Systemic Lupus Erythematosus
Authors: Marianthi Kiriakidou
Journal: Annals of Internal Medicine (2013)

In the ClinicOctober 1, 2013Systemic Lupus ErythematosusMarianthi Kiriakidou, MD, Deborah Cotton, MD, MPH, Darren Taichman, MD, PhD, and Sankey Williams, MDMarianthi Kiriakidou, MDSearch for more papers by this author, Deborah Cotton, MD, MPHSearch for more papers by this author, Darren Taichman, MD, PhDSearch for more papers by this author, and Sankey Williams, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-159-7-201310010-01004 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Systemic lupus erythematosus (SLE, lupus) is a condition in which the immune system attacks healthy cells and tissues throughout the body. Immune system activation in SLE is characterized by exaggerated B-cell and T-cell responses and loss of immune tolerance against self antigens. Production and defective elimination of antibodies, circulation and tissue deposition of immune complexes, and complement and cytokine activation contribute to clinical manifestations that range from mild fatigue and joint pain to severe, life-threatening organ damage.Because the symptoms of SLE vary widely and the condition often goes undiagnosed, it is unclear how many people in the United States have the disease. It is diagnosed 9 times more often in women than in men, which implies pathogenic mechanisms more prevalent in women. These mechanisms, which probably involve effects of sex chromosomes, specific genes, and hormones, have not been completely elucidated. SLE is more common and more severe in African American women, Hispanic women, and those of other ethnic minorities (1).Although there is no cure for SLE, it can be effectively managed with medications; however, mortality is higher in patients with SLE than in the general population. The overall standardized mortality ratio (SMR) (ratio of deaths observed to deaths expected for an age group) for SLE is 2.4. Higher risk for death is associated with female sex, younger age, shorter SLE duration, and African American race (2).ScreeningWhich patients are at elevated risk for lupus?Evidence to determine whether people may be at risk for lupus because of specific genes is insufficient. Early genetic studies, driven by the observation of familial aggregation and high concordance in monozygotic twins, have implicated genes for HLA and early complement components (3). A few rare, single-gene risk factors have been linked to SLE. For example, C1, C2, or C4 genetic deficiencies can cause lupus but account for just 1–2% of cases (3). Recent genome-wide association studies have linked more than 30 gene polymorphisms to lupus (4). However, the functional significance of these variants and their potential implication to SLE pathogenesis remain largely unknown. In addition, sex chromosome genes, and possibly sex hormones and environmental influences, may contribute to immune system dysfunction in genetically predisposed individuals.Should clinicians screen asymptomatic patients for lupus if they are at increased risk?Most experts do not recommend screening asymptomatic persons for lupus, even those with a family history. Nevertheless, the immunologic test for antinuclear antibody (ANA) is often used for SLE screening even though it produces many false-positive results. ANA is detected in 3–5% of healthy individuals or patients with other autoimmune or infectious diseases. Furthermore, serologic evidence of ANAs, which indicates immune system activation, may precede the clinical manifestations required for diagnosis by 3 to 9 years (5). No evidence suggests that treating to modulate the immune system during this clinically "silent" period can stop or delay lupus development.Clinical Bottom Line: ScreeningSingle-gene mutations causing SLE are rare. Although numerous gene variants have been linked to lupus, current evidence is insufficient to support screening for these variants. ANA testing in asymptomatic persons is not useful because immune reaction to nuclear antigens is not SLE-specific, can be detected in healthy individuals, and may precede SLE manifestations by many years.DiagnosisWhat symptoms or physical examination findings should prompt clinicians to consider a diagnosis of lupus?The initial presentation of lupus often mimics a viral syndrome. Such constitutional symptoms as weight loss, fatigue, and low-grade fever are common and may be accompanied by arthralgias or arthritis. Arthritis in lupus is characterized by prolonged morning stiffness and mild to moderate joint swelling. It is nonerosive, may be symmetric or asymmetric, and may affect large or small joints. Large effusions are not as common in lupus as in rheumatoid arthritis, and the synovial fluid is not as inflammatory (6). Joint deformities are not frequent in lupus. Jaccoud arthropathy, which may include reducible ulnar deviation, swan neck deformities, or z-shaped thumb, is present in 2.8–4.3% of