RENAL & CARDIAC MANIFESTATIONS OF SLE

Systemic lupus erythematosus

Patients with SLE are subject to a variety of symptoms, complaints, and inflammatory involvement that can affect virtually every organ

The most common pattern is a mixture of constitutional complaints with skin, musculoskeletal, mild hematologic, and serologic involvement

CLINICAL CRITERIA FOR DIAGNOSIS

Most physicians rely on the ARA revised Criteria for the Classification of SLE

The diagnosis of SLE is made if four or more of the manifestations are present, either serially or simultaneously

When tested against other rheumatic diseases, these criteria have a sensitivity and specificity of approximately 96 percent

ARA Criteria for diagnosis of Systemic Lupus Erythematosus

criterion definition

malar rash fixed erythema, flap or raised, over the mainandevidence

AUTOANTIBODIES

The ANA test is the best screening test for SLE and should be performed whenever SLE is suspected

The ANA is positive in significant titer (usually 1:160 or higher) in virtually all patients with SLE

AUTOANTIBODIES

dsDNA and Sm antibodies• There are two autoantibodies that are highly

specific for SLE• anti-double-stranded DNA (dsDNA) antibodies

• anti-Sm antibodies

• Sensitivity – 66 to 95 percent• Specificity – 75 to 100 percent• Predictive value – 89 to 100 percent

Renal manifestations of SLE

Renal involvement is common in SLE An abnormal urinalysis is present in

approximately 50% of patients at the time of diagnosis and eventually develops in more than 75 percent of cases

The most frequently observed abnormality is proteinuria (80 percent); while approximately 40 percent have hematuria and/or pyuria sometime during the course of their illness

Renal manifestations of SLE

The total incidence of renal involvement among patients with SLE probably exceeds 90 percent since renal biopsy in patients without any clinical evidence of renal disease often reveals a focal or diffuse proliferative glomerulonephritis

There are a number of different types of renal disease in SLE, with immune complex-mediated glomerular diseases being most common

IMMUNE COMPLEX GLOMERULAR DISEASE

Most patients with lupus nephritis have an immune complex-mediated glomerular disease

The standard classification divides these disorders into five different patterns in which (type I) represents no disease• Mesangial (type II)

• Focal proliferative (type III)

• Diffuse proliferative (type IV)

• Membranous (type V)

Mesangial lupus nephritis (type II)

Occurs in 10 to 20% of cases and represents the earliest and mildest form of glomerular involvement

Presents clinically as microscopic hematuria and/or proteinuria; hypertension is uncommon, and the nephrotic syndrome and renal insufficiency are virtually never seen

The renal prognosis is excellent and no specific therapy is indicated unless the patient progresses to more advanced disease

Mesangial proliferative glomerulonephritis. Light micrograph of a mesangial glomerulonephritis showing segmental areas of increased mesangial matrix and cellularity (arrows). This finding alone can be seen in many diseases, including lupus nephritis and IgA nephropathy.

Focal proliferative lupus nephritis (type III)

Occurs in 10 to 20% of cases, but represents more advanced involvement than mesangial disease

Hematuria and proteinuria are seen in almost all patients, some of whom also have the nephrotic syndrome, hypertension, and an elevated plasma creatinine concentration

By definition, less than 50 percent of glomeruli are affected on light microscopy

Electron microscopy shows immune deposits in the subendothelial space of the glomerular capillary wall as well as the mesangium

Focal proliferative lupus nephritis (type III)

The renal prognosis in focal proliferative lupus nephritis is variable

Progressive renal dysfunction appears to be uncommon when less than 25 percent of the glomeruli are affected on light microscopy

On the other hand, more widespread or severe involvement (40 to 50 percent of glomeruli affected, nephrotic range proteinuria, and/or hypertension) has a long-term prognosis that is similar to that of diffuse disease

Memberanoproliferative lupus nephritis. Light micrograph showing a memberanoproliferative pattern in lupus nephritis, characterized by areas of cellular proliferation (long arrows) and by thickening of the glomerular capillary wall (due to immune deposits) that may be prominent enough to form a “wire-loop” (short arrows). Although proliferative changes can be focal (affecting less than 50% of glomeruli), disease ofthis severity is usually diffuse.

