Systemic Lupus Erythematosus Part 3

Musculoskeletal involvement

The arthritis of SLE is typically painful, transient, and symmetrical, involving the wrists, small joints of the hands, elbows, knees, and ankles. Swelling and redness are modest. Less often, SLE arthritis will present as asymmetrical oligoarthritis or intensely inflamed, sustained polyarthritis resembling that of rheumatoid arthritis. Although deformity may occur as a result of ligamentous laxity (reversible subluxations, Jaccoud arthropa-thy),38 rheumatoid-like joint destruction is uncommon.

Inflammatory myositis occurs primarily in patients with overlap features with scleroderma or dermatomyositis. It presents as proximal myopathy; serum levels of muscle enzymes are modestly elevated; and results of electromyography, magnetic resonance imaging, and muscle biopsy, if done, are similar to those seen in dermatomyositis. However, abnormal enzyme levels associated with proximal muscle tenderness or weakness are sufficient for diagnosis in a patient with established SLE.

Lupus does not involve bone directly. However, bone involvement can occur secondary to organ system failure (e.g., renal failure), severe illness (e.g., osteoporosis from inactivity or catabolic state), or treatment (e.g., corticosteroid-induced osteoporosis or avascular necrosis).

Osteoporosis presents as atraumatic fractures of vertebrae or long bones. Its occurrence is a severe threat to SLE patients, even premenopausal women, because of the frequent use of cortico-steroids for treatment and because of inactivity attendant upon polyarthritis and systemic illness.

Avascular necrosis (osteonecrosis) most often occurs in patients who have had a severe flare treated with high-intensity corticosteroid therapy, but this complication can develop in patients who have never received corticosteroid treatment. Marked cushingoid features during steroid treatment and Raynaud phenomenon may be predictors of its occurrence.39 The femoral head is the most commonly involved site, but shoulders, ankles, wrists, metacarpals, and shafts of long bones are also vulnera-ble.40 Typically, affected areas become painful at the initial occurrence of infarction and again years later when the necrotic bone collapses. The most typical presentation of osteonecrosis is sudden hip pain 2 or 3 years after a major flare of lupus. Some patients receiving infusions of high-dose intravenous methylpred-nisolone complain of intense pain at preexisting osteonecrotic sites during and shortly after the infusion. Reducing the cortico-steroid dose at the time of occurrence of pain has no effect on the course of the complication.

Gastrointestinal and hepatic involvement

Esophageal dysfunction is rare in SLE; it occurs primarily in patients with severe Raynaud phenomenon or in patients with scleroderma overlap disease. Gastroduodenal ulcer may occur as a result of treatment but is not directly linked to SLE. Ischemia of the small and large intestines may result from systemic vas-culitis; it presents as abdominal angina, pneumatosis intestinalis, infarction or perforation, or pseudo-obstruction. Intestinal ischemia is a rare complication, occurring only in the most severely ill patients.41

Figure 5 Painless mouth ulcers, most often found on the hard palate but also found on the gums and buccal mucosa, are characteristic of more severe lupus.

Diverticulitis often develops in patients with long-standing SLE, especially after prolonged treatment with corticosteroids. The symptoms of diverticulitis are easily masked by cortico-steroid therapy. Consequently, diverticular perforation or abscess is frequently misdiagnosed, especially in young SLE patients.

Chemical hepatitis may follow use of nonsteroidal anti-inflammatory drugs (NSAIDs) (lupus patients appear to be unusually susceptible to this side effect) or other drugs, such as azathioprine.42 Occasionally, patients suffer concomitant autoimmune hepatitis or primary biliary cirrhosis. In the absence of other causes, abnormalities of liver enzyme levels because of SLE are uncommon.

