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Therapy of diffuse or focal proliferative lupus nephritis - UpToDate

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Official reprint from UpToDate


www.uptodate.com 2016 UpToDate

Therapy of diffuse or focal proliferative lupus nephritis


Authors: Ronald J Falk, MD, Maria Dall'Era, MD, Gerald B Appel, MD
Section Editors: Richard J Glassock, MD, MACP, Brad H Rovin, MD
Deputy Editor: Albert Q Lam, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Nov 11, 2015.
INTRODUCTION The optimal treatment of lupus nephritis (LN) varies with the type of renal histology that is
present in renal biopsy specimens. Immunosuppressive therapy is indicated in patients with diffuse or focal
proliferative LN (class III or IV LN) [1-3]. Immunosuppressive therapy is usually not indicated for minimal
mesangial and mesangial proliferative LN. Treatment of patients with lupus membranous nephropathy (class V
LN) is presented elsewhere. (See "Diagnosis and classification of renal disease in systemic lupus
erythematosus", section on 'Classification' and "Clinical features and therapy of lupus membranous
nephropathy".)
Induction and maintenance immunosuppressive therapy of proliferative LN, as well as nonimmunosuppressive
therapies, will be reviewed here. The treatment of resistant or relapsing proliferative LN and issues related to
end-stage LN are presented separately. (See "Therapy of resistant or relapsing diffuse or focal proliferative lupus
nephritis" and "End-stage renal disease due to lupus nephritis".)
RISK FACTORS FOR PROGRESSION Even with aggressive therapy, some patients with proliferative lupus
nephritis (LN) will have a progressive decline in renal function leading to end-stage renal disease (ESRD).
Clinical risk factors for progression, evident at the time of initial presentation, include an elevated serum
creatinine, hypertension, nephrotic range proteinuria, anemia with a hematocrit below 26 percent, and black and
Hispanic race and ethnicity [4-7]. (See 'Race and ethnicity' below.)
The severity of acute and chronic tubulointerstitial disease and interstitial inflammation as well as the presence of
cellular crescents also correlate with long-term prognosis in LN, as they do in many other chronic progressive
glomerular diseases [5,6,8,9]. (See "Secondary factors and progression of chronic kidney disease", section on
'Tubulointerstitial fibrosis'.)
Risk factors for progression that become evident after initial presentation and during therapy are the frequency
and severity of relapses (renal flares) and the degree to which the abnormal features of renal involvement are
controlled (complete or partial response of proteinuria, hematuria, and the severity of azotemia) (see 'Failure to
achieve a clinical response' below). A complete renal response based upon these clinical criteria may or may not
correspond to a histologic complete remission.
Delayed therapy The likelihood of a successful initial outcome is greater if therapy for LN is initiated relatively
early in the course of the disease. Delaying therapy because of presumed mild disease can be associated with
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increased glomerular injury, progressive tubulointerstitial fibrosis, glomerulosclerosis, and therefore a lesser
response to immunosuppressive drugs [6,10,11].
Patients with persistent, relapsing, or remitting mild hematuria and/or subnephrotic proteinuria often have a
"smoldering" but active disease that causes progressive renal injury [4]. At first, there may be little or no elevation
in the serum creatinine since adaptive glomerular hyperfiltration in the less involved nephrons can initially
maintain the glomerular filtration rate (GFR) despite marked nephron loss [12].
In contrast, prompt diagnosis after the onset of nephritis and subsequent initiation of appropriate therapy are
associated with improved outcomes, regardless of the histologic subclass [6,11]. This issue was addressed in a
study of 91 patients with LN who were followed for a median of six years [11]. There was a much higher rate of
ESRD among patients who had clinically recognized renal disease for greater than or equal to six months prior to
biopsy (47 versus 14 per 1000 patient-years in patients who had an earlier biopsy; hazard ratio [HR] 9.3, 95% CI
1.8-47).
Failure to achieve a clinical response A better long-term prognosis is associated with attaining complete
response of active proliferative LN. Either a complete or partial response is associated with an improved
outcome compared with no response. Partial response is associated with a much greater likelihood of a
subsequent relapse than complete response, and therefore also with a poorer long-term outcome than in those
who achieve a complete response. The criteria used to determine a clinical response are discussed below. (See
'Goal of immunosuppressive therapy' below and 'Complete response versus complete remission' below.)
The importance of attaining a complete response was illustrated in a report from the Lupus Nephritis
Collaborative Study Group of 86 patients with severe LN [13]. The 43 percent of patients who attained a
complete response (ie, an inactive urine sediment, a serum creatinine 1.4 mg/dL [124 micromol/L], and protein
excretion 330 mg/day) had much higher renal survival rates at five years (94 versus 46 percent) and at 10 years
(94 versus 31 percent), compared with those who did not attain a complete response. Improvement was also
noted in patient survival (95 versus 60 percent at 10 years). Similar findings have been reported by others
[14,15].
The value of partial response was demonstrated in a 10-year study of 86 adults with severe LN that evaluated
the correlation among clinical outcomes and partial response (a 50 percent reduction in proteinuria to less than
1.5 g/day and stable serum creatinine), complete response, and no response [14]. Compared with no response,
partial response was associated with significantly higher rates of renal (45 versus 19 percent) and patient (76
versus 46 percent) survival. As in the above study, the best outcomes were observed in those who attained
complete response (renal and patient survival of 94 and 96 percent, respectively).
Features generally predictive of attaining complete response are stable renal function after four weeks on
therapy, lower chronicity index on renal biopsy, white race, and lower baseline proteinuria and serum creatinine
concentration [16]. On the other hand, male gender and earlier development of nephritis from the time of
diagnosis of lupus may be associated with a lower likelihood of sustained complete response [17].
Relapses Relapses of LN (whether nephritic flares [characterized by hematuria and a rise in serum
creatinine] or proteinuric flares [characterized by increased proteinuria with a stable serum creatinine]) and lack
of response to therapy are associated with an increased risk of progressive chronic kidney disease [13,18-20].
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The following examples illustrate the range of findings:


In a series of 70 patients, the likelihood of doubling of the serum creatinine was increased in patients with
nephritic relapses (relative risk 6.8), particularly when the relapses were associated with an acute elevation
in serum creatinine (relative risk 27) [19]. Relapses tend to occur within the first five years after induction
therapy. The average relapse rate is about 8 per 100 patient-years of follow-up but depends upon the nature
of the maintenance therapy and whether a complete or partial response was obtained during induction
therapy.
In a series of 53 patients with LN who experienced a flare, 36 had a poor outcome during a median of six
years (22 developed a new sustained increase in serum creatinine, and 14 had a sustained increase in
creatinine above a previously elevated baseline) [20]. A poor outcome occurred in 29 of 38 patients who had
a proteinuric flare (76 percent) and in 7 of 15 patients who had a nephritic flare (47 percent).
The high risk of relapse provides the rationale for extended (maintenance) immunosuppressive therapy. (See
'Extended (maintenance) therapy' below.)
Class of lupus nephritis The prognostic and therapeutic significance of the degree of activity (active
inflammation) and chronicity (glomerular scarring, tubulointerstitial fibrosis, and atrophy) in diffuse LN has been
somewhat controversial [8,21-23]. (See "Diagnosis and classification of renal disease in systemic lupus
erythematosus", section on 'Classification'.)
Although some investigators have proposed that high levels of chronicity are associated with progressive renal
failure that is less likely to respond to immunosuppressive therapy [8], others have noted that the degree of
activity and chronicity are often similar in patients who progress to renal failure and in those who maintain stable
renal function [23]. The limited utility of these features is in part due to the subjective nature of their determination
and to potential sampling errors [23].
Studies based upon the 2004 International Society of Nephrology/Renal Pathology Society (ISN/RPS)
classification system are likely to help clarify the usefulness of the new subclasses defined by the presence or
absence of active and chronic lesions. Conflicting findings have been reported in retrospective studies. Little
clinical or prognostic difference between the IV-S (segmental) and IV-G (global) subgroups was reported in some
studies, whereas another study noted worse 10-year renal survival in those with persistent class IV-G biopsy
findings after treatment [24-27].
In addition, some investigators postulate that class IV-G (A [active lesions present]) will have the best prognosis
with immunosuppressive regimens, while class IV-S (A/C [both active and chronic lesions present]) will be less
responsive [28]. At present, we do not routinely use these indices to guide therapeutic decisions or to risk stratify
patients.
The following clinical correlations are based largely upon the previous characterization of class IV disease, which
is most closely associated with classes IV-G (A and A/C) and IV-S (A and A/C) disease:
In a pilot study of 135 class IV biopsies, global and segmental diffuse nephritis was observed in 65 and 35
percent of cases, respectively [21].