patients (7). When constitutional symptoms with arthralgias or arthritis are not accompanied by other characteristic manifestations of lupus, such as photosensitive skin rash on the face, neck, or extremities, it is appropriate to conduct a clinical and laboratory evaluation for infection before trying to establish a diagnosis of SLE.Cutaneous manifestations are common and may occur in up to 70% of patients (8). They are categorized as acute, subacute, or chronic. Acute cutaneous lupus consists of indurated or flat erythematous lesions on the malar eminences, scalp, arms, hands, neck, and chest. The malar rash may be confused with rosacea, drug eruption, or polymorphous light eruption, but skin biopsy is rarely necessary when other clinical manifestations and serologic evidence consistent with SLE are present. Subacute cutaneous lupus consists of annular lesions that may coalesce into a polycyclic (overlapping ring-shaped) rash or papulosquamous lesions that do not scar and are distributed where light exposure is most frequent. It is often associated with anti-SSA antibodies. Chronic cutaneous lupus includes discoid lupus and other rare subsets, such as lupus panniculitis, hypertrophic lupus erythematosus (characterized by verrucous lesions), tumid lupus or lupus tumidus (smooth, shiny, red-violet plaques usually on the head and neck), and chilblain lupus (purplish-blue lesions on the fingers, toes, or ears). Discoid lupus is the most common form of the chronic cutaneous disease and is characterized by scarring indurated plaques that resolve with significant depigmentation. Although acute cutaneous lupus is nearly always associated with systemic lupus, discoid lupus is infrequently (3–5%) associated with systemic disease (9).What other clinical manifestations should clinicians look for in potential cases of lupus?Systemic lupus may present in many other ways. Although fever, rash, and arthritis are the classic initial symptoms, abrupt onset with target-organ involvement is also quite common, particularly in Hispanics (61%) and African Americans (45%), as compared with white patients (41%) (10). SLE should be considered when patients, particularly women of reproductive age, present with hematologic, renal, respiratory, or central nervous system (CNS) manifestations, especially hematologic findings, such as thrombocytopenia, leukopenia, lymphopenia, or anemia; renal findings, such as hematuria, proteinuria, cellular casts, or elevated serum creatinine; respiratory symptoms, such as cough, dyspnea, hemoptysis, or pleuritic pain; or CNS signs, such as headache, photophobia, or focal neurologic deficits.Hematologic manifestationsCytopenias are common in patients with lupus, and moderate-to-severe lymphopenia is associated with high disease activity and organ damage (11). Hemolytic anemia is uncommon and usually associated with disease onset, thrombocytopenia, and African American ethnicity (12).Renal manifestationsRenal involvement is a common target-organ manifestation; it has a poor prognosis due to the high risk for organ failure. Up to 50% of SLE patients have some evidence of renal disease at presentation (13). SLE nephritis is associated with a worse prognosis for 10-year survival than the nonrenal disease (14). Compared with the general population, life expectancy is reduced by 12.4, 15.1, and 23.7 years in lupus patients, those with renal disease, and those with renal damage, respectively (15).Respiratory involvementInvolvement of the respiratory system may be primary or secondary. Presenting symptoms and the response to treatment vary, depending on the affected anatomical site. Pleuritis is the most common respiratory SLE manifestation, affecting 30–50% of patients (16). Lupus pleuritis should be diagnosed only after an analysis of pleural fluid and an evaluation for other causes of pleural effusion, such as infection, pulmonary embolism, liver disease, heart disease, and cancer. Bronchoscopy for bacterial, mycobacterial, fungal, and viral cultures may be indicated. Vascular involvement may cause diffuse alveolar hemorrhage, pulmonary hypertension, or thromboembolic disease. Parenchymal damage is less common and may be the result of interstitial lung disease, acute pneumonitis, or bronchiolitis obliterans with organizing pneumonia. Acute lupus pneumonitis is rare and carries a high mortality risk. Infection and pulmonary embolism must always be excluded in patients with suspected lupus pneumonitis.Neuropsychiatric manifestationsNeuropsychiatric SLE manifestations may be caused by vasculopathy, autoantibodies, and inflammatory mediators and include headache, aseptic meningitis, vasculitis, movement disorder, seizure disorder, cognitive dysfunction, psychosis, demyelinating disease, myelopathy, autonomic disorder, and peripheral neuropathy.Ocular manifestationsOcular manifestations include keratoconjuctivitis sicca (with or without the Sjogren syndrome), keratitis, episcleritis, scleritis, uveitis, retinal