Systemic Lupus Erythematosus (Disorders of Immune-Mediated Injury) (Rheumatology) Part 3

Nervous System Manifestations

There are many central nervous system (CNS) and peripheral nervous system manifestations of SLE; in some patients these are the major cause of morbidity and mortality. It is useful to approach this diagnostically by asking first whether the symptoms result from SLE or another condition (such as infection in immunosuppressed individuals). If symptoms are related to SLE, it should be determined whether they are caused by a diffuse process or vascular occlusive disease. The most common manifestation of diffuse CNS lupus is cognitive dysfunction, including difficulties with memory and reasoning. Headaches are also common. When excruciating, they often indicate SLE flare; when milder, they are difficult to distinguish from migraine or tension headaches. Seizures of any type may be caused by lupus; treatment often requires both antiseizure and immunosuppressive therapies. Psychosis can be the dominant manifestation of SLE; it must be distinguished from glucocorticoid-induced psychosis. The latter usually occurs in the first weeks of glucocorticoid therapy, at daily doses of >40 mg of prednisone or equivalent; psychosis resolves over several days after glucocorticoids are decreased or stopped. Myelopathy is not rare and is often disabling; rapid immunosuppressive therapy starting with glucocorticoids is standard of care.

Vascular Occlusions

The prevalence of transient ischemic attacks, strokes, and myocardial infarctions is increased in patients with SLE.

These vascular events are increased in, but not exclusive to, SLE patients with antibodies to phospholipids (aPL). It is likely that antiphospholipid antibodies are associated with hypercoagulability and acute thrombotic events, whereas chronic disease is associated with accelerated atherosclerosis. Ischemia in the brain can be caused by focal occlusion (either noninflammatory or associated with vasculitis) or by embolization from carotid artery plaque or from fibrinous vegetations of Libman-Sacks endocarditis. Appropriate tests for aPL (see below) and for sources of emboli should be ordered in such patients to estimate the need for, intensity of, and duration of antiinflammatory and/or anticoagulant therapies. In SLE, myocardial infarctions are primarily manifestations of accelerated atherosclerosis. The increased risk for vascular events is seven- to tenfold overall, and higher in women <45 years old with SLE. Characteristics associated with increased risk for atherosclerosis include older age, hypertension, dyslipidemia, dysfunctional proinflammatory high-density lipoproteins, repeated high scores for disease activity, high cumulative or daily doses of glucocorticoids, and high levels of homocysteine. When it is most likely that an event results from clotting, long-term anticoagulation is the therapy of choice. Two processes can occur at once— vasculitis plus bland vascular occlusions—in which case it is appropriate to treat with anticoagulation plus immunosuppression. The role of statin therapies in SLE is being investigated.

Pulmonary Manifestations

The most common pulmonary manifestation of SLE is pleuritis with or without pleural effusion. This manifestation, when mild, may respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs); when more severe, patients require a brief course of glucocorticoid therapy. Pulmonary infiltrates also occur as a manifestation of active SLE and are difficult to distinguish from infection on imaging studies. Life-threatening pulmonary manifestations include interstitial inflammation leading to fibrosis, shrinking lung syndrome, and intraalveolar hemorrhage; all of these probably require early aggressive immunosuppressive therapy as well as supportive care.

Cardiac Manifestations

Pericarditis is the most frequent cardiac manifestation; it usually responds to anti-inflammatory therapy and infrequently leads to tamponade. More serious cardiac manifestations are myocarditis and fibrinous endocarditis of Libman-Sacks. The endocardial involvement can lead to valvular insufficiencies, most commonly of the mitral or aortic valves, or to embolic events. It has not been proven that glucocorticoid or other immunosuppressive therapies lead to improvement of lupus myocarditis or endocarditis, but it is usual practice to administer a trial of high-dose steroids along with appropriate supportive therapy for heart failure, arrhythmia, or embolic events. As discussed above, patients with SLE are at increased risk for myocardial infarction, usually due to accelerated atherosclerosis, which probably results from chronic inflammation and/or chronic oxidative damage to lipids and to organs.