Diffuse proliferative lupus nephritis (type IV)

The most common and most severe form of lupus nephritis affecting 40 to 60% of cases

Hematuria and proteinuria are seen in almost all cases, and the nephrotic syndrome, hypertension, and renal insufficiency are all frequently seen

Affected patients typically have significant hypocomplementemia and elevated anti-DNA levels, especially during active disease

Immunosuppressive therapy is generally required to prevent progression of active diffuse proliferative lupus nephritis to ESRD

Diffuse proliferative lupus nephritis. Kidney biopsy from a patient with diffuse proliferative lupus nephritis showing, on immunofluorescence microscopy, massive lumpy bumpy deposits of IgG.

Membranous lupus (type V) Affects 10 to 20 percent of patients Patients typically present with nephrotic syndrome Microscopic hematuria and hypertension also may be

seen at presentation, and the plasma creatinine concentration is usually normal or slightly elevated

Membranous lupus is the one form of lupus nephritis that may present with no other clinical or serologic manifestations of SLE

Most patients maintain a normal or near normal plasma creatinine concentration for five years or more and may not require immunosuppressive therapy

Membranous lupus nephritis. Light micrograph of membranous lupus nephritis. The changes are similar to those in any form of membranous nephropathy with diffuse thickening of the glomerular capillary wall being the major abnormality (short arrows). Focal areas of mesangial expansion and hypercellularity (long arrows) are the only findings suggestive of an underlying disease such as lupus, although they can also be seen in idiopathic membranous nephropathy.

Membranous lupus nephritis. Electron micrograph of membranous lupus nephritis. The subepithelial immune deposits (D) are characteristic of any form of membranous nephropathy, but the intraendothelial tubuloreticular structures (arrow) strongly suggest underlying lupus. GBM = glomerular basement membrane; EP = epithelial cell.

Other Renal manifestations of SLE

In addition to these glomerulopathies, there are three other less common forms of lupus renal disease • interstitial nephritis; • vascular disease; and • renal disease infrequently associated with drug-

induced lupus

Tubulointerstitial nephritis

Tubulointerstitial disease (interstitial infiltrate, tubular injury) is a common finding in lupus nephritis, almost always being seen with concurrent glomerular disease

The severity of the tubulointerstitial involvement is an important prognostic sign, correlating positively with the presence of hypertension, an elevated plasma creatinine concentration, and a progressive course

Vascular disease Involvement of the renal vasculature is not uncommon

in lupus nephritis and its presence can adversely affect the prognosis of the renal disease

The most common problems are immune complex deposition, immunoglobulin microvascular casts, a thrombotic microangiopathy leading to a syndrome similar to TTP, and vasculitis

Vascular immune deposits typically produce no inflammation, but fibrinoid necrosis with vascular narrowing can be seen in severe cases

Vascular disease Other patients present with glomerular and vascular

thrombi, often in association with antiphospholipid antibodies

Renal involvement is characterized by fibrin thrombi in the small arteries and glomerular capillaries and, in some cases, in the larger renal artery branches

These changes may occur as a primary disease or may be superimposed upon one of the immune complex forms of lupus nephritis

Rarely, patients with lupus nephritis develop renal vein thrombosis

Drug-induced lupus

A variety of drugs can induce a lupus-like syndrome, particularly those that are acetylated in the liver, such as hydralazine, procainamide, and less often isoniazid

Renal involvement is uncommon but a proliferative glomerulonephritis or the nephrotic syndrome can occur

Cardiac manifestations of SLE Cardiac disease is common among patients with SLE

as pericardial, myocardial, valvular, and coronary artery involvement can occur

The incidence of these problems can be summarized as follows• Cardiac abnormalities – up to 55 percent• Valvular disease – up to 50 percent• Pericardial disease, usually a clinically silent

effusion – up to 48 percent• Myocardial dysfunction – up to 78 percent

VALVULAR DISEASE Systolic murmurs have been noted in 16 to

44 percent of patients• Structural valvular disease is most common but

anemia, fever, tachycardia, and cardiomegaly can induce functional murmurs

Diastolic murmurs have been noted in one to three percent of patients • They often reflect aortic insufficiency, which

occasionally requires valve replacement.

