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 (0.5-2 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 life-saving 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 these doses.Thereafter, doses are tapered as rapidly as the clinical situation permits, usually to a maintenance dose varying from 5 to 10 mg of prednisone or equivalent per day or from 10 to 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 4-5). Prospective controlled trials in active lupus nephritis show that administration of high doses of glucocorticoids (1000 mg of methylpred-nisolone daily for 3 days) by intravenous routes compared with daily oral routes shortens the time to maximal improvement by a few weeks but does not result in better renal function. 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 patients with lupus nephritis, and always in combination with glucocorticoids. Therefore, the following recommendations apply to treatment of nephritis; there is little information regarding the efficacy of mycophenolate mofetil in other forms of SLE. 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) may be effective but is slower to influence response. 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. Short-term studies with glucocorticoids plus mycophe-nolate mofetil show that this regimen is safer than and not inferior to cyclophosphamide in inducing improvement, and that mycophenolate (or azathioprine) is safer than cyclophosphamide in maintaining improvement after a 6-month induction phase. If cyclophosphamide is used, the recommended dose is 500-750 mg/m2 intravenously, monthly for 3-6 months, then discontinuation with introduction of mycophenolate or azathio-prine.The incidence of ovarian failure,a common effect of cyclophosphamide therapy,can be reduced by treatment with a gonadotropin-releasing hormone agonist prior to each cyclophosphamide dose. European studies have suggested that cyclophosphamide at doses of 500 mg total every 2 weeks for six doses is as effective as the higher dose and longer duration recommended above, over a period of 5-7 years.The great majority of those patients were Caucasian; it is not clear that the data apply to all U.S. populations. Cyclophosphamide and mycophenolate responses begin 3-16 weeks after treatment is initiated,whereas glucocorticoid responses may begin within 24 h. Patients with high serum creatinine levels [e.g., >265 μmol/L (>3.0 mg/dL)] many months in duration and high chronicity scores on renal biopsy are not likely to respond. Regarding the efficacy of mycophenolate compared with cyclophosphamide, most studies of the former are short term (<5 years). Such data are useful but may not adequately describe the overall utility of that approach, since cyclophosphamide compared with glucocorticoids alone reduces ESRD—a change that can be detected in study cohorts ~5 years after therapy is introduced.The recommended duration of cyclophosphamide therapy is controversial. There are data to support treatment (1) once monthly IV for 6 months followed by 2 more years of quarterly doses, (2) for 12 weeks followed by azathioprine, and (3) for 6 months followed by azathioprine or mycopheno-late.In general,cyclophosphamide may be discontinued when it is clear that a patient is improving; possibility of disease flare is reduced by continuing therapy with one of the cytotoxic/immunosuppressive drugs discussed above. Response of lupus nephritis to cyclophosphamide and glucocorticoids is better in Caucasian groups than in African Americans. Mycophenolate may be a better choice for African Americans, but results of long-term studies are needed before this recommendation can be validated.The adverse effects most likely to influence patient choice against the use of cyclophosphamide are a high rate of irreversible ovarian or testicular failure with increasing cumulative doses, nausea and malaise that often accompany each IV dose, alope-cia,and frequent infections.
Since glucocorticoid-plus-cyclophosphamide therapy has many adverse effects and is often disliked by patients, there has been a search for different therapies that are less toxic; this led to the recent study and use of mycophenolate. Azathioprine (a purine antagonist) added to glucocorticoids probably reduces the number of SLE flares and the maintenance glucocorticoid requirement; it can also help sustain improvement induced by faster-acting treatments (glucocorticoids plus mycophenolate or cyclophosphamide). Patients who have homozygous deficiency of the TMPT enzyme, which is required to metabolize the 6-mercaptopurine product of azathioprine, should not receive azathioprine because they are at increased risk for bone marrow suppression. Daily oral azathioprine has fewer adverse effects than cyclophosphamide.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 re-treatment is required. 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 life-threatening disease.The role of leflunomide, a relatively lymphocyte-specific pyrimidine antagonist licensed for use in rheumatoid arthritis, is being studied in patients with SLE. Cyclosporine, which inhibits production of IL-2 and inhibits T lymphocyte functions, has not been studied in prospective controlled trials in SLE but is nonetheless used by some clinicians. Since it has potential nephrotoxicity, but no bone marrow toxicity, the author uses it (in doses of 3-5 mg/kg per day PO) in patients with steroid-resistant cytopenias of SLE or in steroid-resistant patients who have developed bone marrow suppression from standard cytotoxic agents.
It is important to note that there are few if any randomized, controlled, prospective studies of any agents in life-threatening SLE that does not include nephritis. Therefore, use of glucocorticoids plus cyclophosphamide or mycophenolate in other life-threatening conditions is based on studies in nephritis.