vasculitis, occlusion of the retinal artery or vein, retinopathy, and numerous other less common manifestations (17).Gastrointestinal manifestationsGastrointestinal symptoms may include anorexia, nausea, vomiting, abdominal pain, and diarrhea. Other causes of abdominal pain in lupus are mesenteric vasculitis and hepatobiliary disease. Rare gastrointestinal complications include intestinal pseudo-obstruction, protein-losing enteropathy, and pancreatitis. Immunocompromised lupus patients are also prone to enteritis from cytomegalovirus or salmonella infection.Lupus is a multiorgan disease that can mimic infectious diseases, cancer, and other autoimmune conditions. Table 1 lists the American College of Rheumatology (ACR) classification criteria for SLE (18). These criteria facilitate a systematic approach to diagnosis by focusing on the most common SLE manifestations. Four of the 11 criteria are required for classification of systemic lupus. Although intended to assist in classification, the ACR criteria offer a highly sensitive and specific tool for diagnosing SLE, based on objective disease manifestations. However, patients with mild disease may be missed. In 2012 the Systemic Lupus International Collaborating Clinics revised the ACR classification criteria, increasing the sensitivity but not the specificity of detecting SLE compared with the 1997 ACR criteria (19).Table 1. American College of Rheumatology Classification Criteria for SLE*What laboratory tests should clinicians use to diagnose lupus?Clinicians should test for ANA, and if the result is positive, follow-up testing for antigen-specific ANAs, such as those targeting double-stranded DNA (dsDNA) or ribonucleoprotein complexes (Ro/SSA, La/SSB, Smith, and RNP, which are collectively referred to as extractable nuclear antigens) should be done. The specificity of anti ds-DNA antibodies for lupus is >60%. Anti-Smith antibodies are >90% specific for lupus; however, they are detected in only about 30% of lupus patients. The initial laboratory evaluation to assess disease activity and target-organ involvement is described in the Box (Basic Investigations for SLE).Basic Investigations for SLEComplete blood countDirect Coombs test (indicated if patients present with hemolytic anemia and reticulocytosis)Comprehensive metabolic panelErythrocyte sedimentation rateC-reactive proteinUrinalysisSerologic testing (ANA and if positive, anti-DsDNA, anti-SSA/SSB, anti-Smith/RNP anti-phospholipid antibodies); a negative ANA test is inconsistent with the diagnosis of SLEComplement C3 and C4Creatine phosphokinase (indicated in patients presenting with muscle weakness)What other diagnoses should clinicians consider?The chronic fatigue syndrome and fibromyalgia may present with diffuse musculoskeletal symptoms mimicking lupus, or may be secondary to SLE. SLE can be excluded in the absence of inflammatory pain and negative results on serologic evaluation. Rheumatoid arthritis is characterized by symmetric, intensely inflammatory, erosive arthritis (when advanced) and positive results on rheumatoid factor or anti-CCP antibody testing.Such drugs as procainamide, hydralazine, minocycline, isoniazide, and tumor necrosis factor inhibitors can cause drug-induced lupus, a clinical syndrome resembling SLE characterized by fever, serositis, arthritis, and rash. Antihistone antibodies are detected in approximately 75% of patients; however, they can also be seen in SLE and are not pathognomonic. Anti-dsDNA, or antibodies to extractable nuclear antigens, are rare in drug-induced lupus, and symptoms usually abate within days or weeks after drug discontinuation.Small- or medium-vessel vasculitides, thrombotic thrombocytopenic purpura, and viral arthritis, as seen in parvovirus infection and HIV/AIDS, can also mimic SLE. Differential diagnosis relies on laboratory studies, detection of viral serologies, and tissue histopathology. Hematopoietic cancer and malignant lymphoproliferative syndromes may present with positive ANA, anemia, low-grade fever, pleural effusions, and lymphadenopathy and can be misdiagnosed as lupus.When should clinicians consider consulting with a rheumatologist or other specialist for diagnosing patients with possible lupus?Clinicians should consult a rheumatologist in all patients when clinical manifestations and serologic studies suggest SLE. Evidence of renal, pulmonary, CNS, ocular, or gastrointestinal disease necessitates a coordinated, multidisciplinary approach with the help of appropriate specialists. The goal of care is a timely, accurate diagnosis; effective treatment of acute disease; appropriate monitoring and dose adjustment; and early introduction of a steroid-sparing regimen.Clinical Bottom Line: DiagnosisLupus is a multisystem disease that often presents as a diagnostic challenge because it can include cutaneous, renal, respiratory, cardiovascular, CNS, and gastrointestinal manifestations that characterize