III. Adjunctive therapy The panel recommends the use of hydroxychloroquine as primary therapy in all patients with SLE with nephritis, unless contraindicated (Level of evidence C). This conclusion is based on a prospective study (17) that showed a lower relapse rate with continued use of hydroxychloroquine compared with those SLE patients who switched to placebo; recent cross-sectional and prospective study data (18,19) also showed a significant reduction in disease progression, including renal lesions, in SLE patients treated with hydroxychloroquine. In addition, the use of hydroxychloroquine reduces thrombosis-related events in SLE (20,21). All patients with lupus nephritis with 24-hour urine protein quantification above 0.5 g (or equivalent immediate urine protein/creatinine ratio) require the use of RAS antagonists that reduce intraglomerular pressure (non-diabetic nephropathy, Level of Evidence A). In patients with non-diabetic nephropathy, the use of ACEI or ARB analogues reduces urinary protein levels by about 30% and significantly delays the rise in blood creatinine levels and progression to ESRD (22). These drugs are contraindicated in pregnant patients. Treatment with combined ACEI/ARB is fraught with controversy. ACEI or ARB therapy is superior to calcium antagonists and diuretics alone in protecting renal function in patients with CKD (24). The panel recommends close attention to hypertension control with a goal of <=130/80 mm Hg (non-diabetic nephropathy, evidence level A). The recommended goal is based on prospective studies and meta-analysis. These data suggest that this goal is strongly associated with delayed progression of nephropathy compared with higher blood pressure goals or poor control. The panel also recommends statin therapy for patients with LDL >100 mg/dl (Level of Evidence C) (25). Note that when glomerular filtration rate <60 ml/minute/1.73 m2 (equivalent to a blood creatinine level >1.5 mg/dl or 133 umol/L) is a risk factor for atherosclerosis progression (22). SLE itself is also a non-independent risk factor for atherosclerosis progression (26) Finally, the panel recommends that women of childbearing age with active or previous lupus nephritis need to be counseled about the risk of pregnancy related to the disease and treatment. (Evidence level C) IV: Recommendations for induction of remission therapy in patients with ISN class III/IV lupus nephritis The task force panel (TFP) recommended morte-macrolimus (MMF) (2-3 g total daily orally) or intravenous cyclophosphamide combined with glucocorticoids (level A evidence) (Figure 2). Long-term studies of MMF are not as numerous as long-term studies of CYC; data suggest that MMF at a total daily dose of 3 g for a total of 6 months of induction therapy followed by 3 years of low-dose MMF maintenance show good results. The Aspreva Lupus Management Study (ALMS) trial comparing the response of lupus nephritis to MMF plus glucocorticoids had similar efficacy in whites, Asians, and other ethnic groups (primarily African Americans and Latinos). The task force suggested that a lower dose of MMF is required to produce similar efficacy in Asians compared with non-Asians (Level C evidence). Therefore internists should aim for a maximum dose of 3 g daily for non-Asians and 2 g daily for Asians. a recent study showed that low dose treatment in Taiwanese produced a good response. There is evidence that African Americans and Latinos with lupus nephritis do not respond as well to intravenous cyclophosphamide as Caucasians or Asians. For African Americans or Latinos MMF/mycophenolic acid (MPA) may be the first option to induce remission. The exact dose of MMF depends on the clinical situation: in patients with grade III/IV without cytogenic crescent formation and in patients with unavailable renal pathology without proteinuria and stable blood creatinine levels, the task force considered both total daily doses of 2g and 3g to be acceptable, whereas in patients with grade III/IV, cytogenic crescent formation and in patients with proteinuria and recently significantly elevated creatinine, total daily doses of 3g is more beneficial. There is evidence that MPA and enteric-coated mescaline sodium are less likely to produce nausea and diarrhea compared to MMF, but this is also controversial and precise equivalent doses have not been established. Studies using other MMF agents are ongoing. The Core Expert Panel recommends that MMF and MPA appear to be equivalent in inducing remission in lupus nephritis, with a total daily dose of 1440-2160 mg of MPA being approximately equivalent to a total daily dose of 2000-3000 mg of MMF. Some investigators suggest that MMF activity should be measured metabolite MPA at peak serum concentrations (1 hour after one dose) and trough concentrations, and to guide the treatment of SLE. However, there are not enough data to make recommendations for monitoring blood levels. The task force panel recommended 2 regimens of intravenous cyclophosphamide: 1) low-dose “Euro-Lupus” cyclophosphamide (500 mg IV every 2 weeks for a total of 6 doses) followed by daily oral azathioprine (AZA) or daily oral MMF maintenance (level B evidence), and 2) high-dose cyclophosphamide (500-1000 mg/m2 intravenously once a month for a total of 6 doses), with MMF or AZA maintenance (level A evidence) (Figure 2). Previous studies have shown that 30 months of high-dose intravenous cyclophosphamide (the “IHI” regimen), starting