Hematologic involvement

Leukopenia is such a regular feature of SLE that its absence, in untreated disease, should raise suspicion that the diagnosis is incorrect or that infection or tissue necrosis is present. Usually, lymphocyte counts show greater reductions than do granulocyte counts: a leukocyte count of about 3.5/mm3, with 10% lymphocytes, is usual. Leukopenia of this degree seldom places patients at serious risk of infection. There is usually no need to administer granulocyte-macrophage colony-stimulating factor (GM-CSF); there are anecdotal reports that administration of this agent may induce lupus flare.

Thrombocytopenia in SLE is usually low grade, with platelet counts greater than 50,000/mm3. Severe thrombocytopenia may occur, however; idiopathic thrombocytopenic purpura (ITP) may be an initial presentation of SLE.

SLE may result in anemia of chronic disease and anemia from autoimmune hemolysis. The anemia of chronic disease in SLE patients responds to administration of recombinant erythropoietin.

Neurologic involvement

Neurologic signs and symptoms represent one of the most serious and least understood aspects of SLE. The primary neurologic manifestations of SLE consist of generalized and focal (usually vascular) brain disease, myelopathy, peripheral neuropathy, mononeuritis multiplex, and cognitive dysfunction. Secondary neurologic events can also occur; these include seizures from hypertension or hemorrhage, delirium from drugs or uremia, brain or spinal cord abscess, and stroke from atheroma or embolus. Attribution of a specific neurologic symptom to active lupus (which is treatable with immunosuppres-sion), as opposed to a complication of lupus or its treatment (which is treatable by ameliorating the offending problem) requires deep investigation and good clinical judgment. Confusion about diagnostic criteria for neurologic lupus led the ACR to publish nomenclature and case-definition criteria for these syndromes.43

General Brain Disease

Patients with SLE frequently complain of progressive cognitive dysfunction, such as confusion, forgetfulness, and so-called foggy thinking.44,45 Retrospective and cross-sectional studies document a high frequency of poor performance on tests of cognitive function, particularly in the executive, short-term memory, and verbal-processing spheres.46,47 It is not known whether this deficit results from immunologic attack on the brain (by antineu-ronal or other autoantibodies) or diffuse vascular disease. Cognitive dysfunction may respond to corticosteroid therapy. It seldom progresses to advanced dementia.

Headaches are common in SLE. A special form of migraine called lupus headache has been described, but whether it exists as a definable entity remains a matter of debate.

Focal Brain Disease

Seizures, strokes, cranial neuropathies (including blindness), and cerebellar dysfunction may occur in SLE. These events are assumed to result from vascular occlusion, but they may occur in patients with no known thrombotic diathesis, embolization, atherosclerosis, or vasculitis. Stroke is one of the most common presentations of the antiphospholipid antibody syndrome. Seizures are most common in severely active, febrile, multisystem disease. In this circumstance, they generally do not persist after the disease is brought under control.48

Table 5 Cardiopulmonary Manifestations of SLE

Pleuropericarditis

Libman-Sacks endocarditis

Valve insufficiency

Valve stenosis

Ischemic cardiomyopathy

Accelerated atherosclerosis

Antiphospholipid antibody syndrome

Hypertensive heart disease

Vasculitis

Hypertensive heart disease

Pulmonary hypertension

Peripheral arterial insufficiency

Vasculitis

Atherosclerosis

Antiphospholipid antibody syndrome

Peripheral venous thrombosis

Raynaud phenomenon

Complete congenital heart block in newborns with neonatal lupus erythematosus

Myelopathy

Transverse myelitis occurs in two patterns: (1) abrupt onset, with progression in hours from the first symptom, often heralded by a burning, dysesthetic pain in the legs; and (2) slower progression, in a stuttering fashion, worsening over days. Unless treated immediately and aggressively, both forms may progress to advanced paraparesis or paraplegia. Although few direct data exist to support these hypotheses, it is likely that the first form represents vascular occlusion with spinal cord ischemia and the second form represents inflammatory disease. It is mandatory to exclude a space-occupying mass in all such patients.

