Part V. Recommendations for the induction therapy of lupus nephritis type IV or type IV/V with cellular crescent formation
The specialty subcommittee recommended induction therapy with cyclophosphamide or primidone combined with high-dose intravenous glucocorticoid shocks and an initial high-dose glucocorticoid of 1 mg/kg/d orally for this type of lupus nephritis (Table 2). For the purposes of guideline recommendations, the presence of either crescent in a renal biopsy specimen is considered crescentic lupus nephritis. Recently, experts have supported the use of high-dose intravenous cyclophosphamide for cytosolic crescentic lupus nephritis. In general, the formation of crescents predicts a poor prognosis even with appropriate treatment. A recent retrospective study in China showed that primidone (1 g twice a day) was at least as effective as high-dose cyclophosphamide in type IV crescentic LN. Prospective, international studies or trials conducted in North America were not suggestive in this group of patients. Recommendations for the treatment of crescentic LN in pregnant women are described in Part X.
Part VI Recommendations for induction therapy for type V simplex membranous nephropathy LN
The specialty subcommittee recommended initial treatment of type V simplex LN with nephrotic syndrome-range proteinuria with prednisone (0.5 mg/kg/d) combined with MMF 2-3 g/day (level of evidence A) (Table 3). In a retrospective analysis of type V LN showing similar efficacy of MMF 2-3g/d orally combined with prednisone dosed (mean 27mg/d) for 6 months versus intravenous cyclophosphamide (0.5-1mg/kg/month IV for 6 months) combined with oral prednisone, 0-30% of patients had nephrotic syndrome level proteinuria after 6 months of treatment. Other treatment options for membranous nephropathy have been reported; however, there is no consensus among specialty subcommittees regarding recommendations for these treatments. For example, in a prospective trial, 3 treatment groups were compared: alternate-day prednisone (40 mg/m2 orally every other day) tapered after 8 weeks to 10 mg/m2 or alternate-day prednisone combined with intravenous cyclophosphamide 500-1000 mg/m2 every 2 months for a total of 6 doses or alternate-day prednisone combined with cyclosporine 5 mg/kg for 11 months. Remission was achieved in 27% of the prednisone alone group, 60% of the cyclophosphamide treated group, and 83% of the cyclosporine treated for 3-12 months. After the first year of treatment (follow-up period of 36 months), renal recurrence was significantly lower in the cyclophosphamide group than in the cyclosporine group.
Part VII Maintenance therapy for patients with effective induction therapy
The specialty subcommittee recommended azathioprine or primaquine as maintenance therapy. 2 recent prospective trials have studied maintenance therapy after induction therapy for LN. In the larger study, which included the United States, Western Europe, China, Argentina, and Mexico, patients were randomized to azathioprine 2 mg/kg/d or MMF 2 g/day after 6 months of remission on high doses of cyclophosphamide or primidone. The maximum dose of prednisone was 10 mg. At more than 3 years of follow-up, primidone treatment failure was better than azathioprine (failure endpoints included death, end-stage renal disease, 1-fold rise in serum creatinine, and recurrence of nephropathy), and data were better in each cell of the composite score. More serious side effects were seen with azathioprine than with primaquine, and in smaller studies conducted in Western and Southern Europe, all patients received small doses of cyclophosphamide, regardless of initial treatment response, and maintenance therapy was randomized to the azathioprine group with a target dose of 2 mg/Kg/d or the MMF group with a target dose of 2 g/d. There was no meaningful difference in prognosis between the two groups at the 4-year follow-up time, including death, renal disease recurrence, end-stage renal disease, and a more than 2-fold rise in blood creatinine. The specialty subcommittee did not recommend a dose reduction regimen for the maintenance phase of therapy, and to date, there are insufficient data to guide clinicians on how to reduce or discontinue azathioprine or primaquine.
Part VIII Recommendations for Changing Treatment Regimens in Patients Who Have Failed Induction
For those patients who have failed 6-month treatment (based on clinician judgment), the committee recommends a switch between CYC and MMF, along with administration of the hormonal shock therapy recommended in IV for 3 days (level of evidence C) [Figure 2]. Cyclophosphamide at either low or high doses can be used in the white cohort mentioned in IV. However, there is evidence that the strength of evidence for treatment effectiveness of the above regimens is not as strong as that for induction of remission. The committee also mentioned the convertible use of cyclophosphamide with AZA regimens for failure or worsening of 6-month induction therapy for nephritis and for AZA (level of evidence C). The committee did not reach consensus on the use of neurocalcine inhibitors during this discussion. However, there is evidence that neurocalcine inhibitors can be used as induction agents for refractory lupus nephritis and show their effectiveness in treatment.
Non-blinded trials have concluded that lupus nephritis responds to treatment with rituximab. However, in prospective, randomized and placebo-controlled trials, no significant difference was shown between rituximab and placebo after 1 year of treatment (with MMF and glucocorticoid-based therapy).