with once monthly for a total of 6 doses and then quarterly for a total of 2 years, is more effective in preventing kidney disease outbreaks than the shorter 6-month regimen. However, today more regimens greater than 3-6 months plus AZA or MMF maintenance have shown good long-term efficacy. Limited prospective trials comparing daily oral cyclophosphamide with high-dose intravenous therapy have shown similar efficacy and toxicity. If treated with cyclophosphamide, The Core Expert Panel recommends low-dose “Euro-Lupus” intravenous cyclophosphamide for Caucasians of Western or Southern European ancestry in Beijing (Level B evidence). In patients studied in Europe, the low-dose and high-dose regimens were equivalent in terms of efficacy, and the low-dose group was less likely to develop serious infections. The low-dose and high-dose regimens have not been compared in non-Caucasian races. A 10-year follow-up comparison of the low-dose and high-dose regimens showed similar rates of flares of lupus nephritis, end-stage renal disease, and creatinine multiplication. The task force panel recommended high-dose intravenous hormone shocks (Pulse IV glucocorticoids) (500-1000 mg methylprednisolone 3 times daily) in combination with immunosuppressive therapy, followed by daily oral hormones (0.5C1 mg/kg/d), then tapered to the minimum necessary to control the disease (C level of evidence). Initial induction of remission therapy with high-dose hormone shocks is recommended based on expert opinion; some recent prospective studies have applied high-dose hormone shocks (750 mg/d methylprednisolone x 3) at initial therapy, while others have not. There are insufficient data to provide a specific approach to hormone dose reduction, as nephritis and extrarenal manifestations vary widely among individuals. There are no consistent results regarding the efficacy of monthly methylprednisolone applications versus monthly intravenous cyclophosphamide. A long-term follow-up study suggests that combining monthly intravenous methylprednisolone and intravenous cyclophosphamide is beneficial over intravenous cyclophosphamide alone. Although AZA has been used to treat lupus nephritis, the task force panel did not recommend it as the drug of choice for induction of remission therapy. In one study, AZA was shown to be less effective in inducing remission than cyclophosphamide combined with standard doses of glucocorticoids. In the long term (1-5 years of treatment), AZA is less effective than cyclophosphamide in the prevention of lupus nephritis outbreaks as remission-inducing and maintenance therapy, and cyclophosphamide is less effective in slowing the progression of chronic renal pathology. The Specialty Group recommends that most patients be followed for 6 months after cyclophosphamide or MMF-induced remission therapy before making adjustments to the treatment regimen rather than adjusting the glucocorticoid dose, unless there is clear evidence of a 3-month exacerbation (proteinuria or blood creatinine elevation of 50% or more; level A evidence). A recent study retrospectively analyzed a high-quality study showing a 25% reduction in proteinuria and/or normalization of C3 and/or C4 serum levels in patients with lupus nephritis showing a better renal response after 8 weeks of cyclophosphamide or MMF-induced remission therapy. Similarly, reductions in serum creatinine and proteinuria to 1g/24h at 6 months after treatment suggest a good long-term prognosis. Approximately 50% of SLE patients with severe lupus nephritis show definite improvement in renal disease indicators after 6 months of MMF or cyclophosphamide treatment, with the proportion responding to treatment increasing to 65-80% at 12-24 months of treatment. Fertility issues are often a concern in young SLE patients with lupus nephritis. In one discussion, thetask force panel recommended MMF over cyclophosphamide for patients who wished to preserve fertility because high doses of cyclophosphamide cause permanent sterility in both men and women (Grade A evidence of gonadotoxicity). In one study, women with lupus nephritis on high-dose cyclophosphamide (500-1000 mg/m2 IV monthly x 6 months, some of which were treated quarterly for another 18 months) developed age-related permanent amenorrhea: 12% occurred at <25 years, 27% at <30 years, and 62% at ≥31 years. Furthermore, when women aged >25 years were treated with high-dose cyclophosphamide for 6 months (cumulative dose 4.4-10 g), persistent amenorrhea occurred in 17% of patients, compared with 64% in the additional per-quarter treatment group. Thus, 6 months of high-dose intravenous cyclophosphamide was associated with persistent infertility in 10% of young women and a greater proportion in older women. 6 months of cyclophosphamide plus 1 dose per quarter was associated with a higher incidence of infertility. In the Euro-Lupus Lupus Nephritis trial, menopause occurred in 4.5% of patients at low doses (cyclophosphamide 500 mg IV every 2 weeks x 6, cumulative dose 3 g) compared to 4.3% in the high dose group. Thetask force panel has no known results on the use of leuprolide as a method of fertility protection in SLE patients treated with cyclophosphamide. They also observed that MMF can be teratogenic (US FDA Class D). Therefore, internists should be sure that patients are not pregnant before prescribing MMF or MPA and should discontinue the drug for at least 6 weeks before attempting pregnancy.