TABLE 4-5

MEDICATIONS FOR THE MANAGEMENT OF SLE
MEDICATION	DOSE RANGE	DRUG INTERACTIONS	SERIOUS OR COMMON ADVERSE EFFECTS
NSAIDs, salicylates (Ecotrina and St. Joseph’s aspirina approved by FDA for use in SLE)	Doses toward upper limit of recommended range usually required	A2R/ACE inhibitors, glucocorticoids, fluconazole, methotrexate, thiazides	NSAIDs: Higher incidence of aseptic meningitis, transaminitis, decreased renal function, vasculitis of skin; entire class, especially COX-2-specific inhibitors, may increase risk for myocardial infarction Salicylates: ototoxicity, tinnitus Both: GI events and symptoms, allergic reactions, dermatitis, dizziness, acute renal failure, edema, hypertension
Topical glucocorticoids	Mid-potency for face; mid to high potency other areas	None known	Atrophy of skin, contact dermatitis, folliculitis, hypopigmentation, infection
Topical sunscreens	SPF 15 at least; 30+ preferred	None known	Contact dermatitis
Hydroxychloroquinea (quinacrine can be added or substituted)	200-400 mg qd (100 mg qd)	None known	Retinal damage, agranulocytosis, aplastic anemia, ataxia, cardiomyopathy, dizziness, myopathy, ototoxicity, peripheral neuropathy, pigmentation of skin, seizures, thrombocytopenia Quinacrine usually causes diffuse yellow skin coloration
DHEA (dehydroepi-androsterone)	200 mg qd	Unclear	Acne, menstrual irregularities, high serum levels of testosterone
Methotrexate (for dermatitis, arthritis)	10-25 mg once a week, PO or SC, with folic acid; decrease dose if CrCl <60 mL/min	Acitretin, leflunomide, NSAIDs and salicylates, penicillins, probenecid, sulfonamides, trimethoprim	Anemia, bone marrow suppression, leukopenia, thrombocytopenia, hepatotoxicity, nephrotoxicity, infections, neurotoxicity, pulmonary fibrosis, pneumonitis, severe dermatitis, seizures
Glucocorticoids, orala (several specific brands are approved by FDA for use in SLE)	Prednisone, prednisolone: 0.5-1 mg/kg per day for severe SLE 0.07-0.3 mg/kg per day or qod for milder disease	A2R/ACE antagonists, antiarrhythmics class III, β2, cyclosporine, NSAIDs and salicylates, phenothiazines, phenytoins, quinolones, rifampin, risperidone, thiazides, sulfonylureas, warfarin	Infection, VZV infection, hypertension, hyperglycemia, hypokalemia, acne, allergic reactions, anxiety, aseptic necrosis of bone, cushingoid changes, CHF, fragile skin, insomnia, menstrual irregularities, mood swings, osteoporosis, psychosis
Methylprednisolone sodium succinate, IVa (approved for lupus nephritis)	For severe disease, 1 g IV qd X 3 days	As for oral glucocorticoids	As for oral glucocorticoids (if used repeatedly); anaphylaxis
Cyclophosphamideb IV Oral	7-25 mg/kg q month X 6; consider mesna administration with dose 1.5-3 mg/kg per day Decrease dose for CrCl <25 mL/min	Allopurinol, bone marrow suppressants, colony-stimulating factors, doxorubicin, rituximab, succinylcholine, zidovudine	Infection, VZV infection, bone marrow suppression, leukopenia, anemia, thrombocytopenia, hemorrhagic cystitis (less with IV), carcinoma of the bladder, alopecia, nausea, diarrhea, malaise, malignancy, ovarian and testicular failure
Mycophenolate mofetilb	2-3 g/d PO; decrease dose if CrCl <25 mL/min	Acyclovir, antacids, azathioprine, bile acid-binding resins, ganciclovir, iron, salts, probenecid, oral contraceptives	Infection, leukopenia, anemia, thrombocytopenia, lymphoma, lymphoproliferative disorders, malignancy, alopecia, cough, diarrhea, fever, GI symptoms, headache, hypertension, hypercholesterolemia, hypokalemia, insomnia, peripheral edema, transaminitis, tremor, rash