A slowly progressive and intermittent myelopathy, very much resembling multiple sclerosis (so-called MS-like or lupoid sclerosis), develops in some lupus patients. There is no definitive way to exclude concomitant MS in these patients except by the association of the myelopathy with SLE and by its failure to progress in the way MS usually does. In this form of lupus myelopathy, cerebrospinal fluid examinations may reveal oligo-clonal bands, but MRI studies are atypical for MS.

Peripheral Neuropathy

Stocking-and-glove neuropathy is a slowly progressive lesion that tends to occur in patients with continuing, active disease. Its pathogenesis is unclear; it may result from direct immune attack on peripheral nerves or from vasculitic occlusion of the vasa ner-vora. Abrupt loss of motor and sensory function, such as sudden occurrence of footdrop or wristdrop, is diagnosed as mononeuri-tis multiplex. This is a very serious manifestation indicating vas-culitis of the vasa nervora; it implies systemic vasculitis, as well.

Renal involvement

Approximately half of lupus patients develop lupus nephritis, and approximately 10% overall will progress to dialysis or transplantation. Lupus nephritis presents as proteinuria (or an other wise abnormal urinalysis), hypertension, or a rising serum cre-atinine level, all of variable degree. In its early stages, lupus nephritis is painless and asymptomatic. In more advanced stages, edema, anemia, symptomatic hypertension, and symptomatic uremia occur. Patients with inflammatory forms of nephritis are usually hypocomplementemic; most have high levels of anti-DNA or anti-Sm antibody. Signs or symptoms of disease active in other organ systems need not accompany lupus nephritis.

The World Health Organization (WHO) pathologic classification of lupus nephritis has been revised. The revised criteria differ from previous classifications by taking into account normal biopsies, scarring, and tubulointerstitial changes; in addition, they incorporate information from immunofluorescence and electron microscopy studies [see Table 6].49 This classification includes indices of disease activity and chronicity, which delineate acute necrosis, inflammatory infiltrate, crescent formation, scarring, and tubular atrophy to provide further prognostic informa-tion.9 Electron microscopy demonstrates immune complex deposits in subepithelial spaces in membranous lupus nephritis and in subendothelial spaces in proliferative lupus nephritis, as well as in mesangial locations. Characteristic tubuloreticular structures, thought to be RNA degradation products, also appear. Immunofluorescence studies demonstrate IgG, IgM, and C3 deposits in the same distributions. Vascular inflammation or endothelial proliferation is also seen.

Although lupus nephritis may present as anuria, acute hypertension, or fluid retention, most often it is first noted by an abnormal urinalysis. If left untreated, lupus nephritis progresses to renal insufficiency over months to years. Biopsy is necessary primarily when the result will change treatment. Urinalysis and blood chemistry results correlate only roughly with biopsy findings [see Table 7].

Special presentations

Neonatal Lupus Syndrome

Approximately 25% of infants born to mothers with anti-SS- A or anti-SS-B antibody will develop a photosensitive rash or thrombocytopenia, both of which are transient. A very small number of these infants will develop complete congenital heart block in utero. Both the cardiac and the skin manifestations constitute the neonatal lupus syndrome. Either can be present independently. The syndrome appears to result from transplacental passage of maternal antibody, and it subsides when the antibody disappears. However, the heart block persists and may be lethal. The antibody likely targets transiently expressed antigens in the fetal conducting system; signals for apoptosis and fibrosis are upregulated.50

Table 6 International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003

Class	Name	Description	Clinical Presentation
I	Minimal mesangial	Normal light microscopy, mesangial immune deposits by immunofluorescence	Normal urinalysis, normal function
II	Mesangial proliferative	Infiltrating cells and proliferation of mesangium	Mild proteinuria, celluria, normal function
	Focal active Focal active and chronic Focal chronic	Infiltrating cells and immune complex deposits in portions of the glomerulus and in < 50% of glomeruli (active) or scarring (chronic)	Variable proteinuria, celluria, normal function
	Diffuse and active (A), global (G), segmental (S), chronic (C)	Infiltrating cells and moderate immune complex deposits in entire glomeruli and in a 50% of glomeruli with segmental or global lesions, with or without scarring	Variable proteinuria, celluria; often severe, decreasing function
V	Membranous	Global or segmental subendothelial immune deposits by light, immunofluorescence, or electron microscopy, with or without mesangial lesions	Marked proteinuria, slowly decreasing function
VI	Advanced sclerotic	a 90% of glomeruli globally sclerosed without residual activity	Variable proteinuria, decreased function