Special Conditions in SLE That May Require Additional or Different Therapies
Pregnancy and Lupus 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 nephritis.Suppression of disease activity can be achieved by administration of systemic glucocorticoids. A placental enzyme, 11-ß-dehydrogenase 2, deactivates glucocorticoids; it is more effective in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone. Therefore, maternal SLE 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. In SLE patients with aPL (on at least two occasions) and prior fetal losses, treatment with heparin (standard or low-molecular-weight) plus low-dose aspirin has been shown in prospective controlled trials to increase significantly the proportion of live births. 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; there-fore,the presence of anti-Ro requires vigilant monitoring of fetal heart rates with prompt intervention (delivery if possible) if distress occurs.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 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 2.0-2.5 is recommended for patients with one episode of venous clotting; an INR of 3.0-3.5 is recommended for patients with recurring clots or arterial clotting, particularly in the central nervous sys-tem.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 and elevated serum levels of lactate dehydrogenase. Plasma exchange or extensive plasmapheresis is usually life-saving; there is no evidence that cytotoxic drugs are effective.
Lupus Dermatitis 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 andantimalarials;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).
PREVENTIVE THERAPIES 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 longterm 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.
EXPERIMENTAL THERAPIES Figure 4-3 shows the targets of several new biologicals, and mycopheno-late, all of which are currently in clinical trials. Most strategies target T or B lymphocytes, particularly those undergoing activation, rather than entire cell populations. Some therapies, as indicated by bold boxes, are licensed by the U.S. Food and Drug Administration for use in diseases other than SLE. Several studies have employed vigorous 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. A recent 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.
Patient Outcomes, Prognosis, and Survival
Survival in patients with SLE in the United States, Canada, Europe, and China is approximately 95% at 5 years, 90% at 10 years, and 78% at 20 years. In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse prognosis than Caucasians, whereas Africans in Africa and Hispanic Americans with a Puerto Rican origin do not. The relative importance of gene mixtures and environmental differences accounting for ethnic differences is not known. In societies where modern medical care (and organ transplantation) is available only to those who can pay, glucocorticoid therapies are usually the sole therapy for severe lupus; prognosis is worse than in the developed world. Poor prognosis (~50% mortality in 10 years) in most series is associated with (at the time of diagnosis) high serum creatinine levels [>124 μη^^ (>1.4 mg/dL)],hypertension, nephrotic syndrome (24-h urine protein excretion >2.6 g), anemia [hemoglobin <124 g/L (<12.4 g/dL)],hypoalbu-minemia, hypocomplementemia, aPL, male sex, and ethnicity (African-American, Hispanic, and mestizo heritage). Data regarding outcomes in SLE patients with renal transplants show mixed results: some series have a twofold increase in graft rejection compared to patients with other causes of ESRD, whereas others show no differences. Overall patient survival is comparable (85% at 2 years). Lupus nephritis occurs in approximately 10% of transplanted kidneys. Disability in patients with SLE is common due primarily to chronic fatigue, arthritis, and pain, as well as renal disease. As many as 25% of patients may experience remissions, sometimes for a few years, but these are rarely permanent. The leading causes of death in the first decade of disease are systemic disease activity, renal failure, and infections; subsequently, thromboembolic events become increasingly frequent causes of mortality.
Drug-Induced Lupus
This is a syndrome of positive ANA associated with symptoms such as fever, malaise, arthritis or intense arthralgias/myalgias, serositis, and/or rash. The syndrome appears during therapy with certain medications and biologic agents, is predominant in Caucasians, has less female predilection than SLE, rarely involves kidneys or brain, is rarely associated with anti-dsDNA, is commonly associated with antibodies to histones, and usually resolves over several weeks after discontinuation of the offending medication.The list of substances that can induce lupus-like disease is long. Among the most frequent are the antiar-rhythmics procainamide, disopyramide, and propafenone; the antihypertensive hydralazine; several angiotensinconverting enzyme inhibitors and beta blockers; the antithyroid propylthiouracil; the antipsychotics chlorpro-mazine and lithium; the anticonvulsants carbamazepine and phenytoin; the antibiotics isoniazid, minocycline, and macrodantin; the antirheumatic sulfasalazine; the diuretic hydrochlorothiazide; the antihyperlipidemics lovastatin and simvastatin; and interferons and TNF inhibitors. ANA usually appears before symptoms; however, many of the medications mentioned above induce ANA in patients who never develop symptoms of drug-induced lupus. It is appropriate to test for ANA at the first hint of relevant symptoms and to use test results to help decide whether to withdraw the suspect agent.
FIGURE 4-3
Experimental therapies for SLE in clinical trials in 2006. Green boxes surround interventions that are licensed for use by the U.S. Food and Drug Administration in diseases other than SLE. Blue boxes surround experimental products that are not licensed for use in any disease. APRIL, a proliferation- inducing ligand; BCMA, B cell maturation antigen; BCR, B cell receptor; BLyS, B lymphocyte stimulator; CTLA4, cytotoxic T cell lymphocyte antigen; DR, human leukocyte antigen molecule; IMPDH, inosine monophosphate dehydrogenase; MP/DC, macrophage/dendritic cell; TCR, T cell receptor.