TABLE 4-5

MEDICATIONS FOR THE MANAGEMENT OF SLE
MEDICATION	DOSE RANGE	DRUG INTERACTIONS	SERIOUS OR COMMON ADVERSE EFFECTS
Azathioprineh	2-3 mg/kg per day PO; decrease frequency of dose if CrCl <50 mL/min	ACE inhibitors, allopurinol, bone marrow suppressants, interferons, mycophenolate mofetil, rituximab, warfarin, zidovudine	Infection, VZV infection, bone marrow suppression, leukopenia, anemia, thrombocytopenia, pancreatitis, hepatotoxicity, malignancy, alopecia, fever, flulike illness, GI symptoms

^aIndicates medication is approved for use in SLE by the U.S. Food and Drug Administration. ^hIndicates the medication has been used with glucocorticoids in the trials showing efficacy.

Hematologic Manifestations

The most frequent hematologic manifestation of SLE is anemia, usually normochromic normocytic, reflecting chronic illness. Hemolysis can be rapid in onset and severe, requiring high-dose glucocorticoid therapy, which is effective in most patients. Leukopenia is also common and almost always consists of lymphopenia, not granulocytopenia; this rarely predisposes to infections and by itself usually does not require therapy. Thrombocytopenia may be a recurring problem. If platelet counts are >40,000^L and abnormal bleeding is absent, therapy may not be required. High-dose glucocorticoid therapy (e.g., 1 mg/kg per day of prednisone or equivalent) is usually effective for the first few episodes of severe thrombocytopenia. Recurring or prolonged hemolytic anemia or thrombocytopenia, or disease requiring an unacceptably high dose of daily glucocorticoids, should be treated with an additional strategy.

Gastrointestinal Manifestations

Nausea, sometimes with vomiting, and diarrhea can be manifestations of an SLE flare, as can diffuse abdominal pain caused by autoimmune peritonitis and/or intestinal vasculitis. Increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are common when SLE is active. These manifestations usually improve promptly during systemic glucocorticoid therapy. Vasculitis involving the intestine may be life-threatening; perforations, ischemia, bleeding, and sepsis are frequent complications. Aggressive immunosuppressive therapy with high-dose glucocorticoids is recommended for short-term control; evidence of recurrence is an indication for additional therapies.

Ocular Manifestations

Sicca syndrome (Sjögren’s syndrome; Chap. 8) and nonspecific conjunctivitis are common in SLE and rarely threaten vision. In contrast, retinal vasculitis and optic neuritis are serious manifestations: blindness can develop over days to weeks. Aggressive immunosuppression is recommended, although there are no controlled trials to prove effectiveness. Complications ofglucocorticoid therapy include cataracts (common) and glaucoma.

Laboratory Tests

Laboratory tests serve (1) to establish or rule out the diagnosis; (2) to follow the course of disease, particularly to suggest that a flare is occurring or organ damage is developing; and (3) to identify adverse effects of therapies.

Tests for Autoantibodies

Diagnostically, the most important autoantibodies to detect are ANA since the test is positive in >95% of patients, usually at the onset of symptoms. A few patients develop ANA within 1 year of symptom onset; repeated testing may thus be useful. ANA-negative lupus exists but is very rare in adults and is usually associated with other autoantibodies (anti-Ro or anti-DNA). High-titer IgG antibodies to doublestranded DNA (dsDNA) (but not to single-stranded DNA) are specific for SLE. There is no international standardized test for ANA; variability between different service laboratories is high. Enzyme-linked immunosorbent assays (ELISA) and immunofluorescent reactions of sera with the dsDNA in the flagellate Crithidia luciliae have ~60% sensitivity for SLE; identification of high-avidity anti-dsDNA in the Farr assay is not as sensitive but may correlate better with risk for nephritis. Titers of anti-dsDNA vary over time. In some patients, increases in quantities of anti-dsDNA herald a flare, particularly of nephritis or vasculitis. Antibodies to Sm are also specific for SLE and assist in diagnosis; anti-Sm antibodies do not usually correlate with disease activity or clinical manifestations. aPL are not specific for SLE, but their presence fulfills one classification criterion and they identify patients at increased risk for venous or arterial clotting, thrombocytopenia, and fetal loss. There are two widely accepted tests that measure different antibodies (anticar-diolipin and the lupus anticoagulant): (1) ELISA for anticardiolipin (internationally standardized with good reproducibility) and (2) a sensitive phospholipid-based activated prothrombin time such as the dilute Russell venom viper test. Some centers also recommend measurement of antibodies to β2 glycoprotein 1, a serum protein cofactor that is the target of most antibodies to cardiolipin and some lupus anticoagulants. High titers of IgG anticardiolipin (>50 IU) indicate high risk for a clinical episode of clotting. Quantities of aPL may vary markedly over time; repeated testing is justified if clinical manifestations of the antiphospholipid antibody syndrome (APS) appear. To make a diagnosis of APS, with or without SLE, requires the presence of clotting and/or repeated fetal losses plus at least two positive tests for aPL, at least 12 weeks apart.

