemic lupus erythematosus (SLE). This small-sized vessel of the dermis shows fibrinoid necrosis of the wall with infiltration of polymorphonuclear leukocytes and extravasation of red blood cells. In addition, there is fragmentation of the nuclei of the neutrophils (karyorrhexis). These changes are consistent with necrotizing (leukocytoclastic vasculitis) (Histologic section, Hematoxylin and Eosin, 40X).

Figure 82. Systemic lupus erythematosus (SLE). This small-sized vessel of the dermis shows fibrinoid necrosis of the wall with infiltration of polymorphonuclear leukocytes and extravasation of red blood cells. In addition, there is fragmentation of the nuclei of the neutrophils (karyorrhexis). These changes are consistent with necrotizing (leukocytoclastic vasculitis) (Histologic section, Hematoxylin and Eosin, 40X).

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