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Despite effective immunosuppressive therapy, progressive scarring can occur over a period of years after
the inflammation has resolved. This late decline in function is generally associated with a bland urine
sediment and, on renal biopsy, marked scarring with little or no active inflammation. (See "Diagnosis and
classification of renal disease in systemic lupus erythematosus", section on 'Advanced sclerosing lupus
nephritis (class VI)'.)
Race and ethnicity A number of studies have noted worse outcomes in black (African-American or AfricanCaribbean) and Hispanic patients compared with non-Hispanic white patients [5,16,18,29-34]. The following
observations illustrate the range of findings:
In a report from the Glomerular Disease Collaborative Network, for example, the renal survival rate after
cyclophosphamide therapy for diffuse proliferative LN was 95 percent at five years in white patients
compared with 79 percent at one year and 58 percent at five years in black patients [29]. This difference
was independent of other risk factors such as age, hypertension, and the activity or chronicity index. Similar
findings were reported from the Lupus Nephritis Collaborative Study Group of 86 patients with severe LN
[16]. At 10 years, blacks had, compared with whites, significantly lower rates of renal survival (38 versus 68
percent) and patient survival (59 versus 81 percent).
In a retrospective study of 213 patients with LN, doubling of the serum creatinine or the development of
ESRD was significantly higher among both black and Hispanic patients compared with non-Hispanic white
patients at a mean follow-up of 37 months (31 and 18 versus 10 percent, respectively) [32].
The adverse outcomes in black and Hispanic patients may be due to socioeconomic factors, biologic-genetic
factors, and/or more severe disease at disease onset [16,29-32,35,36].
NONIMMUNOSUPPRESSIVE THERAPY Late progression in lupus nephritis (LN), as with any form of chronic
kidney disease, is often due at least in part to nonimmunologic factors such as intraglomerular hypertension
[12,37,38]. Chronic kidney disease is also associated with a marked increase in coronary heart disease morbidity
and mortality. (See "Secondary factors and progression of chronic kidney disease" and "Chronic kidney disease
and coronary heart disease".)
As a result, patients with chronic kidney disease are typically treated with the following regimen:
Aggressive antihypertensive and, in patients with proteinuria, antiproteinuric therapy with blockade of the
renin-angiotensin system (eg, angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor
blocker [ARB]). Goal blood pressure and goal protein excretion are discussed elsewhere. (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on
'Effect of renin-angiotensin system inhibitors on progression of CKD' and "Antihypertensive therapy and
progression of nondiabetic chronic kidney disease in adults", section on 'Proteinuria goal' and
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on
'Blood pressure goal'.)
Lipid lowering with statin therapy, since chronic kidney disease is a risk factor for cardiovascular morbidity
and mortality. In addition, there is weak and inconsistent evidence that statins may slow the progression of
the underlying renal disease. (See "Prevention of cardiovascular disease events in those with established
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disease or at high risk" and "Statins and chronic kidney disease" and "Chronic kidney disease and coronary
heart disease".)
PRINCIPLES OF IMMUNOSUPPRESSIVE THERAPY Immunosuppressive therapy for proliferative lupus
nephritis (LN) consists of induction and maintenance phases:
Initial (induction) therapy involves the administration of potent immunosuppressive drugs to achieve a renal
response. The duration of the initial therapy period varies; it can be as short as three months or as long as
one year but averages about six months.
Once a renal response is achieved, less aggressive extended (maintenance) immunosuppressive therapy is
given for a prolonged period to prevent relapse. Nonimmunosuppressive therapies are also given to slow
nonimmunologic progression of the renal disease. (See 'Goal of immunosuppressive therapy' below and
'Extended (maintenance) therapy' below.)
Indications Aggressive immunosuppressive therapy is indicated in patients with proliferative LN who are at
high risk for progressive renal failure. This includes virtually all patients with focal or diffuse proliferative
glomerulonephritis. Such patients may also have evidence of lupus membranous nephropathy, but treatment is
directed against the proliferative component of the disease. This recommendation is broadly similar to that made
by the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for glomerulonephritis
[1] and by the American College of Rheumatology (ACR) guidelines for LN [2].
Goal of immunosuppressive therapy The goal of immunosuppressive therapy is resolution of inflammatory
and immunologic activity, with achievement of a complete response. The definition of a complete response is
presented below. (See 'Complete response versus complete remission' below.)
As noted above, failure to achieve a renal response, particularly complete response, is associated with worse
long-term outcomes in patients with proliferative LN. (See 'Failure to achieve a clinical response' above.)
Complete response versus complete remission A clinical "response" is not synonymous with a
histologic "remission". Only a repeat kidney biopsy demonstrating the absence of active inflammatory lesions can
establish a complete remission. Some experts routinely perform kidney biopsies in their patients treated for
proliferative LN (regardless of the clinical response to therapy), and routine biopsies have also been incorporated
into some randomized trials.
However, in common practice, most patients treated for proliferative LN do not undergo repeat kidney biopsy to
determine the histological effects of therapy. Rather, they are typically followed with clinical measures such as
serum creatinine, urine protein excretion, and urine microscopy. These parameters are used to judge the clinical
response to therapy.
There is no consensus definition of complete response in patients with proliferative LN who are treated with
immunosuppressive therapy. Among such patients, cessation of inflammation is often characterized by a
reduction in protein excretion, a reduction in or stabilization of the serum creatinine, and resolution of hematuria,
pyuria, and cellular casts. Thus, most definitions of complete response have incorporated the following elements:
A substantial reduction in urine protein excretion Clinical studies have used various definitions of a
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proteinuria response. The Lupus Nephritis Collaborative Study Group, for example, defined a complete
proteinuria response as protein excretion 0.33 g/day [13]. Large randomized trials such as the Aspreva
Lupus Management Study (ALMS), Lupus Nephritis Assessment With Rituximab (LUNAR), and Abatacept
and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS) trials defined a complete
proteinuria response as 0.5 g/day [39-41], whereas the Euro-Lupus Nephritis Trial (ELNT) used a definition
of <1.0 g/day [42].
Improvement or stabilization of the serum creatinine Renal function in patients with a complete clinical
response has also been defined differently in different studies, including a normal serum creatinine [39], a
serum creatinine <1.2 mg/dL (106 micromol/L) [40], a serum creatinine 1.4 mg/dL (124 micromol/L) [13], or
a serum creatinine within 15 to 25 percent of the baseline value [40,41].
Improvement of the urinary sediment Many but not all definitions of complete response in clinical
studies required an improvement in the urinary sediment. Several studies specified a reduction in the
number of red blood cells (RBC) to 10 high-power field or 5 RBC/high-power field [13,41], whereas others
also required the absence of RBC casts [39].
However, not all successfully treated patients who have a histologic remission have a complete clinical
response. The reasons are as follows:
Proteinuric chronic kidney disease can result from irreversible scarring despite resolution of inflammation
Hematuria may persist for various reasons (for example, cyclophosphamide-induced bladder injury)
The serum creatinine and protein excretion may not return to normal due to irreversible injury during the active
phase of the disease and, as can occur in most forms of proteinuric chronic kidney disease, progressive
glomerulosclerosis with increasing nonnephrotic proteinuria can occur over time in the absence of inflammation
[12]. (See "Secondary factors and progression of chronic kidney disease".)
Although reduced proteinuria is an important marker of a successful response to immunosuppressive therapy,
the maximum reduction in protein excretion is typically seen much later (ie, by many months) than resolution of
the activity of the urine sediment. In several trials of diffuse proliferative LN, proteinuria ranging from 1 to 1.6
g/day after six months of induction therapy was associated with satisfactory long-term renal outcomes [43,44].
Delayed renal recovery after removal of the offending stimulus is well described in other settings. As an example,
studies in patients with drug-induced membranous nephropathy have shown that the average time to resolve
proteinuria is one year after discontinuation of the offending drug, with some patients requiring three years
[45,46]. Similar findings are described among patients with poststreptococcal glomerulonephritis [47]. (See
"Causes and diagnosis of membranous nephropathy" and "Poststreptococcal glomerulonephritis".)
We believe that attaining an inactive urinary sediment (ie, no dysmorphic RBC and no RBC casts) is an essential
component of a complete renal response. However, low-level non-dysmorphic hematuria may persist in patients
with inactive disease due, for example, to cyclophosphamide-induced bladder toxicity, and such patients may
require cystoscopy to exclude cyclophosphamide-induced bladder cancer. Evaluation of the urine sediment by
microscopic examination should be performed by a nephrologist or other clinician experienced in this procedure.
(See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology' and "General toxicity of
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cyclophosphamide in rheumatic diseases", section on 'Bladder toxicity'.)