VALVULAR DISEASE

Mitral valve involvement is most common; a mild to moderate regurgitant murmur may be heard but most patients remain asymptomatic

Mitral valve prolapse appears to occur with increased frequency in lupus, occurring in 25 percent of cases

Verrucous endocarditis Libman-Sacks endocarditis is a not uncommon

complication of SLE In one report of 74 patients, seven had verrucous lesions

detected by TTE However, a higher frequency (43 percent) has been

noted when more sensitive TEE is performed In addition, Libman-Sacks endocarditis is often

associated with antiphospholipid antibodies Verrucous endocarditis is typically asymptomatic However, the verrucae can fragment and produce

systemic emboli

PERICARDIAL DISEASE Pericardial involvement is the second most

common echocardiographic lesion in SLE, and is the most frequent cause of symptomatic cardiac disease

Pericardial effusion occurs at some point in over one-half of patients, and a benign pericarditis may precede the clinical signs of lupus

Pericardial disease is usually asymptomatic, and is generally diagnosed by echocardiography performed for some other reason

PERICARDIAL DISEASE

Symptomatic pericarditis typically presents with positional substernal chest pain with an audible rub on auscultation

The pericardial fluid is a fibrinous exudate or transudate that may contain antinuclear antibodies, LE cells, low complement levels, and immune complexes

The pericardium may reveal foci of inflammatory lesions with immune complexes

PERICARDIAL DISEASE The course is benign in the large majority of patients

with pericardial disease Symptomatic pericarditis often responds to an NSAID,

especially indomethacin Patients who do not tolerate or respond to an NSAID

can be treated with prednisone The most serious consequence is the development of

purulent pericarditis in the immunosuppressed, debilitated patient

Large effusions, suggestive of tamponade, and constrictive pericarditis are rare in SLE

MYOCARDITIS Myocarditis is an uncommon, often asymptomatic

manifestation of SLE with a prevalence of 8 to 25% It should be suspected if there is resting tachycardia

disproportionate to body temp., EKG abnormalities and unexplained cardiomegaly

Echocardiography may reveal abnormalities in both systolic and diastolic function of the left ventricle

Acute myocarditis may accompany other manifestations of acute SLE, particularly pericarditis

Myocarditis should be treated with prednisone plus usual therapy for congestive heart failure if present

CONDUCTION ABNORMALITIES Conduction defects, which may represent a sequel of active or

past pericarditis and/or myocarditis have been noted in 34 to 70 percent of patients with SLE

Congenital heart block may be part of the neonatal lupus syndrome

Many mothers of these infants have either SLE or Sjögren's syndrome, antibodies to Ro (SS-A) and/or La (SS-B), and are HLA-DR3 positive

The anti-Ro and anti-La antibodies may induce autoimmune injury that prevents normal development of the conduction fibers

It is recommended that anti-Ro antibody titers be measured early in pregnancy in women with SLE

CORONARY ARTERY DISEASE Coronary artery disease has been recognized in 2 to 16%

of patients with SLE and can lead to acute myocardial infarction in young women

Coronary disease, leading to angina, myocardial infarction, congestive heart failure, and death, is becoming an increasing problem, particularly in the young patient with long-standing SLE maintained on corticosteroids

In one report, coronary disease (defined as angina, myocardial infarction, or sudden death) occurred in 8.3 percent of 229 patients and was responsible for 3 of 10 deaths

Patients with SLE should be made aware of the importance of risk factor reduction

Patients with lupus should be advised to stop smoking, exercise, consider the use of hormone replacement therapy, and follow measures designed to improve lipid profiles

Hydroxychloroquine should be used in preference to prednisone whenever possible and aspirin should be prescribed for its antiplatelet properties

Symptomatic coronary artery disease should be treated as in patients without lupus

CORONARY ARTERY DISEASE

VENOUS THROMBOSIS

Thrombophlebitis has been reported in approximately 10 percent of patients with SLE

It generally involves the lower extremity, but can also affect the renal veins and inferior vena cava

Risk factors for venous thrombosis include antiphospholipid antibodies and the use of oral contraceptives, particularly in association with smoking cigarettes