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.
Diagnostically, the most important autoantibodies to detect are ANA as 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 rare in adults and is usually associated with other autoantibodies (anti-Ro or anti-DNA). High-titer IgG antibodies to double-stranded 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, especially when associated with declining levels of C3 or C4 complement. 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 (anticardiolipin 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. The higher the titers of IgG anticardiolipin (>40 IU is considered high), and the greater the number of different aPL that are detected, the greater is the 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 (Chap. 320). To classify a patient as having APS, with or without SLE, by international criteria requires the presence of ≥1 clotting episode and/or repeated fetal losses plus at least two positive tests for aPL, at least 12 weeks apart; however, many patients with anti-phospholipid syndrome do not meet these stringent criteria, which are intended for inclusion of patients into studies.
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 urinalysis for hematuria and proteinuria, hemoglobin levels, platelet counts, 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 gene expression in peripheral blood cells, soluble IL-2 levels, and urinary levels of TNF-like weak inducer of apoptosis (TWEAK), neutrophil gelatinase-associated lipocalin (NGAL), or monocyte chemotactic protein 1 (MCP-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 may be advisable (30 mg of prednisone daily for 2 weeks has been shown to prevent flares in patients with rising anti-DNA plus falling complement). 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 induce improvement of acute flares and then maintain improvements with 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, justifying 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 319-5.
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 cyclooxygenase-2 specifically, may increase risk for myocardial infarction. Acetaminophen to control pain may be a good strategy, but NSAIDs are more effective in some patients. 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 withdrawal of hydroxychloroquine results in increased numbers of disease flares. Hydroxychloroquine reduces accrual of tissue damage over time. Because of potential retinal toxicity, patients receiving antimalarials should undergo ophthalmologic examinations 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. Dermatitis should be managed with topical sunscreens, antimalarials, and topical glucocorticoids and/or tacrolimus. Since recent data show that mycophenolate mofetil, and belimumab (added to background therapies of glucocorticoids-plus-antimalarial-plus immunosuppressive) reduce disease activity in nonrenal manifestations of SLE, it is reasonable to consider these interventions in patients with persistent disease activity despite standard therapies. Azathioprine or methotrexate may also be considered for such patients (Table 319-5).
Life-Threatening SLE: Proliferative Forms of Lupus Nephritis
The mainstay of treatment for any inflammatory life-threatening or organ-threatening manifestations of SLE is systemic glucocorticoids (0.5–1 mg/kg per day PO or 1000 mg of methylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent). Evidence that glucocorticoid therapy is lifesaving comes from retrospective studies from the predialysis era; survival is significantly better in people with DPGN treated with high-dose daily glucocorticoids (40–60 mg of prednisone daily for 4–6 months) versus lower doses. Currently, high doses are recommended for much shorter periods; recent trials of interventions for severe SLE employ 4–6 weeks of 0.5 to 1 mg/kg/day of prednisone or equivalent. Thereafter, doses are tapered as rapidly as the clinical situation permits, usually to a maintenance dose varying from 5–10 mg of prednisone or equivalent per day or from 10–20 mg every other day. Most patients with an episode of severe lupus require many years of maintenance therapy with low-dose glucocorticoids, which can be increased to prevent or treat disease flares. Frequent attempts to gradually reduce the glucocorticoid requirement are recommended since virtually everyone develops important adverse effects (Table 319-5). Prospective controlled trials in active lupus nephritis show that induction of improvement by administration of high doses of glucocorticoids (1000 mg of ethylprednisolone daily for 3 days) by IV routes compared with daily oral routes shortens the time to maximal improvement by a few weeks but ultimately improvements are similar. It has become standard practice to initiate therapy for active, potentially life-threatening SLE with high-dose IV glucocorticoid pulses, based on studies in lupus nephritis. This approach must be tempered by safety considerations, such as the presence of conditions adversely affected by glucocorticoids (infection, hyperglycemia, hypertension, osteoporosis, etc.).