numerous other conditions. The ACR classification criteria can be used to guide the diagnosis of systemic lupus.TreatmentWhat medications are used to treat lupus?Clinicians use a broad range of medications to treat lupus, including glucocorticoids, antimalarial agents, and nonsteroidal anti-inflammatory drugs (NSAIDs)(Table 2). Hydroxychloroquine prevents disease flares and is considered the cornerstone of SLE treatment. Glucocorticoids are first-line agents for most SLE manifestations, with dosage and treatment duration based on clinical experience and consensus. Immunosuppressive treatment in lupus nephritis is based on histopathologic classifications. Treatment of other lupus manifestations is based on sparse evidence from clinical trials and clinical experience and often requires immunosuppressive therapy and a multidisciplinary approach.Table 2. Drug Treatment for SLEHow should clinicians initiate therapy in a stable patient who is not having a flare?Hydroxychloroquine and other antimalarial agents have been used to treat inflammatory arthritides for at least 50 years (20). In addition to preventing lupus relapses and reducing the risk for congenital heart block in neonatal SLE, hydroxychloroquine has antithrombotic effects that are particularly important to SLE patients with antiphospholipid antibody-related prothrombotic diathesis (21). Hydroxychloroquine is generally well-tolerated, and the rare risk for retinopathy is directly related to the years of exposure to the drug and the age of the patient.In a study of 29 cases of antimalarial retinal toxicity over a period of 30 years, all patients were older than 40 years and had had exposure to the agents over 5 years (22).Skin hyperpigmentation and rare cases of neuromuscular or cardiac toxicity have also been reported.How should clinicians choose therapy for a patient who is having a flare?Severe SLE manifestations, such as lupus nephritis, alveolar hemorrhage, or CNS vasculitis, should be treated with glucocorticoids administered intravenously (IV) in conjunction with immunosuppressive medications. Glucocorticoids can be gradually withdrawn once remission is achieved. Oral prednisone or methlyprednisolone is used for arthritis, pleuropericarditis, cutaneous vasculitis, and uveitis.Early studies demonstrated that glucocorticoids could ameliorate SLE, although subsequent controlled trials showed that the therapeutic effect was not sustained (23). Early studies also linked glucocorticoids to improved survival in severe SLE (24), but similar studies have not been done for mild or moderate disease. Current decisions about glucocorticoid dosage and the duration of treatment for specific manifestations rely largely on clinical experience because too few clinical trials have been done.An early study comparing 100 mg with 1000 mg of IV methylprednisolone suggested that 3 daily doses of 1000 mg did not have a significant advantage over 3 daily doses of 100 mg (25). A more recent randomized study showed that a dose of 1000 mg to 1500 mg over 3 days is as effective as doses ranging from 2000 mg to 5000 mg over 3 days and is associated with a decreased risk for infections (26).Significant overlap exists between lupus manifestations and some glucocorticoid complications, including osteoporosis, avascular bone necrosis, myopathy, and psychosis. Furthermore, despite the abundance of observational data on glucocorticoid toxicity, evidence from randomized, controlled clinical trials (RCTs) is limited. Table 2 summarizes the 2002 European League Against Rheumatism recommendations on glucocorticoid treatment (27). These recommendations define a low daily dose of prednisone (or equivalent) as ≤7 mg. Low doses are associated with relatively low risk for toxicity, although monitoring for cushingoid symptoms, osteoporosis, cataracts, glaucoma, hyperglycemia, and hypertension is probably justified. Prolonged treatment with medium to high doses carries a higher risk for complications, including myopathy, psychosis, hyperlipidemia, and atherosclerosis. However, the prevalence and incidence of these complications in different corticosteroid regimens are still unclear (28).How should clinicians choose drug therapy for cutaneous mani-festations?Commonly used topical treatments for all forms of cutaneous lupus (acute, subacute, and chronic) include tacrolimus, R-salbutamol pimecrolimus, clobetasol, betamethasone, or photoprotection. Their efficacy has been shown by RCTs. Such trials have also shown efficacy of systemic hydroxychloroquine or chloroquine in cutaneous SLE. Although other immunosuppressive or biologic agents, such as methotrexate, mycophenolate mofetil, azathioprine, and rituximab, may be used for cutaneous lupus, evidence is based on case reports or prospective, nonrandomized studies (9).How should clinicians choose drug therapy for lupus arthritis?Low-dose glucocorticoids and antimalarials are first-line agents for treating arthritis