Maintenance therapy for proliferative LN
For most patients with active LN, six months of modern effective therapy will improve markers of disease activity, including anti-DNA antibody levels, serum complement, GFR, and degree of hematuria and proteinuria. However, some proteinuria and urinary sediment abnormalities are often still present at this time. Regimens of maintenance therapy have been devised to avoid relapses and flares of disease activity.
Although low-dose daily or alternate day corticosteroids (equivalent of 5-10 mg/day prednisone) are commonly used as part of most maintenance regimens, there are no controlled studies to verify their necessity. Both controlled trials and meta-analyses clearly document the important role of continuing immunosuppressive medications during the maintenance phase of LN therapy.
Although both oral and IV cyclophosphamide have been effectively used for induction therapy of LN, their use should be limited to three to six months to avoid toxic side effects (e.g., alopecia, bladder toxicity, infertility, increased risk of long-term neoplasms).
A study of 59 patients with severe LN who responded to six to eight monthly pulses of IV cyclophosphamide as induction therapy clearly showed the superiority of maintenance regimens with either oral MMF or oral azathioprine compared with IV cyclophosphamide administered every third month.13 Azathioprine and MMF both proved superior at maintaining remissions and preventing mortality or ESRD, with fewer adverse effects, including fewer days of hospitalization, fewer episodes of amenorrhea, and fewer severe infections.
Two more recent trials compared these two oral agents in the maintenance phase of severe LN. The ALMS maintenance trial looked at 227 patients who had responded to a regimen of either six months of oral MMF or to IV monthly cyclophosphamide as induction therapy for severe LN.23 MMF maintenance (1g twice daily) proved superior to that with azathioprine maintenance (2 mg/kg/day).
At three years, MMF proved superior to azathioprine in terms of total renal endpoints, relapse rate, doubling of serum creatinine, ESRD, and requirement for new additional immunosuppressive agents, regardless of which initial therapy the patients received, their racial background, or in what country they were treated. In the MAINTAIN Nephritis Trial, patients starting with six months of the Euro-Lupus regimen of IV cyclophosphamide and steroids were randomized to MMF or azathioprine for four years.24
Although neither drug proved statistically superior, there were fewer relapses with the MMF in this smaller, largely Caucasian population. In both studies, researchers observed excellent patient and renal survival rates, supporting the longer use of maintenance immunosuppressive drugs. There are only limited data on the use of other immunosuppressive drugs such as cyclosporine and tacrolimus as maintenance agents in LN.25,26 Likewise, repeated dosing of rituximab either every six months or when the CD19-20 B cell count rises has been used in a number of patients.
A number of adjunctive agents have proved helpful in treating LN patients, including renoprotective measures such as blockade of the renin angiotensin system in proteinuric patients, optimal blood pressure control, and the use of statins for both their lipid lowering and pleiotropic effects. Use of antimalarials may help with extrarenal symptoms, but there are only limited data on their effect in renal involvement.
Measures to prevent cardiovascular disease and future coagulation events in patients who are antiphospholipid positive with a previous clotting event are also recommended. As osteoporosis and avascular necrosis of bone have become important long-term health issues for many LN patients, it is important to minimize the use of corticosteroids and encourage the use of vitamin D and calcium supplements along with other agents to reduce bone loss.
Membranous lupus nephropathy
Patients with membranous lupus and subnephrotic proteinuria do extremely well regardless of treatment. There is no consensus on management with immunosuppressive agents. In membranous LN patients with nephrotic syndrome, both monthly pulse IV cyclophosphamide and oral cyclosporine have proven superior to oral prednisone therapy in inducing complete and partial remissions.26
In the two large recent trials of MMF versus IV cyclophophamide induction in LN, 84 of the 510 patients had pure membranous lupus nephropathy.27 Both drugs proved equivalent in inducing partial and complete remissions of the nephrotic syndrome.
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