Cytotoxic/immunosuppressive agents added to glucocorticoids are recommended to treat serious SLE. Almost all prospective controlled trials in SLE involving cytotoxic agents have been conducted in combination with glucocorticoids in patients with lupus nephritis. Therefore, the following recommendations apply to treatment of nephritis. Either cyclophosphamide (an alkylating agent) or mycophenolate mofetil (a relatively lymphocyte-specific inhibitor of inosine monophosphatase and therefore of purine synthesis) is an acceptable choice for induction of improvement in severely ill patients; azathioprine (a purine analogue and cycle-specific antimetabolite) is probably less effective but may be used if the other immunosuppressives are not tolerated or not available. In patients whose renal biopsies show ISN grade III or IV disease, early treatment with combinations of glucocorticoids and cyclophosphamide reduces progression to ESRD and improves survival; this difference can be seen after approximately 5 years of therapy. Shorter-term studies with glucocorticoids plus mycophenolate mofetil (prospective randomized trials of 6 months) show that this regimen is similar to cyclophosphamide in inducing improvement. Comparisons are complicated by effects of race, since higher proportions of blacks (and other non-Asian, non-white races) respond to mycophenolate than to cyclophosphamide, whereas similar proportions of whites and Asians respond to each drug. Regarding toxicity, diarrhea is more common with mycophenolate while herpetic infections, amenorrhea, and leukopenia are more common with cyclophosphamide; rates of severe infections and death are similar in some studies, although mycophenolate is less toxic than cyclophosphamide in others. Therapeutic responses to cyclophosphamide and mycophenolate begin 3–16 weeks after treatment is initiated, whereas glucocorticoid responses may begin within 24 h. For maintenance therapy, mycophenolate may be better than azathioprine in preventing flares and progression of lupus nephritis; either drug is acceptable and both are safer than cyclophosphamide. If cyclophosphamide is used for induction therapy, the recommended “National Institutes of Health (NIH)” dose (based on clinical trials at that institution) is 500–750 mg/m2 intravenously, monthly for 6 months, followed by maintenance with daily oral mycophenolate or azathioprine. The incidence of ovarian failure, a common effect of cyclophosphamide therapy, can be reduced by treatment with a gonadotropin-releasing hormone agonist (e.g., Lupron 3.75 mg IM) prior to each monthly cyclophosphamide dose. Since cyclophosphamide has many adverse effects and is generally disliked by patients, alternative approaches using lower doses have been tested. European studies have shown that IV cyclophosphamide at doses of 500 mg every 2 weeks for six doses (“low dose”) is as effective as the recommended higher dose given for a longer duration in the NIH regimen (“high dose”). All patients were maintained on azathioprine after the course of cyclophosphamide was completed. Ten-year follow-up has shown no differences in the high-dose and low-dose groups (death or ESRD in 9–20% in each group). The majority of the European patients were white; it is not clear that the data apply to U.S. populations. Patients with high serum creatinine levels [e.g., ≥265 μmol/L (≥3 mg/dL)] many months in duration and high chronicity scores on renal biopsy are not likely to respond to immunosuppression. In general, it may be better to induce improvement in a black or Hispanic patient with proliferative glomerulonephritis with mycophenolate (2–3 g daily) rather than with cyclophosphamide, with the option to switch if no evidence of response is detectable after 3–6 months of treatment. For whites and Asians, induction with either mycophenolate or cyclophosphamide is acceptable. Cyclophosphamide may be discontinued when it is clear that a patient is improving; the number of SLE flares is reduced by maintenance therapy with mycophenolate (1.5–2 g daily) or azathioprine (2 mg/kg/d). Both cyclophosphamide and mycophenolate are potentially teratogenic; patients should be off either medication for at least 3 months before attempting to conceive. If azathioprine is used either for induction or maintenance therapy, patients may be prescreened for homozygous deficiency of the TMPT enzyme (which is required to metabolize the 6-mercaptopurine product of azathioprine) since they are at higher risk for bone marrow suppression.
Good improvement occurs in ∼80% of lupus nephritis patients receiving either cyclophosphamide or mycophenolate at 1–2 years of follow-up. However, at least 50% of these individuals have flares of nephritis over the next 5 years, and retreatment is required; such individuals are more likely to progress to ESRD. Long-term outcome of lupus nephritis to most interventions is better in whites than in blacks. Chlorambucil is an alkylating agent that can be substituted for cyclophosphamide; the risk of irreversible bone marrow suppression may be greater with this agent. Methotrexate (a folinic acid antagonist) may have a role in the treatment of arthritis and dermatitis, but probably not in nephritis or other life-threatening disease. Small controlled trials (in Asia) of leflunomide, a relatively lymphocyte-specific pyrimidine antagonist licensed for use in rheumatoid arthritis, have suggested it can suppress disease activity in some SLE patients. Cyclosporine and tacrolimus, which inhibit production of IL-2 and T lymphocyte functions, are used by some clinicians particularly for membranous lupus nephritis. Since they have potential nephrotoxicity, but little bone marrow toxicity, the author uses them for periods of only a few months in patients with steroid-resistant cytopenias of SLE, or in steroid-resistant patients who have developed bone marrow suppression from standard cytotoxic agents.