Table 7 Likely Renal Biopsy Findings According to Urinalysis and Serum Creatinine Results

Urinalysis		Creatinine Level	Most Likely Pathology
Protein	Cells
None	None	Normal	Normal or mesangial
Little	WBCs	Normal	Mesangial, focal proliferative
Moderate	WBCs, RBCs	Normal	Mesangial, focal or diffuse proliferative
Moderate	WBCs, RBCs, casts	Normal or elevated	Focal or diffuse proliferative
Severe	WBCs, RBCs, casts	Normal or elevated	Diffuse proliferative, membranoproliferative
Severe	Few	Normal or elevated	Membranous
Moderate	WBCs	Normal or elevated	Interstitial (tubular) disease (in patients with acidosis or electrolyte abnormalities)

AntiphospholipiC Antibody Syndrome

Between one third and one half of lupus patients have anti-cardiolipin antibody, lupus anticoagulant, or both. When either of these antibodies is present in high titer, patients are susceptible to recurrent thromboembolic disease, thrombocytopenia, livedo reticularis, and cardiac valvular disease. Women are susceptible to recurrent pregnancy loss. These symptoms, combined with positive blood tests, constitute the antiphospholipid syndrome (APS).51 In the absence of lupus, the disorder is termed primary APS (PAPS); and when lupus or another rheumatic disease is present, the syndrome is designated secondary APS (SAPS). Current research suggests that the true antigen for the syndrome is the phospholipid binding protein, beta2-glycopro-tein I, rather than negatively charged phospholipids themselves. In some patients, antibody to an alternative phospho-lipid binding protein, such as prothrombin, induces the same syndrome. It is not known what induces clotting events in individual patients, but evidence of endothelial activation or injury, such as circulating endothelial cells, appears to be associated with thromboembolic episodes. The sites of thrombosis are not inflammatory and are best treated by anticoagulation rather than by immunosuppression. However, studies of pregnancy loss in animal models indicate that complement activation is a critical component of fetal injury, suggesting anew the possible involvement of the innate immune system in the development of APS.

Laboratory tests

Tests of a variety of body fluids may be abnormal in patients with SLE [see Table 8]. Not all tests are abnormal in all patients. If lupus is suspected, an antinuclear antibody test, a complete blood count, and a urinalysis should be performed; if the results of these tests are all normal, SLE is excluded. However, because lupuslike illnesses are also usually suspected, it is often efficient also to obtain at first visit the following tests: erythrocyte sedimentation rate (ESR) or C-reactive protein level; assays for antibodies against dsDNA, Sm, RNP, SS-A, and SS-B; partial throm-boplastin time (or other screening test for lupus anticoagulant) and cardiolipin antibodies; and a chemistry profile that includes liver function tests and serum creatinine level.

The antinuclear antibody (ANA) assay is a screening test for lupus. The ANA assay is almost always positive in high titer (> 1:80) in untreated patients with active disease, but a positive result does not by itself confirm a diagnosis of lupus. Only the anti-dsDNA antibody and anti-Sm antibodies, when present in high titer, are diagnostic of lupus. Anti-dsDNA antibody and complement levels are rough guides to disease activity, but many patients remain well for long periods of time with severely abnormal tests. Hypocomplementemia reflects prolifer-ative lupus nephritis but not other aspects of SLE, including membranous lupus nephritis. The ESR remains elevated in many otherwise well SLE patients, as does the C-reactive protein level.