Evidence from open and recent prospective clinical studies supports the use of cyclosporine and tacrolimus for the treatment of LN; further prospective clinical trials are ongoing. A recent clinical study showed that tacrolimus for lupus nephritis was comparable to high-dose cyclophosphamide (IV) in terms of efficacy in complete or partial remission at 6 months. In another clinical study conducted over 4 years, the use of cyclosporine or azathioprine had similar efficacy in preventing relapses of lupus nephritis in patients receiving maintenance therapy.
If a patient’s disease worsens after 3 months of treatment with glucocorticoids plus cyclophosphamide or primidone, the expert committee recommends that clinicians use either of the options discussed (Level of Evidence C). Although the combination regimens of primidone with neurocalcine inhibitors and rituximab with primidone have been studied and have the potential to be used in patients who have failed with the recommended induction therapy. However, the strength of the evidence for them is insufficient and hardly a topic for this discussion.
Belimumab, which was recently approved by the FDA for the treatment of SLE, has not been studied in the treatment of lupus nephritis. Patients with active SLE were treated with either belimumab in IV or placebo, in addition to concomitant glucocorticoid or immunosuppressive therapy. After 52 weeks of treatment, the proportion of patients in remission was significantly higher in the belimumab (10 mg/kg/month) group than in the placebo group. Although lupus nephritis was not evaluated in the design, approximately 14-18% of patients had baseline 24-hour urine protein levels greater than 2 g. In a post hoc analysis there was a tendency for urine protein (P < 0.0631) and renal disease flares to remit in the belimumab (10 mg/kg/month) group after 53 weeks of treatment (P < 0.03). the FDA recommends this drug for those with active The FDA recommends this drug for patients with SLE with active lesions, regardless of prior regimen use.
Part IX Confirmation of vascular lesions and renal abnormalities in patients with SLE
Several types of vascular lesions can be present in the renal tissue of patients with SLE, including vasculitis, fibrous necrosis causing narrowing of small arteries (“mild” vasculopathy), thrombotic microangiopathy, and thrombosis of renal veins. In summary, vasculitis is the most common lesion in lupus nephritis described above. TMA is associated with TTP, and the expert committee recommends plasma exchange as the treatment of choice for TMA.
Part X Management of Lupus Nephritis in Pregnant Patients
The Expert Committee recommended several approaches for the management of pregnant women with lupus (Level of Evidence C) [Figure 4]. Patients with prelupus who do not have evidence of active systemic or renal disease do not need to be given treatment specific for nephritis. Those patients with mildly active systemic lesions are given hydroxychloroquine therapy; this regimen may reduce lupus activity in pregnant patients. If there is clinically active nephritis or activity of significant extrarenal lesions, the clinician may then administer the necessary doses of glucocorticoids to control the disease, adding azathioprine if necessary. High doses of glucocorticoid therapy may put the mother at increased risk for complications such as hypertension and diabetes mellitus. Primidone, cyclophosphamide, and methotrexate should be contraindicated because they can increase the rate of fetal malformations. Although azathioprine is included in class D for use in pregnant patients and crossover design analysis has shown a low risk of fetal abnormalities, it should not be used in pregnant patients at doses greater than 2 mg/kg. For patients with persistent nephritis activity and definite or suspected type III or IV with crescent, delivery after 28 weeks may be considered for a viable fetus.
D. Detection of lupus nephritis activity
The Expert Committee has listed the recommendations for lupus testing in Table 3, which were generated by expert vote (Level of Evidence C). Testing for drugs and biologic agents used to treat lupus nephritis has been mentioned elsewhere [Ref. 76
Discussion
This report improves the methodology for evaluating guidelines to describe the ACR guideline recommendations, i.e., definition, treatment, and testing for lupus nephritis. While previous guidelines mostly gave broad principles of treatment, this guideline focuses more on nephritic lesions, including the use of unconventional drugs in early-stage patients. The guideline contains experimental data on the use of drugs such as primidone, glucocorticoids, and rituximab, and also clarifies the use of drugs in special circumstances, such as in pregnant patients. A limitation of the report is that there is no agreement on the definitions of remission, relapse, and effectiveness. The data in this report do not provide information on hormone dosing and immunosuppressive dose reduction strategies. Although some new therapeutic approaches have been used in the treatment of patients with SLE, data on the treatment of lupus nephritis with these approaches have not been published. These areas still need active research to improve the treatment of lupus nephritis and also to help update guidelines in the future.
Nephritis remains a serious complication of SLE, and the number of patients with SLE increased each year between 1982 and 1995, with the incidence of progression to end-stage renal failure showing no signs of decreasing until 2004. Although new treatments are being used, the results are still unsatisfactory. The incidence of standardized end-stage renal failure remains high among young people in the southern United States and among African Americans. We look to the Society to develop guidelines to reduce this trend. We hope that the Society will develop guidelines to reduce this trend and to better evaluate whether patients who receive guideline-recommended regimens develop end-stage renal failure as little as possible. Given that lupus nephritis has a near-lethal prognosis, we still have a long way to go. With these guideline recommendations, we will continue to fight to improve outcomes and reduce morbidity and mortality.