Use of biologicals directed against B cells for active SLE is under intense study. Use of anti-CD20 (Rituximab), particularly in those patients with SLE who are resistant to the more standard combination therapies discussed above, is controversial. Several open trials have shown efficacy in a majority of such patients—both for nephritis and for extrarenal lupus. However, recent prospective placebo-controlled randomized trials did not show a difference between anti-CD20 and placebo when added to standard combination therapies. In contrast, recent trials of anti-BLyS (belimumab, directed against the ligand of the BLyS/BAFF receptor on B cells that promotes B cell survival and differentiation to plasmablasts) showed a small, but statistically significant, better suppression of disease activity in comparison to placebo, when added to standard combhnation therapies. The US FDA has approved belimumab for treatment of SLE: it has not been studied in active nephritis or central nervous system lupus.
It is important to note that there are few if any randomized, controlled, prospective studies of any agents in life-threatening SLE that do not include nephritis. Therefore, use of glucocorticoids plus byclophosphamide or mycophenolate in other life-threatening conditions is based on studies in nephritis.
Special Conditions in SLE that May Require Additional or Different Therapies
Crescentic Lupus Nephritis
The presence of cellular or fibrotic crescents in glomeruli with proliferative glomerulonephritis (INS-IVG)] indicates a worse prognosis than in patients without this feature. There are few large prospective controlled trials showing efficacy of cyclophosphamide, mycophenolate, or cyclosporine in such cases. Most authorities currently recommend that cyclophosphamide in the NIH-recommended high dose or high doses of mycophenolate are the induction therapies of choice, in addition to glucocorticoids.
Membranous Lupus Nephritis
Most SLE patients with membranous (INS-V) nephritis also have proliferative changes and should be treated for proliferative disease; however, some have pure membranous changes. Treatment for this group is less well defined; recent prospective controlled trials suggest that alternate-day glucocorticoids plus cyclophosphamide or mycophenolate or cyclosporine are all effective in the majority of patients in reducing proteinuria; whether they preserve renal function over the lonf term is more controversial.
Fertility rates for men and women with SLE are probably normal. However, rate of fetal loss is increased (approximately two- to threefold) in women with SLE. Fetal demise is higher in mothers with high disease activity, antiphospholipid antibodies, and/or active nephritis. Suppression of disease activity can be achieved by administration of systemic glucocorticoids. A placental enzyme, 11-β-dehydrogenase 2, deactivates glucocorticoids; it is more effective in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone. Glucocorticoids are listed by the FDA as pregnancy category A (no evidence of teratogenicity in human studies); cyclosporine, tacrolimus, and rituximab are listed as category C (may be teratogenic in animals but no good evidence in humans); azathioprine, hydroxychloroquine, mycophenolate mofetil, and cyclophosphamide are category D (there is evidence of teratogenicity in humans. but benefits might outweigh risks in certain situations); and methotrexate is category X (risks outweigh benefits). Therefore, active SLE in pregnant women should be controlled with prednisone/prednisolone at the lowest effective doses for the shortest time required. Adverse effects of prenatal glucocorticoid exposure (primarily betamethasone) on offspring may include low birth weight, developmental abnormalities in the CNS, and predilection toward adult metabolic syndrome. It is likely that each of these glucocorticoids and immunosuppressive medications get into breast milk, at least in low levels; patients should consider not breast-feeding if they need therapy for SLE. In SLE patients with aPL (on at least two occasions) and prior fetal losses, treatment with heparin (usually low-molecular-weight) plus low-dose aspirin has been shown in prospective controlled trials to increase significantly the proportion of live births; however, a recent prospective trial showed no differences in fetal outcomes in women taking aspirin compared to those on aspirin plus low-molecular-weight heparin. An additional potential problem for the fetus is the presence of antibodies to Ro, sometimes associated with neonatal lupus consisting of rash and congenital heart block. The latter can be life-threatening; therefore, the presence of anti-Ro requires vigilant monitoring of fetal heart rates with prompt intervention (delivery if possible) if distress occurs. To date, treatments of mother to reverse established heart block in the fetus, newborn, or infant (other than insertion of a pacemaker) have not been successful. Women with SLE usually tolerate pregnancy without disease flares. However, a small proportion develops severe flares requiring aggressive glucocorticoid therapy or early delivery. Poor maternal outcomes are highest in women with active nephritis or irreversible organ damage in kidneys, brain, or heart.