Pregnant patients Issues related to pregnancy in women with LN and the safety of immunosuppressive
drugs to treat active lupus during pregnancy are discussed in detail separately. (See "Pregnancy in women with
systemic lupus erythematosus" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic
diseases during pregnancy and lactation".)
INITIAL (INDUCTION) THERAPY Initial (induction) therapy refers to the initial intensive therapeutic regimen
given in an attempt to induce a renal response and disease quiescence. We agree with the Kidney Disease:
Improving Global Outcomes (KDIGO) clinical practice guidelines, American College of Rheumatology (ACR), and
the joint European League Against Rheumatism and European Renal Association-European Dialysis and
Transplant Association (EULAR/ERA-EDTA) guidelines that initial therapy should consist of glucocorticoids
combined with either cyclophosphamide or mycophenolate mofetil [1-3]. If, during the first three months of initial
therapy, there is clinical progression of renal disease (eg, worsening serum creatinine and/or proteinuria), the
immunosuppressive agent should be changed (ie, cyclophosphamide changed to mycophenolate mofetil or
mycophenolate mofetil changed to cyclophosphamide).
Initial therapy is followed in almost all patients by a more prolonged period of extended (maintenance) therapy,
designed to reduce the frequency of relapses and minimize treatment-related toxicity. (See 'Extended
(maintenance) therapy' below.)
Approach to initial (induction) therapy For initial therapy in patients with diffuse or focal proliferative lupus
nephritis (LN), we recommend immunosuppressive therapy with either intravenous (or oral) cyclophosphamide or
a mycophenolate mofetil-based regimen. Glucocorticoids are also given as part of the induction regimen. This
recommendation is in general agreement with KDIGO, ACR, and EULAR/ERA-EDTA guidelines [1-3]. The data
supporting our recommendations are discussed below. (See 'Cyclophosphamide' below and 'Mycophenolate
mofetil' below.)
The choice between cyclophosphamide and mycophenolate mofetil depends upon a variety of factors. As
examples:
Ancestry Limited studies suggest that black and Hispanic patients may be more likely to achieve a
response with mycophenolate mofetil [39]. Among such patients, it is important to recognize that long-term
data on the efficacy of mycophenolate mofetil are limited since most of the trials had a follow-up of less than
one year. (See 'Mycophenolate mofetil' below.)
Patient preference Patient preference is important. As an example, a woman of childbearing age may
want to avoid the ovarian toxicity of cyclophosphamide.
There is no consensus about initial dosing and subsequent tapering of glucocorticoids for induction therapy in
patients with LN. Potential regimens are presented below. (See 'Dosing of glucocorticoids' below.)
If a cyclophosphamide-based induction regimen is chosen, our suggestions pertaining to specific dosing are
discussed below. (See 'Dosing of cyclophosphamide' below.)
If a mycophenolate mofetil-based regimen is chosen as initial therapy, the preferred dose is the one used in the
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Aspreva Lupus Management Study (ALMS) trial, which is discussed below. (See 'Mycophenolate mofetil' below.)
Preferred therapy: Glucocorticoids plus either cyclophosphamide or mycophenolate mofetil In patients
with proliferative LN, the preferred immunosuppressive therapy to induce a renal response is either a
combination of glucocorticoids plus cyclophosphamide or glucocorticoids plus mycophenolate mofetil.
Glucocorticoids As discussed later, glucocorticoid therapy alone is associated with significantly lower
long-term efficacy compared with cyclophosphamide plus glucocorticoids for initial therapy. In patients with
severe active disease (eg, acute kidney injury, crescentic glomerulonephritis, severe extrarenal disease),
glucocorticoid therapy is initiated with intravenous pulse methylprednisolone (250 to 1000 mg given over 30
minutes daily for three days) to induce a rapid immunosuppressive effect. Conventional doses of oral prednisone
may be ineffective in these patients, and a response to intravenous cyclophosphamide, which is begun at the
same time as glucocorticoid therapy, is not seen for 10 to 14 days. In patients without severe active disease, we
use conventional doses of oral glucocorticoids (eg, 0.5 to 1 mg/kg per day of prednisone) without a pulse; the
doses are described below.
The benefit of pulse methylprednisolone to induce a rapid response among patients with severe LN is derived
primarily from demonstration of efficacy in patients with rapidly progressive (crescentic) glomerulonephritis of all
causes. (See "Overview of the classification and treatment of rapidly progressive (crescentic)
glomerulonephritis", section on 'Treatment'.)
Dosing of glucocorticoids As noted above, patients with severe active disease should receive pulse
methylprednisolone (usually 500 mg given over 30 minutes daily for two to three days) prior to initiation of oral
glucocorticoids. There is no consensus about the best oral glucocorticoid regimen, and there are no data
suggesting that one regimen is superior to another.
One option is the glucocorticoid taper that was used in the ALMS trial, described below (see 'Mycophenolate
mofetil' below). Oral prednisolone was begun at a dose of 60 mg/day, then tapered every two weeks by 10
mg/day until 40 mg/day was reached. The dose was then tapered by 5 mg/day until 10 mg/day was reached.
Further tapering was allowed if the patient was stable for four weeks. Another option is the tapering regimen
used by the Lupus Nephritis Collaborative Study Group (table 1).
Choosing between cyclophosphamide and mycophenolate mofetil Both cyclophosphamide and
mycophenolate mofetil are preferred agents in the treatment of proliferative LN. Comparative trials do not
establish that one is superior to the other. However, certain factors influence our choice between these two
drugs:
Mycophenolate mofetil is often preferred in black and Hispanic patients since limited data suggest that
mycophenolate mofetil is more effective in such individuals. These findings are presented below. (See
'Mycophenolate mofetil' below.)
We usually prefer mycophenolate mofetil in women of childbearing age since cyclophosphamide may
adversely affect fertility. (See "General principles of the use of cyclophosphamide in rheumatic diseases",
section on 'Infertility risk'.)
Cyclophosphamide A number of clinical trials have demonstrated a benefit of intravenous
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cyclophosphamide plus glucocorticoids compared with glucocorticoids alone or with azathioprine on renal
survival among patients with proliferative LN.
Efficacy of cyclophosphamide Landmark trials performed at the National Institutes of Health (NIH)
compared monthly intravenous cyclophosphamide plus prednisone with azathioprine plus prednisone or
prednisone alone [48,49]. At 10 to 12 years, the probability of avoiding renal failure among survivors was 90
percent with intravenous cyclophosphamide, 60 percent with azathioprine, and 20 percent with prednisone alone
[48]. In the NIH and other trials, the outcomes with azathioprine were better than those with prednisone alone
during the first 10 years of follow-up, but not during longer follow-up, and were clearly inferior to
cyclophosphamide [48,50].
These differences in outcome between intravenous cyclophosphamide plus glucocorticoids and glucocorticoids
alone became apparent after several years. In one of the NIH trials, for example, treatment failure (defined as
doubling of the serum creatinine, requiring supplemental immunosuppression, or death) was significantly less
likely with combination therapy than with methylprednisolone alone [51]. However, the treatment failure curves
did not diverge until two to three years [51], and the end-stage renal disease (ESRD) curve did not diverge until
five or more years [48].
In a 2004 meta-analysis, cyclophosphamide plus glucocorticoids compared with glucocorticoids alone (most
patients were from NIH trials) significantly reduced the risk of doubling of the serum creatinine in four trials of 228
patients (24 versus 40 percent, risk ratio [RR] 0.59, 95% CI 0.4-0.88), had no effect on mortality in five trials of
226 patients (21 versus 17 percent, RR 0.98, 95% CI 0.53-1.82), and increased the risk of ovarian failure in three
trials of 147 patients (47 versus 19 percent, RR 2.18, 95% CI 1.1-4.34) [50].
As a result of concerns about toxicity, less intensive cyclophosphamide regimens have been evaluated. The
efficacy of less intensive regimens has been evaluated in a number of trials [40,42,44,52,53]. The Euro-Lupus
Nephritis Trial (ELNT), for example, was a comparative trial of primarily white patients with mild to moderate
renal insufficiency (mean serum creatinine 1.15 mg/dL [102 micromol/L]) that showed equivalent outcomes at a
median of 41 months with the shorter (lower-dose, ie, 500 mg intravenously every two weeks for a total of six
doses) and longer (higher-dose) intravenous cyclophosphamide regimens, each followed by maintenance
therapy with azathioprine [42]. The similarity in outcomes persisted at 10 years, regardless of the baseline
severity in renal function [54]. On multivariate analysis, a good early response to therapy was predictive of better
long-term outcomes [55]. This lower dose cyclophosphamide regimen was also effective in the Abatacept and
Cyclophosphamide Combination Efficacy and Safety Study (ACCESS) trial, which included a large proportion of
black and Hispanic patients [40].
Although pulse intravenous cyclophosphamide has been best studied for induction therapy in diffuse proliferative
LN and is most widely used, daily oral cyclophosphamide has also been used [43,52,56], including in a shortcourse regimen followed by azathioprine or cyclosporine maintenance [56].
Dosing of cyclophosphamide If cyclophosphamide is used, most experts prefer to use the shorter
(lower-dose) regimen implemented in the ACCESS and Euro-Lupus Nephritis trials, regardless of the patient's
race and ethnicity, rather than the longer (higher-dose) regimen implemented in the NIH trial. The lower-dose
regimen consists of intravenous cyclophosphamide, 500 mg every two weeks for a total of six doses. In contrast,

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some authorities prefer the longer (higher-dose) NIH regimen when using cyclophosphamide in AfricanAmerican, African-Caribbean, and Hispanic patients, and use the shorter (lower-dose) regimen in non-Hispanic
white patients.
The lack of consensus is due mainly to differing interpretations of the available data, plus the clinical experience
of the authors and editors:
Experts who almost exclusively use the shorter (lower-dose) regimen believe that, although the ELNT
provided inadequate information about the treatment of black and Hispanic patients, the subsequent
ACCESS trial established that the regimen used in the ELNT is effective in these patient subgroups.
In the ELNT, only 9 percent of patients were characterized as African-Caribbean or black [42], and the
majority of those were randomly assigned to longer (higher-dose) therapy; only three African-Caribbean or
black patients received shorter (lower-dose) cyclophosphamide. Because of these limited data in patients of
African and Hispanic descent, some experts hesitate to use a shorter, lower-dose cyclophosphamide
regimen in these patient subgroups.
However, the ACCESS trial provided data that the Euro-Lupus cyclophosphamide regimen may be
efficacious in black and Hispanic patients [40]. The ACCESS trial was conducted in North America, and 37
and 41 percent of the patients were black and Hispanic, respectively. This trial is discussed in detail below.
(See 'Costimulatory blockade with CTLA4-Ig' below.)
Experts who use the longer (higher-dose) regimen in black and Hispanic patients cite clinical experience
that the lower-dose regimen may be inadequate to achieve a response in such patients.
The longer, higher-dose regimen involves pulse intravenous cyclophosphamide (0.5 to 1 g/m2) monthly for six to
seven months. If the leukocyte nadir after the first pulse of cyclophosphamide (usually 10 to 14 days postinfusion) is less than 4000/microL and/or the absolute neutrophil count (ANC) is less than 1500/microL, the dose
at the next infusion should be reduced by 0.25 g/m2 body surface area or even transiently withheld if the counts
are very low. If, on the other hand, the total white cell nadir is greater than 4000/microL, the ANC is greater than
1500/microL, and the patient has not improved, the cyclophosphamide dose at the next infusion may be
increased by 0.25 g/m2 body surface area. The maximum dose is 1 g/m2 body surface area.
As noted above, some authorities use oral rather than intravenous cyclophosphamide. If oral cyclophosphamide
is used, the dose is typically 1.0 mg/kg per day, titrating up to 1.5 mg/kg per day (reduced as needed to maintain
a white blood cell [WBC] count greater than 3000 cells/microL and an ANC greater than 1500 cells/microL),
continued for two to four months.
After initial treatment with cyclophosphamide, extended (maintenance) therapy commences with azathioprine or
mycophenolate mofetil rather than the longer course of cyclophosphamide used in the early NIH trials. (See
'Extended (maintenance) therapy' below.)
Mycophenolate mofetil Mycophenolate mofetil is an alternative to cyclophosphamide as initial therapy
for proliferative LN. Several prospective trials have addressed this issue with mycophenolate being at least
equivalent (but not superior) to cyclophosphamide.