in lupus. Methotrexate is often used for arthritis or cutaneous disease, particularly in patients without other systemic manifestations.A double-blind RCT showed that methotrexate is effective in controlling cutaneous and articular symptoms in SLE (29). These findings were also supported by a recent open-label trial (30) and an RCT showing that methotrexate can be used as a steroid-sparing agent in SLE (31).Methotrexate antagonizes folic acid and inhibits purine and pyrimidine synthesis. In addition, it increases extracellular adenosine release. Adenosine seems to be an important mediator of the anti-inflammatory effect of methotrexate.How should clinicians choose and dose drug therapy for lupus nephritis?Induction therapyThe indications for kidney biopsy are in the Box: Indications for Kidney Biopsy in Patients With SLE; the currently accepted classification system for biopsy results are in the Box: Histopathologic Classification of Lupus Nephritis.Indications for Kidney Biopsy in Patients With SLE*Increasing serum creatinine without compelling alternative causesConfirmed proteinuria ≥1.0 g/24 h (either 24-h urine specimens or spot protein creatinine ratio)Combination of the following: Proteinuria ≥0.5 ≥1.0 g/24 h + hematuria (≥5 red blood cells/high-power field) or proteinuria ≥0.5 ≥1.0 g/24 h + cellular casts* From reference 38.Histopathologic Classification of Lupus NephritisClass I: Minimal mesangialClass II: Mesangial proliferativeClass III: Focal proliferativeClass IV: Diffuse proliferative (with active, active and chronic, or chronic lesions)Class V: Membranous (with or without coexisting class III or IV lupus nephritis)Class VI: Advanced sclerosing lupus nephritis with >90% globally sclerotic glomeruliClass I or II lupus nephritis does not require immunosuppressive therapy. Class III or IV is treated aggressively. Until recently, cyclo-phosphamide combined with intravenous glucocorticoids has been the standard of care for induction therapy of class III and IV lupus nephritis. Cyclophosphamide is an alkylating agent that promotes DNA cross-linking and affects T- and B-cell proliferation and antibody production. It is usually dosed according to total body surface area and adjusted for decreased creatinine clearance. Cyclophosphamide toxicity includes hematologic, infectious, urologic, reproductive, and rare pulmonary complications and bladder, skin, myeloproliferative, and oropharyngeal cancers. To date, there is no definitive evidence from clinical trials to guide clinicians on the dose of glucocorticoids for induction therapy of lupus nephritis. Current ACR recommendations are based on expert opinion and consensus.Early open-label trials and RCTs showed short-term efficacy of glucocorticoids for treatment of lupus nephritis. Subsequently, an RCT comparing cyclophosphamide to glucocorticoids showed superiority of cyclophosphamide for induction therapy of proliferative lupus nephritis. Nonresponse was more common in the group treated with IV glucocorticoids and the probability of achieving remission was higher in the glucocorticoid plus cyclophosphamide group (32).Long-term follow-up of the study participants indicated that an increase in creatinine by 50% or 100% was less common in patients receiving combination treatment (33).Over the past decade, several studies have shown efficacy of mycophenolate mofetil for induction therapy in lupus nephritis (34–). This drug is metabolized to mycophenolic acid, an inhibitor of inosine 5-monophosphate dehydrogenase, which is required for de novo synthesis of guanosine nucleotides. Mycophenolate mofetil inhibits lymphocyte proliferation, induces apoptosis of activated T-cells, and inhibits adhesion molecule expression and fibroblast proliferation. Gastrointestinal toxicity is common and may respond to dose reduction or enteric-coated formulation. Hematologic toxicity is also common, ranging from mild cytopenias to red cell aplasia. Mycophenolate mofetil is contraindicated in pregnancy because of case reports suggesting teratogenicity (37).In a meta-analysis of 4 selected RCTs evaluating the efficacy of mycophenolate mofetil vs. cyclophosphamide for induction therapy, when data on maintenance therapy were excluded mycophenolate mofetil was not superior to cyclophosphamide in lupus nephritis (36).Recently updated guidelines recommend using either cyclophosphamide or mycophenolate mofetil combined with glucocorticoids for induction therapy of class III or IV proliferative lupus nephritis (38). Response to cyclophosphamide or mycophenolate mofetil may differ based on race. Asians and Europeans seem to respond better to cyclophosphamide than Hispanics and African Americans (38).Maintenance therapyCurrent guidelines recommend either mycophenolate mofetil or azathioprine for maintenance therapy in lupus nephritis. Both are superior to cyclophosphamide for this purpose (39). Evidence from 2 studies of comparative efficacy of mycophenolate