Lupus and Antiphospholipid Antibody Syndrome (Chap. 20)
Patients with SLE who have venous or arterial clotting, and/or repeated fetal losses, and at least two positive tests for aPL have APS and should be managed with long-term anticoagulation. A target international normalized ratio (INR) of 2–2.5 is recommended for patients with one episode of venous clotting; an INR of 3–3.5 is recommended for patients with recurring clots or arterial clotting, particularly in the central nervous system. Recommendations are based on both retrospective and prospective studies of posttreatment clotting events and adverse effects from anticoagulation.
Microvascular Thrombotic Crisis (Thrombotic Thrombocytopenic Purpura, Hemolytic-Uremic Syndrome)
This syndrome of hemolysis, thrombocytopenia, and microvascular thrombosis in kidneys, brain, and other tissues carries a high mortality rate and occurs most commonly in young individuals with lupus nephritis. The most useful laboratory tests are identification of schistocytes on peripheral blood smears, elevated serum levels of lactate dehydrogenase, and antibodies to ADAMS13. Plasma exchange or extensive plasmapheresis is usually life-saving; most authorities recommend concomitant glucocorticoid therapy; there is no evidence that cytotoxic drugs are effective.
Patients with any form of lupus dermatitis should minimize exposure to ultraviolet light, employing appropriate clothing and sunscreens with a sun protection factor of at least 15. Topical glucocorticoids and antimalarials (such as hydroxychloroquine) are effective in reducing lesion severity in most patients and are relatively safe. Systemic treatment with retinoic acid is a useful strategy in patients with inadequate improvement on topical glucocorticoids and antimalarials; adverse effects are potentially severe (particularly fetal abnormalities), and there are stringent reporting requirements for its use in the United States. Extensive, pruritic, bullous, or ulcerating dermatitides usually improve promptly after institution of systemic glucocorticoids; tapering may be accompanied by flare of lesions, thus necessitating use of a second medication such as hydroxychloroquine, retinoids, or cytotoxic medications such as methotrexate or azathioprine. In therapy-resistant lupus dermatitis there are reports of success with topical tacrolimus (caution must be exerted because of the possible increased risk for malignancies) or with systemic dapsone or thalidomide (the extreme danger of fetal deformities from thalidomide requires permission from and supervision by the supplier).
Prevention of complications of SLE and its therapy include providing appropriate vaccinations (the administration of influenza and pneumococcal vaccines has been studied in patients with SLE; flare rates are similar to those receiving placebo) and suppressing recurrent urinary tract infections. In addition, strategies to prevent osteoporosis should be initiated in most patients likely to require long-term glucocorticoid therapy and/or with other predisposing factors. Control of hypertension and appropriate prevention strategies for atherosclerosis, including monitoring and treatment of dyslipidemias, management of hyperglycemia, and obesity, are recommended.
Studies of highly targeted experimental therapies for SLE are in progress. They include targeting (1) activated B lymphocytes with anti-BLyS, or TACI-Ig; (2) inhibition of IFNα; (3) inhibition of B/T cell second signal co-activation with CTLA-Ig; and (4) inhibition of innate immune activation via TLR7 or TLR7 and 9, and induction of regulatory T cells with peptides from immunoglobulins or autoantigens. A few studies have employed vigorous untargeted immunosuppression with high-dose cyclophosphamide plus anti–T cell strategies, with rescue by transplantation of autologous hematopoietic stem cells for the treatment of severe and refractory SLE. One U.S. report showed an estimated mortality rate over 5 years of 15% and sustained remission in 50%. It is hoped that the next edition of this text will recommend more effective and less toxic approaches to treatment of SLE based on some of these strategies.