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Efficacy of mycophenolate mofetil The best data are from an international trial (ALMS) that
compared induction therapy with mycophenolate mofetil or cyclophosphamide in 370 patients with LN: diffuse
proliferative LN with or without lupus membranous nephropathy was present in 68 percent; focal proliferative LN
with or without lupus membranous nephropathy in 16 percent; and pure lupus membranous nephropathy in 16
percent [39]. The mean urine protein-to-creatinine ratio was 4.1, and the mean serum creatinine was 1.1 mg/dL
(100 micromol/L).
The following regimens were used:
Mycophenolate mofetil (0.5 g twice daily in week 1, 1 g twice daily in week 2, and a target of 1.5 g twice
daily thereafter or, if not tolerated, 1 g three to two times daily). Mycophenolate mofetil was taken before
meals and with a glass of water.
Monthly intravenous cyclophosphamide (0.75 g/m2 first dose, followed by five infusions of 0.5 to 1 g/m2).
All patients were also treated with oral daily glucocorticoids (using prednisolone or an equivalent dose of
another preparation). The prednisolone regimen used in this trial is presented above. (See 'Dosing of
glucocorticoids' above.)
The primary outcome was a prespecified reduction in the urine protein-to-creatinine ratio to less than 3 or by at
least 50 percent. Secondary outcomes included stabilization or improvement of the serum creatinine, reduction
of protein excretion to less than 0.5 g/day, and attainment of an inactive urinary sediment.
At 24 weeks, there was no difference between groups in the percentage of patients who achieved the primary
endpoint or secondary endpoints (56 versus 53 percent), in the response rate between patients with focal or
diffuse proliferative LN and those with lupus membranous nephropathy, or in the rate of adverse effects. In a
post-hoc analysis, mycophenolate mofetil therapy was associated with a significantly higher response rate in
black and Hispanic patients (60 versus 39 percent, odds ratio [OR] 2.4, 95% CI 1.1-5.4) [57]. Worse outcomes
associated with cyclophosphamide in blacks were also observed in another study [29], although other
investigators found no racial differences in the response to cyclophosphamide [58].
In a meta-analysis that included 45 trials involving 2846 patients, there were no significant differences between
cyclophosphamide- and mycophenolate mofetil-based induction therapy with respect to mortality, incidence of
ESRD, and relapse during induction [59,60]. However, mycophenolate mofetil produced a numerically higher rate
of complete responses (19.5 versus 13.8 percent), although this was not statistically significant. Major infections
were also similar with both drugs, but mycophenolate mofetil therapy resulted in less ovarian failure and
alopecia.
The findings from these trials and the meta-analyses of these trials suggest that, compared with
cyclophosphamide, a mycophenolate mofetil induction regimen provides similar efficacy. In addition, limited data
suggest that mycophenolate mofetil may be more effective than cyclophosphamide and therefore preferred in
black and Hispanic patients [29,57], although this is based upon post-hoc analysis.
There are several limitations to the findings in the mycophenolate mofetil trials [61]. As an example, the duration
of follow-up was short (6 to 12 months) in most of the trials [39,62]. This important limitation is highlighted by
previous studies comparing cyclophosphamide plus glucocorticoids with glucocorticoids alone; in those trials
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[51], the advantage of cyclophosphamide therapy in preserving kidney function was not observed for three to five
years. Thus, longer follow-up is required to determine whether renal outcomes are similar between
mycophenolate mofetil and cyclophosphamide.
Dosing of mycophenolate mofetil If mycophenolate mofetil is used, we prefer the regimen used in
the ALMS trial [39]. Specifically, we give 0.5 g of mycophenolate mofetil twice daily for the first week, then 1 g
twice daily for the second week, and thereafter increase the dose to 1.5 g twice daily. If 1.5 g twice daily is not
tolerated, we change the dosing schedule to 1 g thrice daily; if still not tolerated, we reduce the dose to 1 g twice
daily. We usually continue mycophenolate mofetil at these doses for six months.
Monitoring patients during initial (induction) therapy During initial (induction) immunosuppressive
therapy, we typically schedule follow-up visits every two to four weeks for the first three months. In stable
patients, the duration between follow-up visits can then be extended to every two to three months. The goal of
these visits is to evaluate the patient's response to therapy (ie, whether or not a clinical response is achieved)
and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression) (see 'Goal of
immunosuppressive therapy' above). The following data are obtained during these visits:
History and physical examination
Quantification of urine protein excretion (usually with a urine protein-to-creatinine ratio, but some experts
occasionally perform a 24 hour urine)
Serum creatinine (as well as a basic metabolic profile)
Urinalysis (with microscopy)
Serum complement levels (C3 and C4)
Complete blood count (which is monitored weekly in patients receiving higher-dose cyclophosphamide) and
liver function tests
Some authorities also monitor anti-DNA antibody levels
Preventing toxicity Immunosuppressive therapy with cyclophosphamide, mycophenolate mofetil, and/or
high-dose glucocorticoids has both infectious and noninfectious toxicities that warrant prophylaxis. The
recommended regimens are discussed elsewhere:
For prevention of Pneumocystis pneumonia
For prevention of cyclophosphamide-induced bladder and gonadal toxicity
For minimizing glucocorticoid-induced bone loss and other adverse effects (see "Prevention and treatment
of glucocorticoid-induced osteoporosis" and "Major side effects of systemic glucocorticoids")
Patients who are resistant to initial therapy A significant number of patients fail to achieve any response to
initial induction treatment. In general, we treat cyclophosphamide-resistant patients with mycophenolate mofetil,
and mycophenolate mofetil-resistant patients with cyclophosphamide. Treatment-resistant LN is discussed in