mofetil vs. azathioprine is conflicting (40, 41). Treatment duration is guided by clinical experience.In a study of 227 patients with lupus nephritis class III, IV, or V who showed a clinical response to a 24-week induction with either cyclophosphamide or mycophenolate mofetil, patients were randomly assigned to treatment with mycophenolate mofetil (2 g/d) or azathioprine (2 mg/kg/d). After 3 years of follow up, mycophenolate mofetil was significantly superior to azathioprine with respect to time to treatment failure (primary end point), time to renal flare, and time to rescue therapy (40).In contrast, an open-label study showed no significant difference in patients treated with mycophenolate mofetil vs. azathioprine for maintenance treatment of lupus nephritis over a period of 4 years. All patients in the study were initially treated with low-dose cyclophosphamide for induction therapy (41).Calcineurin inhibitors, such as cyclosporine, are also used for maintenance therapy.A multicenter, randomized, open pilot trial compared the efficacy of cyclosporine vs. azathioprine for maintenance therapy of lupus nephritis. Seventy-five patients with lupus nephritis IV, Vc, or Vd, initially treated with IV glucocorticoids (1 mg/kg/3 d) followed by oral cyclophosphamide and prednisone for a median of 90 days, were randomized to treatment with azathioprine or cyclosporine for 2 (core study) and 4 years. Azathioprine and cyclosporine were equally effective in preventing disease flares, the primary outcome of the study. Proteinuria, a secondary end point, decreased significantly with both treatments. Blood pressure and creatinine clearance did not change significantly with either treatment; extrarenal manifestations and clinical activity decreased with both treatments (42).Data from this study indicate that cyclosporine and azathioprine are equally effective for maintenance treatment of lupus nephritis and have similar effects on blood pressure and renal function.Tacrolimus, also a calcineurin inhibitor, may be used to treat diffuse proliferative or membranous lupus nephritis. Meta-analysis of data from open-label trials, case–control studies, and RCTs showed that tacrolimus may be effective as induction and maintenance therapy for lupus nephritis or in treatment of refractory lupus nephritis with persistent proteinuria (43).Rituximab is a monoclonal antibody directed against CD20, a membrane protein expressed on B-cells. Rituximab depletes B-cells from the peripheral blood. Open-label trials indicated improvement of lupus nephritis after B-cell depletion; however, RCTs did not show statistically significant response compared with placebo (44–46).Current ACR guidelines propose mycophenolate mofetil or azathioprine as preferred maintenance therapy for proliferative lupus nephritis. Calcineurin inhibitors or rituximab combined with glucocorticoids may be used for patients with an adequate response to cyclophosphamide or mycophenolate mofetil (38). To date, no RCT has directly compared calcineurin inhibitors to mycophenolate mofetil for maintenance treatment of class III or IV lupus nephritis.How should clinicians choose drug therapy for membranous nephritis?Pure membranous nephritis is not associated with endocapillary proliferation and presents with variable degrees of proteinuria. The progression of renal dysfunction is slow compared with that of class III or IV lupus nephritis. The evidence to guide treatment of membranous lupus nephritis is limited.A retrospective analysis of 2 large RCTs showed similar efficacy of mycophenolate mofetil and cyclophosphamide for induction therapy of class V lupus nephritis (47).A prospective study of mycophenolate mofetil combined with renoprotective therapy (with angiotensin inhibitors or angiotensin-receptor blockers) showed that most patients achieved complete or partial remission at 6 months and sustained effect for a mean follow-up of 18 months (48).Based on this evidence, current guidelines from the ACR for membranous lupus nephritis recommend treatment with mycophenolate mofetil. Tacrolimus and azathioprine have also been studied for induction or maintenance treatment.A recent open-label trial showed that tacrolimus or mycophenolate mofetil combined with steroids were both effective in controlling membranous lupus nephritis (49).An RCT comparing azathioprine with tacrolimus, both combined with prednisone, for maintenance therapy of membranous nephritis suggests similar low rates in relapse with both regimens (50).How should clinicians choose therapy for neuropsychiatric lupus?Treatment of serious neuropsychiatric SLE manifestations is relatively empirical and includes IV glucocorticoids, immunoglobulin, and cyclophosphamide.An RCT comparing cyclophosphamide with glucocorticoids after 3 days of IV immunoglobulin for treatment of transverse myelitis in lupus showed that relapse was more common in the steroid group (51).Case reports and small, uncontrolled st