An additional autoantibody test with predictive value (not used for diagnosis) detects anti-Ro, which indicates increased risk for neonatal lupus, sicca syndrome, and SCLE. Women with child-bearing potential and SLE should be screened for aPL and anti-Ro.

Standard Tests for Diagnosis

Screening tests for complete blood count, platelet count, and urinalysis may detect abnormalities that contribute to the diagnosis and influence management decisions.

Tests for Following Disease Course

It is useful to follow tests that indicate the status of organ involvement known to be present during SLE flares. These might include hemoglobin levels, platelet counts, urinalysis, and serum levels of creatinine or albumin. There is great interest in identification of additional markers of disease activity. Candidates include levels of anti-DNA antibodies, several components of complement (C3 is most widely available), activated complement products (including those that bind to the C4d receptor on erythrocytes), IFN-inducible genes, soluble IL-2, and urinary adiponectin or monocyte chemotactic protein 1. None is uniformly agreed upon as a reliable indicator of flare or of response to therapeutic interventions. The physician should determine for each patient whether certain laboratory test changes predict flare. If so, altering therapy in response to these changes has been shown to prevent flares. In addition, given the increased prevalence of atherosclerosis in SLE, it is advisable to follow the recommendations of the National Cholesterol Education Program for testing and treatment, including scoring of SLE as an independent risk factor, similar to diabetes mellitus.

Treatment:

Systemic Lupus Erythematosus

There is no cure for SLE,and complete sustained remissions are rare. Therefore, the physician should plan to control acute, severe flares and then develop maintenance strategies that suppress symptoms to an acceptable level and prevent organ damage. Usually patients will endure some adverse effects of medications.Therapeutic choices depend on (1) whether disease manifestations are life-threatening or likely to cause organ damage,justi-fying aggressive therapies; (2) whether manifestations are potentially reversible; and (3) the best approaches to preventing complications of disease and its treatments. Therapies,doses,and adverse effects are listed in Table 4-5.

Conservative Therapies For Management of Non-LIfE-Threatening Disease

Among patients with fatigue, pain, and autoantibodies of SLE, but without major organ involvement, management can be directed to suppression of symptoms. Analgesics and antimalarials are mainstays. NSAIDs are useful analgesics/anti-inflammatories,particularly for arthritis/ arthralgias. However,two major issues currently indicate caution in using NSAIDs. First, SLE patients compared with the general population are at increased risk for NSAID-induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction. Second, all NSAIDs, particularly those that inhibit cyclooxy-genase-2 specifically, may increase risk for myocardial infarction. Acetaminophen to control pain may be a good strategy, but NSAIDs may be more effective in some patients, and the relative hazards of NSAIDs compared with low-dose glucocorticoid therapy have not been established. Antimalarials (hydroxychloroquine, chloroquine, and quinacrine) often reduce dermatitis, arthritis, and fatigue. A randomized, placebo-controlled, prospective trial has shown that hydroxychloroquine reduces the number of disease flares; it may also reduce accrual of tissue damage over time. Because of potential retinal toxicity, patients receiving antimalarials should undergo ophthalmologic examinations at least annually. A placebo-controlled prospective trial suggests that administration of dehydroepiandrosterone may reduce disease activity. If quality of life is inadequate in spite of these conservative measures, treatment with low doses of systemic glucocorticoids may be necessary.