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detail elsewhere. (See "Therapy of resistant or relapsing diffuse or focal proliferative lupus nephritis".)
Less preferred therapies Calcineurin inhibitors (such as tacrolimus), B cell-directed therapies such as
rituximab, and costimulatory blockers such as abatacept have been examined as induction therapies in patients
with LN. However, cyclophosphamide and mycophenolate mofetil remain the preferred agents.
Tacrolimus Tacrolimus has been compared with both intravenous cyclophosphamide and mycophenolate
mofetil as induction therapy in trials of Chinese patients with LN. Largely due to short-term follow-up, these
limited data are insufficient to support the use of tacrolimus as induction therapy for severe LN, except possibly
for patients who cannot tolerate either cyclophosphamide or mycophenolate mofetil, or in patients who are
pregnant. (See 'Patients with both diffuse proliferative LN and lupus membranous nephropathy' below.)
The following trials are illustrative:
A "multitarget" regimen that combined use of tacrolimus (4 mg/day), low-dose mycophenolate mofetil (1
g/day), and prednisone was compared with cyclophosphamide (using the high-dose regimen discussed
above) and prednisone in 368 patients with LN (47 percent with proliferative LN, 19 percent with lupus
membranous nephropathy, and 34 percent with both) [63] (see 'Dosing of cyclophosphamide' above). At 24
weeks, the rate of complete response, defined as 24-hour urine protein of 0.4 g or less, serum albumin of
3.5 g/dL or more, normal serum creatinine, and absence of an active urine sediment, was significantly
greater in the multitarget group (46 versus 26 percent). The overall response rate (complete or partial
response) was also significantly higher with multitarget therapy (84 versus 63 percent). Serious adverse
events, particularly infections, were more common with multitarget therapy (7 versus 3 percent), as was
dropout due to adverse events (6 versus 2 percent). This study is limited by the lack of long-term follow-up
of kidney function and by the fact that tacrolimus can reduce proteinuria through a hemodynamic
mechanism (which may be unrelated to immunologic recovery). This effect of tacrolimus is important
because all of the patients in this trial had a normal serum creatinine at baseline, and therefore, proteinuria
reduction without immunological recovery could have been classified as a response.
Tacrolimus was compared with intravenous cyclophosphamide for induction therapy in a multicenter
noninferiority trial that included 61 Chinese patients with focal or diffuse proliferative LN [64]. Patients
received glucocorticoids plus either tacrolimus (titrated to a trough level of 5 to 10 ng/mL) or
cyclophosphamide (500 to 1000 mg/m2 monthly for six pulse treatments). At six months, there was no
difference among groups in the number who achieved complete response (defined as protein excretion less
than 300 mg/day, normal urinalysis, and stable kidney function).
In a similar study, 60 Chinese patients with focal or diffuse proliferative LN or membranous lupus were
randomly assigned to induction therapy with glucocorticoids combined with tacrolimus, mycophenolate
mofetil, or cyclophosphamide [65]. There were no differences in the proportion who achieved complete or
partial response and no differences in the occurrence of adverse events, although the duration of follow-up
was short (six months).
Rituximab The effect of rituximab therapy combined with glucocorticoids and mycophenolate mofetil for
induction therapy in proliferative LN was evaluated in the multinational Lupus Nephritis Assessment with
Rituximab (LUNAR) study [41]. Patients (n = 144) with class III or class IV LN were randomly assigned to receive
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an intravenous infusion of placebo or 1 g of rituximab on baseline and at 2, 24, and 26 weeks. All patients also
received mycophenolate mofetil 1 g given three times daily for at least 52 weeks, intravenous
methylprednisolone 1000 mg given twice during the first three days of therapy, and a tapering dose of
prednisone. Patients were followed for 52 weeks for the occurrence of complete or partial response. The
following findings were noted:
The incidence of complete or partial response was numerically higher with rituximab as compared with
placebo (57 versus 46 percent), but this difference was not statistically significant.
Rituximab produced greater reductions in anti-DNA titers and larger improvements in complement levels as
compared with placebo.
Two patients died, both in the rituximab group, although these were not considered to be related to
rituximab. The frequency of serious infections and hospitalizations, at least over the short term, were similar
with rituximab and placebo.
Thus, there are insufficient data to support the use of rituximab as initial induction therapy for proliferative LN.
The use of rituximab in patients with resistant or relapsing LN is discussed elsewhere. (See "Therapy of resistant
or relapsing diffuse or focal proliferative lupus nephritis", section on 'Rituximab for cyclophosphamide and MMF
resistance'.)
Costimulatory blockade with CTLA4-Ig CTLA4-Ig (abatacept) is a fusion protein that binds CD80 (B7-1)
and CD86 (B7-2) on antigen-presenting cells, thereby acting as a competitive inhibitor of the CD28-B7 T cell
costimulation. Abatacept is effective in the treatment of rheumatoid arthritis and has also been evaluated for the
treatment of systemic lupus erythematosus (SLE). (See "T-cell targeted therapies for rheumatoid arthritis",
section on 'Abatacept' and "Overview of the management and prognosis of systemic lupus erythematosus in
adults", section on 'Other therapies'.)
There are insufficient data to support the use of abatacept in the initial treatment of proliferative LN. Abatacept
has been studied as add-on therapy in the following trials:
In the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study (ACCESS) trial, 134
patients with active class III or IV LN (48 percent also had class V) were treated with cyclophosphamide and
glucocorticoids in combination with either abatacept or placebo [40]. All patients received six 500 mg doses
of intravenous cyclophosphamide at two-week intervals and oral glucocorticoids (tapered to 10 mg/day by
week 12), similar to the Euro-Lupus regimen described above (see 'Dosing of cyclophosphamide' above),
followed by 2 mg/kg/day of azathioprine until week 24. Patients assigned to the treatment group received
monthly infusions of abatacept (500 to 750 mg, depending upon the weight of the patient), and those
assigned to the control group received placebo infusions. Most patients who had a complete or partial
response at 24 weeks continued therapy with glucocorticoids, azathioprine, and, among those originally in
the treatment group, abatacept until week 52; however, patients in the treatment group who had a complete
response at 24 weeks were continued only on low-dose oral glucocorticoids.
Abatacept did not produce any significant benefits as compared with placebo. The rate of complete
response at 24 weeks (ie, urine protein-to-creatinine ratio less than 0.5, serum creatinine of 1.2 mg/dL [106
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micromol/L] or less or within 125 percent of baseline, and successful taper of prednisone to 10 mg/day by
week 12) was 33 percent with abatacept and 31 percent with placebo. The rate of total response (complete
or partial) was identical (59 percent in both groups). At one year, the total response rate was 64 percent in
the abatacept group and 68 percent in the placebo group. Adverse events were similar between the two
groups.
In another trial, 298 patients with class III or IV LN were treated with mycophenolate mofetil and
glucocorticoids dosed similarly to the ALMS trial (see 'Mycophenolate mofetil' above) and then randomly
assigned to placebo, standard-dose abatacept (10 mg/kg), or higher-dose abatacept (30 mg/kg initially
followed by 10 mg/kg) [66]. All therapies were continued for 52 weeks; abatacept was given at baseline, two
weeks, four weeks, and then monthly for the remainder of the year. As with the ACCESS trial, abatacept
therapy did not result in any additional benefit. Both doses of abatacept were associated with a higher
incidence of infection (especially herpes zoster and gastroenteritis).
Patients with both diffuse proliferative LN and lupus membranous nephropathy Patients with combined
diffuse proliferative LN and lupus membranous nephropathy have a worse prognosis than those with diffuse
proliferative disease alone, which has raised the possibility that such patients may benefit from more intensive
therapy. These observations led to a clinical trial of 40 patients that showed significantly better outcomes with
mycophenolate mofetil plus tacrolimus compared with intravenous cyclophosphamide; all patients were treated
with glucocorticoids. Because 26 of the 40 patients had previously been treated with cyclophosphamide or
mycophenolate mofetil, we have elected to present the data in the topic on resistant or relapsing disease. (See
"Therapy of resistant or relapsing diffuse or focal proliferative lupus nephritis", section on 'Diffuse proliferative LN
plus lupus membranous nephropathy'.)
EXTENDED (MAINTENANCE) THERAPY Up to 50 percent of patients with proliferative lupus nephritis (LN)
relapse following reduction in or cessation of immunosuppressive therapy [67-72]. The relapse rates range from
5 to 15 per 100 patient-years, with an average of about 8 per 100 patient-years for the first five years of follow-up
[72]. Relapse is more common when partial rather than complete response is obtained with induction therapy.
Thus, once a patient has attained a complete or partial response, immunosuppression is continued to help
maintain the response and decrease the risk of developing end-stage renal disease (ESRD) (maintenance
therapy). This recommendation is consistent with that made by the Kidney Disease: Improving Global Outcomes
(KDIGO) clinical practice guidelines for glomerulonephritis [1]. (See "Therapy of resistant or relapsing diffuse or
focal proliferative lupus nephritis", section on 'Relapsing disease'.)
Choice of agent for extended (maintenance) therapy The two most commonly used drugs for maintenance
therapy in patients with LN are mycophenolate mofetil and azathioprine. In general, we prefer mycophenolate
mofetil as a maintenance agent rather than azathioprine or other drugs. The optimal duration of maintenance
therapy is not well defined, although durations of 12 to 24 months have been best studied [42,44,56,67,73].
However, azathioprine is preferred in women who have achieved a complete response and want to become
pregnant. Mycophenolate mofetil has a boxed warning because of an increased risk of congenital malformations
and spontaneous abortion. Transitioning such patients from mycophenolate mofetil to azathioprine is unlikely to
result in a flare of nephritis [74]. In addition, we also use azathioprine for maintenance therapy in patients who
are intolerant to mycophenolate mofetil.
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Patients who are intolerant to both mycophenolate mofetil and azathioprine can be treated with cyclosporine. In
one trial, cyclosporine was as effective as azathioprine but was associated with more adverse effects [56].
Preference for mycophenolate mofetil The choice between azathioprine and mycophenolate mofetil, the
two most commonly used agents for maintenance therapy in patients with proliferative LN, was best evaluated in
a meta-analysis of six trials involving 514 patients, three of which compared azathioprine with mycophenolate
mofetil for maintenance therapy [59,60]. Although there were no significant differences in the risk of mortality or
ESRD, mycophenolate mofetil therapy resulted in a significantly lower rate of renal relapse (16.4 versus 30.2
percent). The rate of adverse effects was similar with both drugs. Details of the three trials included in this metaanalysis that compared mycophenolate mofetil with azathioprine are as follows [44,73,75]:
The MAINTAIN Nephritis Trial was a randomized, open-label trial that included 105 European patients (83
Caucasian) with biopsy-proven LN and protein excretion exceeding 500 mg/day [73]. Diffuse proliferative LN
was present in 61, focal proliferative LN in 33, and lupus membranous nephropathy in 11. All patients were
treated with three daily 750 mg doses of intravenous methylprednisolone followed by oral glucocorticoids
plus six 500 mg intravenous doses of cyclophosphamide over 10 weeks. On week 12, maintenance therapy
was initiated with either azathioprine (2 mg/kg per day) or mycophenolate mofetil (2 g/day). Renal relapse
was defined as one or more of the following: recurrence or development of nephrotic syndrome; a 33
percent or greater increase in serum creatinine within one month; or a threefold increase in proteinuria
accompanied by hematuria.
At three years, there was no significant difference between the mycophenolate mofetil and azathioprine
groups in the rate of renal relapse (19 versus 25 percent), systemic flares, or steroid withdrawal. In addition,
protocol biopsies at two years revealed no significant histologic differences between the groups [76].
Adverse events were similar in the two groups except for leukopenia and anemia, which occurred more
frequently in the azathioprine group (14 versus 2 patients).
Ten-year follow-up data from the MAINTAIN trial confirm similar efficacy between mycophenolate mofetil and
azathioprine as maintenance agents. There was no difference in time to renal flare, ESRD, or death
between the mycophenolate mofetil and azathioprine groups [77].
The ALMS Maintenance Trial was a multinational study in which 227 patients who had achieved a renal
response with either mycophenolate mofetil or cyclophosphamide were randomly assigned to
mycophenolate mofetil (1 g twice daily) or azathioprine (2 mg/kg per day) as maintenance therapy for 36
months [78]. Results from the induction phase of the ALMS trial are discussed above. (See 'Mycophenolate
mofetil' above.)
Among patients who responded to induction therapy with either mycophenolate mofetil or
cyclophosphamide, treatment failure at 36 months (defined by renal relapse, the need to intensify therapy,
doubling of the serum creatinine, or death) was significantly lower with mycophenolate mofetil compared
with azathioprine groups (16 versus 32 percent). The superiority of mycophenolate mofetil was independent
of the type of induction therapy, race, or region.
In the third randomized trial, 59 patients with severe LN (46 with diffuse proliferative, 12 with focal

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proliferative, and 1 with membranous lupus) received induction therapy with four to a maximum of seven
consecutive monthly cycles of intravenous pulse cyclophosphamide and glucocorticoids [44]. All but three of
the patients were black or Hispanic, who typically have a worse prognosis than whites and respond less well
to cyclophosphamide [29]. Remission was induced in 83 percent, and patients who remitted early had fewer
cycles of cyclophosphamide. The patients were then randomly assigned to maintenance therapy with one of
the following plus low-dose oral prednisone (0.1 to 0.2 mg/kg per day): mycophenolate mofetil (500 to 3000
mg/day), azathioprine (1 to 3 mg/kg per day), or intravenous cyclophosphamide (0.5 to 1 g/m2 every three
months). The median treatment duration was 24, 29, and 30 months for the cyclophosphamide,
mycophenolate mofetil, and azathioprine groups, respectively.
The primary endpoints were renal and patient survival. At six-year follow-up, the event-free survival rate for
the composite endpoint for patient and renal survival was significantly higher with mycophenolate mofetil
and azathioprine compared with cyclophosphamide (90 and 80 versus 45 percent), which was also
associated with more infections and a higher incidence of amenorrhea. Seventeen patients (29 percent) had
a renal relapse (three, six, and eight patients in the mycophenolate mofetil, azathioprine, and
cyclophosphamide groups, respectively). The relapse rate was significantly higher with cyclophosphamide
compared with mycophenolate mofetil.
In summary, mycophenolate mofetil compared with azathioprine is associated with a statistically and clinically
significant reduction in relapse rate, and no increase in adverse effects.
Approach to extended (maintenance) therapy We recommend continuing immunosuppression (ie,
extended therapy, maintenance therapy) in patients who achieve a complete or partial response with initial
therapy. Patients who do not achieve a complete or partial response are discussed separately. (See "Therapy of
resistant or relapsing diffuse or focal proliferative lupus nephritis".)
In patients who receive intravenous cyclophosphamide as initial therapy, extended (maintenance) therapy is
started two to four weeks after the last dose of cyclophosphamide when the following criteria are met: the white
blood cell (WBC) count is >3000 cells/microL, and the absolute neutrophil count (ANC) is >1500 cells/microL.
The risk of infection is increased when the ANC is less than 1000 cells/microL (table 2). The ANC is equal to the
product of the total WBC count and the fraction of polymorphonuclear cells and band forms noted on the
differential analysis (calculator 1). In patients who receive oral cyclophosphamide as initial therapy, we initiate
extended therapy immediately after discontinuation of cyclophosphamide, provided the WBC count is >3000
cells/microL and the ANC is >1500 cells/microL.
In patients who receive mycophenolate mofetil as initial therapy, the dose of mycophenolate mofetil is gradually
lowered over time, usually starting after six months of therapy at the initial dose. The long-term dose of
mycophenolate is usually lower than the initial dose. As an example, the long-term dose is often 1000 to 2000
mg/day, whereas the initial dose is often 2000 to 3000 mg/day.
Dosing and duration of extended (maintenance) therapy Our approach to dosing and duration of extended
(maintenance) therapy is based upon the protocols used in the trials presented above (see 'Preference for
mycophenolate mofetil' above):
The usual extended therapy dose of mycophenolate mofetil is 1000 mg twice daily. The dose may be
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tapered over time in stable patients. In one trial, the mycophenolate mofetil dose was 1500 mg/day in the
first year, 1000 to 1250 mg/day in the second year, and 500 to 1000 mg/day in the third year [44].
The azathioprine dose is 2 mg/kg per day to a maximum of 150 to 200 mg/day.
The duration of extended therapy is 18 to 24 months or longer, and some expert panels suggest that
extended therapy be continued for three years or longer [3].
Glucocorticoid therapy during extended (maintenance) therapy Low-dose oral prednisone (or its
equivalent) is continued in most patients receiving extended (maintenance) therapy. The goal is to attain the
minimum prednisone dose required for control of extrarenal symptoms, which varies among patients. In different
trials, the extended prednisone dose ranged from 0.05 to 0.2 mg/kg per day [42,44,56,67].
Patients who remain asymptomatic can be slowly tapered off prednisone. Once the prednisone dose reaches 5
mg/day, tapering should proceed at a rate of 1 mg/day reduction in dose every four weeks. However, some
clinicians prefer prolonged low-dose prednisone therapy (eg, 5 mg/day or less).
Monitoring patients during extended (maintenance) therapy Once patients are transitioned from their
initial to their extended (maintenance) immunosuppressive regimen, we generally perform follow-up visits every
three months to determine whether or not the patient is experiencing a flare or toxicity from therapy. The
following are components of these visits:
History and physical examination
Quantification of urine protein excretion (usually a urine protein-to-creatinine ratio)
Serum creatinine
Urinalysis (with microscopy)
Complement levels (C3 and C4)
Laboratory studies to monitor for drug toxicity (eg, a complete blood count and liver function tests)
Some authorities also monitor anti-DNA antibody levels
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
Basics topic (see "Patient education: Lupus and kidney disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
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Even with aggressive therapy, many patients with proliferative lupus nephritis (LN) will have a progressive
decline in renal function leading to end-stage renal disease (ESRD). Clinical risk factors for progression,
evident at the time of initial presentation, include an elevated serum creatinine, hypertension, nephrotic
range proteinuria, anemia, black and Hispanic race and ethnicity, and the severity of acute and chronic
tubulointerstitial disease and interstitial inflammation as well as the presence of cellular crescents. Risk
factors for progression that become evident after initial presentation and during therapy are the absence of a
complete or partial clinical response and the frequency and severity of relapses (renal flares). Delaying
therapy because of presumed mild disease is also associated with adverse outcomes. (See 'Risk factors for
progression' above.)
Late progression in LN, as with any form of chronic kidney disease, is often due at least in part to
nonimmunologic factors such as intraglomerular hypertension. Chronic kidney disease is also associated
with a marked increase in coronary heart disease morbidity and mortality. As a result, patients with LN who
have chronic kidney disease are often treated with antihypertensive therapy, usually with and angiotensinconverting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and with lipid lowering using a
statin. (See 'Nonimmunosuppressive therapy' above.)
Aggressive immunosuppressive therapy is indicated in patients with proliferative LN who are at high risk for
progressive renal failure. This includes virtually all patients with focal or diffuse proliferative
glomerulonephritis. The goal of immunosuppressive therapy is resolution of inflammatory and immunologic
activity, with achievement of a complete clinical response. (See 'Principles of immunosuppressive therapy'
above.)
Immunosuppressive therapy for proliferative LN consists of initial (induction) and extended (maintenance)
therapy. Initial therapy refers to the initial intensive therapeutic regimen given in an attempt to induce a renal
response and disease quiescence. Initial therapy is followed in almost all patients by a more prolonged
period of extended (maintenance) therapy, designed to reduce the frequency of relapses, and minimize
treatment-related toxicity. (See 'Principles of immunosuppressive therapy' above.)
For initial therapy in patients with diffuse or focal proliferative LN, we recommend immunosuppressive
therapy with glucocorticoids plus either intravenous (or oral) cyclophosphamide or mycophenolate mofetil,
rather than other immunosuppressive regimens such as glucocorticoid monotherapy or azathioprine (Grade
1A). The choice between cyclophosphamide and mycophenolate mofetil depends in part upon a variety of
factors, including ancestry and patient preference. We usually prefer mycophenolate mofetil in black and
Hispanic patients, and also in women of childbearing age. (See 'Approach to initial (induction) therapy'
above and 'Glucocorticoids' above and 'Choosing between cyclophosphamide and mycophenolate mofetil'
above.)
In patients with severe active disease (eg, acute kidney injury, crescentic glomerulonephritis, severe
extrarenal disease), glucocorticoid therapy is initiated with intravenous pulse methylprednisolone (250
mg to 1000 mg given over 30 minutes daily for three days) to induce a rapid immunosuppressive effect,
followed by conventional doses. In patients without severe active disease, we use conventional doses
of oral glucocorticoids (eg, 0.5 to 1 mg/kg per day of prednisone) without a pulse. There is no
consensus about the best oral glucocorticoid regimen. One option is oral prednisolone at a dose of 60
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mg/day, tapered every two weeks by 10 mg/day until 40 mg/day is reached, then tapered by 5 mg/day
until 10 mg/day is reached. Another option is the tapering described in the table (table 1).
If cyclophosphamide is used instead of mycophenolate mofetil as initial therapy, most experts give
intravenous cyclophosphamide, 500 mg every two weeks for a total of six doses. However, some
authorities prefer a longer (higher-dose) regimen consisting of pulse intravenous cyclophosphamide
(0.5 to 1 g/m2) monthly for six to seven months. Oral cyclophosphamide is also occasionally used.
If mycophenolate mofetil is used instead of cyclophosphamide as initial therapy, we give 0.5 g of
mycophenolate mofetil twice daily for the first week, then 1 g twice daily for the second week, and
thereafter increase the dose to 1.5 g twice daily. If 1.5 g twice daily is not tolerated, we change the
dosing schedule to 1 g thrice daily; if still not tolerated, we reduce the dose to 1 g twice daily. We
usually continue mycophenolate mofetil at these doses for six months.
During initial (induction) immunosuppressive therapy, we typically schedule follow-up visits every two to four
weeks for the first three months. In stable patients, the duration between follow-up visits can then be
extended to every two to three months. The goal of these visits is to evaluate the patient's response to
therapy (ie, whether or not a clinical response is achieved) and the toxicity of the regimen (ie, adverse
effects, infections due to immunosuppression). (See 'Monitoring patients during initial (induction) therapy'
above.)
A significant number of patients fail to achieve an adequate response to initial treatment. In general, we treat
cyclophosphamide-resistant patients with mycophenolate mofetil, and mycophenolate mofetil-resistant
patients with cyclophosphamide. (See "Therapy of resistant or relapsing diffuse or focal proliferative lupus
nephritis".)
We continue immunosuppression (ie, extended [maintenance] therapy) in patients who achieve a complete
or partial response with initial therapy. In patients who receive intravenous cyclophosphamide as initial
therapy, extended (maintenance) therapy is started two to four weeks after the last dose of
cyclophosphamide when the following criteria are met: the white blood cell (WBC) count is >3000
cells/microL, and the absolute neutrophil count (ANC) is >1500 cells/microL. The risk of infection is
increased when the ANC is less than 1000 cells/microL (table 2). In patients who receive oral
cyclophosphamide as initial therapy, we initiate extended therapy immediately after discontinuation of
cyclophosphamide, provided the WBC count is >3000 cells/microL and the ANC is >1500 cells/microL. In
patients who receive mycophenolate mofetil as initial therapy, the dose of mycophenolate mofetil is
gradually lowered over time, usually starting after six months of therapy at the initial dose. The long-term
dose of mycophenolate is usually lower than the initial dose. (See 'Extended (maintenance) therapy' above
and 'Approach to extended (maintenance) therapy' above.)
The two most commonly used drugs for extended (maintenance) therapy in patients with LN are
mycophenolate mofetil and azathioprine. For patients who achieve a complete or partial response with
cyclophosphamide or mycophenolate mofetil, we recommend extended therapy with mycophenolate mofetil
rather than other agents, such azathioprine or cyclosporine (Grade 1B). The usual mycophenolate mofetil
dose is 1000 mg twice daily. However, azathioprine is preferred in women who have achieved a complete

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response and want to become pregnant. In addition, we also use azathioprine for maintenance therapy in
patients who are intolerant to mycophenolate mofetil. Patients who are intolerant to both mycophenolate
mofetil and azathioprine can be treated with cyclosporine. The duration of extended therapy is 18 to 24
months or longer, and some expert panels suggest that extended therapy be continued for three years or
longer. (See 'Choice of agent for extended (maintenance) therapy' above and 'Dosing and duration of
extended (maintenance) therapy' above.)
Low-dose oral prednisone (or its equivalent) is continued in most patients receiving extended therapy. The
goal is to attain the minimum prednisone dose required for control of extrarenal symptoms, which varies
among patients. Patients who remain asymptomatic can be slowly tapered off prednisone. Once the
prednisone dose reaches 5 mg/day, tapering should proceed at a rate of 1 mg/day reduction in dose every
four weeks. (See 'Glucocorticoid therapy during extended (maintenance) therapy' above.)
Once patients are transitioned from their initial to their extended immunosuppressive regimen, we generally
perform follow-up visits every three months to determine whether or not the patient is experiencing a flare or
toxicity from therapy. (See 'Monitoring patients during extended (maintenance) therapy' above.)
ACKNOWLEDGMENT UpToDate would like to thank Dr. Peter Schur, who contributed to earlier versions of
this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. KDIGO. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl 2012; 2:209.
http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-GN-Guideline.pdf (Accessed on December
23, 2013).
2. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening,
treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64:797.
3. Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European
Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations
for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012; 71:1771.
4. Appel GB, Cohen DJ, Pirani CL, et al. Long-term follow-up of patients with lupus nephritis. A study based
on the classification of the World Health Organization. Am J Med 1987; 83:877.
5. Austin HA 3rd, Boumpas DT, Vaughan EM, Balow JE. Predicting renal outcomes in severe lupus nephritis:
contributions of clinical and histologic data. Kidney Int 1994; 45:544.
6. Contreras G, Pardo V, Cely C, et al. Factors associated with poor outcomes in patients with lupus nephritis.
Lupus 2005; 14:890.
7. Sis A, Ramos-Casals M, Bov A, et al. Outcomes in biopsy-proven lupus nephritis: evaluation of 190
white patients from a single center. Medicine (Baltimore) 2010; 89:300.
8. Schwartz MM, Lan SP, Bernstein J, et al. Role of pathology indices in the management of severe lupus
glomerulonephritis. Lupus Nephritis Collaborative Study Group. Kidney Int 1992; 42:743.
http://www.uptodate.com.secure.sci-hub.cc/contents/therapy-of-difource=search_result&search=lupus%20treatment&selectedTitle=4~150

Pgina 21 de 28

Therapy of diffuse or focal proliferative lupus nephritis - UpToDate

12/12/16 7'52 p. m.

9. Hsieh C, Chang A, Brandt D, et al. Predicting outcomes of lupus nephritis with tubulointerstitial
inflammation and scarring. Arthritis Care Res (Hoboken) 2011; 63:865.
10. Esdaile JM, Joseph L, MacKenzie T, et al. The benefit of early treatment with immunosuppressive agents in
lupus nephritis. J Rheumatol 1994; 21:2046.
11. Faurschou M, Starklint H, Halberg P, Jacobsen S. Prognostic factors in lupus nephritis: diagnostic and
therapeutic delay increases the risk of terminal renal failure. J Rheumatol 2006; 33:1563.
12. Chagnac A, Kiberd BA, Farias MC, et al. Outcome of the acute glomerular injury in proliferative lupus
nephritis. J Clin Invest 1989; 84:922.
13. Korbet SM, Lewis EJ, Schwartz MM, et al. Factors predictive of outcome in severe lupus nephritis. Lupus
Nephritis Collaborative Study Group. Am J Kidney Dis 2000; 35:904.
14. Chen YE, Korbet SM, Katz RS, et al. Value of a complete or partial remission in severe lupus nephritis. Clin
J Am Soc Nephrol 2008; 3:46.
15. Chan TM, Tse KC, Tang CS, et al. Long-term outcome of patients with diffuse proliferative lupus nephritis
treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 2005; 14:265.
16. Korbet SM, Schwartz MM, Evans J, et al. Severe lupus nephritis: racial differences in presentation and
outcome. J Am Soc Nephrol 2007; 18:244.
17. Barber CE, Geldenhuys L, Hanly JG. Sustained remission of lupus nephritis. Lupus 2006; 15:94.
18. Illei GG, Takada K, Parkin D, et al. Renal flares are common in patients with severe proliferative lupus
nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients
participating in randomized controlled studies. Arthritis Rheum 2002; 46:995.
19. Moroni G, Quaglini S, Maccario M, et al. "Nephritic flares" are predictors of bad long-term renal outcome in
lupus nephritis. Kidney Int 1996; 50:2047.
20. Parikh SV, Nagaraja HN, Hebert L, Rovin BH. Renal flare as a predictor of incident and progressive CKD in
patients with lupus nephritis. Clin J Am Soc Nephrol 2014; 9:279.
21. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus
erythematosus revisited. J Am Soc Nephrol 2004; 15:241.
22. Austin HA 3rd, Muenz LR, Joyce KM, et al. Diffuse proliferative lupus nephritis: identification of specific
pathologic features affecting renal outcome. Kidney Int 1984; 25:689.
23. Schwartz MM, Lan SP, Bernstein J, et al. Irreproducibility of the activity and chronicity indices limits their
utility in the management of lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis
1993; 21:374.
24. Yokoyama H, Wada T, Hara A, et al. The outcome and a new ISN/RPS 2003 classification of lupus
nephritis in Japanese. Kidney Int 2004; 66:2382.
25. Mittal B, Hurwitz S, Rennke H, Singh AK. New subcategories of class IV lupus nephritis: are there clinical,
histologic, and outcome differences? Am J Kidney Dis 2004; 44:1050.
26. Hill GS, Delahousse M, Nochy D, Barity J. Class IV-S versus class IV-G lupus nephritis: clinical and
morphologic differences suggesting different pathogenesis. Kidney Int 2005; 68:2288.
27. Markowitz GS, D'Agati VD. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years.
Kidney Int 2007; 71:491.
http://www.uptodate.com.secure.sci-hub.cc/contents/therapy-of-difource=search_result&search=lupus%20treatment&selectedTitle=4~150

Pgina 22 de 28

Therapy of diffuse or focal proliferative lupus nephritis - UpToDate

12/12/16 7'52 p. m.

28. Glassock RJ. Reclassification of lupus glomerulonephritis: back to the future. J Am Soc Nephrol 2004;
15:501.
29. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal
survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int 1997; 51:1188.
30. Alarcn GS, McGwin G Jr, Bastian HM, et al. Systemic lupus erythematosus in three ethnic groups. VII
[correction of VIII]. Predictors of early mortality in the LUMINA cohort. LUMINA Study Group. Arthritis
Rheum 2001; 45:191.
31. Barr RG, Seliger S, Appel GB, et al. Prognosis in proliferative lupus nephritis: the role of socio-economic
status and race/ethnicity. Nephrol Dial Transplant 2003; 18:2039.
32. Contreras G, Lenz O, Pardo V, et al. Outcomes in African Americans and Hispanics with lupus nephritis.
Kidney Int 2006; 69:1846.
33. Lau KK, Jones DP, Hastings MC, et al. Short-term outcomes of severe lupus nephritis in a cohort of
predominantly African-American children. Pediatr Nephrol 2006; 21:655.
34. Adler M, Chambers S, Edwards C, et al. An assessment of renal failure in an SLE cohort with special
reference to ethnicity, over a 25-year period. Rheumatology (Oxford) 2006; 45:1144.
35. Ward MM. Medical insurance, socioeconomic status, and age of onset of endstage renal disease in
patients with lupus nephritis. J Rheumatol 2007; 34:2024.
36. Lin CP, Adrianto I, Lessard CJ, et al. Role of MYH9 and APOL1 in African and non-African populations with
lupus nephritis. Genes Immun 2012; 13:232.
37. Valeri A, Radhakrishnan J, Estes D, et al. Intravenous pulse cyclophosphamide treatment of severe lupus
nephritis: a prospective five-year study. Clin Nephrol 1994; 42:71.
38. Cheigh JS, Kim H, Stenzel KH, et al. Systemic lupus erythematosus in patients with end-stage renal
disease: long-term follow-up on the prognosis of patients and the evolution of lupus activity. Am J Kidney
Dis 1990; 16:189.
39. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction
treatment of lupus nephritis. J Am Soc Nephrol 2009; 20:1103.
40. ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide
Combination Efficacy and Safety Study. Arthritis Rheumatol 2014; 66:3096.
41. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus
nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012; 64:1215.
42. Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the EuroLupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.
Arthritis Rheum 2002; 46:2121.
43. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus
nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000; 343:1156.
44. Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med
2004; 350:971.
45. Hall CL, Fothergill NJ, Blackwell MM, et al. The natural course of gold nephropathy: long term study of 21
patients. Br Med J (Clin Res Ed) 1987; 295:745.
http://www.uptodate.com.secure.sci-hub.cc/contents/therapy-of-difource=search_result&search=lupus%20treatment&selectedTitle=4~150

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12/12/16 7'52 p. m.

46. Hall CL, Jawad S, Harrison PR, et al. Natural course of penicillamine nephropathy: a long term study of 33
patients. Br Med J (Clin Res Ed) 1988; 296:1083.
47. Potter EV, Lipschultz SA, Abidh S, et al. Twelve to seventeen-year follow-up of patients with
poststreptococcal acute glomerulonephritis in Trinidad. N Engl J Med 1982; 307:725.
48. Steinberg AD. The treatment of lupus nephritis. Kidney Int 1986; 30:769.
49. Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in
combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549.
50. Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev
2004; :CD002922.
51. Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse
methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus
nephritis. Ann Intern Med 2001; 135:248.
52. Yee CS, Gordon C, Dostal C, et al. EULAR randomised controlled trial of pulse cyclophosphamide and
methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and
prednisolone in lupus nephritis. Ann Rheum Dis 2004; 63:525.
53. Levey AS, Lan SP, Corwin HL, et al. Progression and remission of renal disease in the Lupus Nephritis
Collaborative Study. Results of treatment with prednisone and short-term oral cyclophosphamide. Ann
Intern Med 1992; 116:114.
54. Houssiau FA, Vasconcelos C, D'Cruz D, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial
comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010; 69:61.
55. Houssiau FA, Vasconcelos C, D'Cruz D, et al. Early response to immunosuppressive therapy predicts good
renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis
Trial. Arthritis Rheum 2004; 50:3934.
56. Moroni G, Doria A, Mosca M, et al. A randomized pilot trial comparing cyclosporine and azathioprine for
maintenance therapy in diffuse lupus nephritis over four years. Clin J Am Soc Nephrol 2006; 1:925.
57. Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis
treatment: the ALMS study. Rheumatology (Oxford) 2010; 49:128.
58. McKinley A, Park E, Spetie D, et al. Oral cyclophosphamide for lupus glomerulonephritis: an underused
therapeutic option. Clin J Am Soc Nephrol 2009; 4:1754.
59. Henderson LK, Masson P, Craig JC, et al. Induction and maintenance treatment of proliferative lupus
nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2013; 61:74.
60. Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev 2012;
12:CD002922.
61. Contreras G, Sosnov J. Role of mycophenolate mofetil in the treatment of lupus nephritis. Clin J Am Soc
Nephrol 2007; 2:879.
62. Walsh M, James M, Jayne D, et al. Mycophenolate mofetil for induction therapy of lupus nephritis: a
systematic review and meta-analysis. Clin J Am Soc Nephrol 2007; 2:968.
63. Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized
trial. Ann Intern Med 2015; 162:18.
http://www.uptodate.com.secure.sci-hub.cc/contents/therapy-of-difource=search_result&search=lupus%20treatment&selectedTitle=4~150

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64. Chen W, Tang X, Liu Q, et al. Short-term outcomes of induction therapy with tacrolimus versus
cyclophosphamide for active lupus nephritis: A multicenter randomized clinical trial. Am J Kidney Dis 2011;
57:235.
65. Li X, Ren H, Zhang Q, et al. Mycophenolate mofetil or tacrolimus compared with intravenous
cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012;
27:1467.
66. Furie R, Nicholls K, Cheng TT, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month,
randomized, double-blind study. Arthritis Rheumatol 2014; 66:379.
67. Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as continuous induction and
maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005; 16:1076.
68. Swaak AJ, van den Brink HG, Smeenk RJ, et al. Systemic lupus erythematosus. Disease outcome in
patients with a disease duration of at least 10 years: second evaluation. Lupus 2001; 10:51.
69. Ioannidis JP, Boki KA, Katsorida ME, et al. Remission, relapse, and re-remission of proliferative lupus
nephritis treated with cyclophosphamide. Kidney Int 2000; 57:258.
70. Mosca M, Bencivelli W, Neri R, et al. Renal flares in 91 SLE patients with diffuse proliferative
glomerulonephritis. Kidney Int 2002; 61:1502.
71. Moroni G, Gallelli B, Quaglini S, et al. Withdrawal of therapy in patients with proliferative lupus nephritis:
long-term follow-up. Nephrol Dial Transplant 2006; 21:1541.
72. Grootscholten C, Berden JH. Discontinuation of immunosuppression in proliferative lupus nephritis: is it
possible? Nephrol Dial Transplant 2006; 21:1465.
73. Houssiau FA, D'Cruz D, Sangle S, et al. Azathioprine versus mycophenolate mofetil for long-term
immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;
69:2083.
74. Fischer-Betz R, Specker C, Brinks R, et al. Low risk of renal flares and negative outcomes in women with
lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Rheumatology
(Oxford) 2013; 52:1070.
75. Wofsy D, Appel GB, Dooley MA. Aspreva Lupus Management Study maintenance results. Lupus 2010; 19
(Suppl):CS12.5.
76. Stoenoiu MS, Aydin S, Tektonidou M, et al. Repeat kidney biopsies fail to detect differences between
azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN
Nephritis Trial. Nephrol Dial Transplant 2012; 27:1924.
77. Tamirou F, D'Cruz D, Sangle S, et al. Long-term follow-up of the MAINTAIN Nephritis Trial, comparing
azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis 2016;
75:526.
78. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for
lupus nephritis. N Engl J Med 2011; 365:1886.
Topic 3059 Version 32.0

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GRAPHICS
Potential option for tapering dose of prednisone after initiation of induction therapy
for severe lupus nephritis in adults
Oral prednisone dose (mg)
Weeks

Patients <80 kg

Patients 80 kg

Weeks 1 to 14: Daily dose given in the morning


1-4

60 mg in two divided doses

80 mg in two divided doses

5-6

50 mg

70 mg in two divided doses

7-8

50 mg

60 mg

9-10

40 mg

50 mg

11-12

40 mg

40 mg

13-14

30 mg

40 mg

Weeks 15 through 52: Alternating daily doses, given in the morning


15

30 mg alternating with 25 mg

40 mg alternating with 35 mg

16

30 mg alternating with 20 mg

40 mg alternating with 30 mg

17

30 mg alternating with 15 mg

40 mg alternating with 15 mg

18

30 mg alternating with 10 mg

40 mg alternating with 20 mg

19

30 mg alternating with 5 mg

40 mg alternating with 15 mg

20

30 mg on alternate days only (ie,


no prednisone on opposite alternate
days)

40 mg alternating with 10 mg

21

25 mg alternate days only

40 mg alternating with 5 mg

22

20 mg alternate days only

40 mg on alternate days only (ie,


no prednisone on opposite alternate
days)

23

20 mg alternate days only

30 mg alternate days only

23-52

20 mg alternate days only

25 mg alternate days only

From: Lupus Nephritis, 2nd ed, Lewis EJ, Schwartz MM, Korbet SM (Eds), Oxford University Press 2011. Reproduced by
permission of Oxford University Press. Copyright 2010. www.oup.com.
Graphic 90681 Version 3.0

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Relation of absolute neutrophil count to risk of infection


Absolute neutrophil
count

Risk management

>1500/microL (>1.5 x

None

1000 to 1500/microL

No significant risk of infection; fever can be managed on an outpatient basis

500 to 999/microL

Some risk of infection; fever can occasionally be managed on an outpatient


basis

200 to 499/microL

Significant risk of infection; fever should always be managed on an inpatient


basis with parenteral antibiotics; few clinical signs of infection

<200/microL

Very significant risk of infection; fever should always be managed on an


inpatient basis with parenteral antibiotics; few or no clinical signs of infection

10 9/liter)

The correlation between absolute neutrophil count and infectious risk only applies to conditions in which the
bone marrow neutrophil reserve is diminished. Refer to UpToDate topics on neutropenia for further discussions
of the causes of neutropenia and the estimation of infectious risk.
Graphic 63903 Version 9.0

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Contributor Disclosures
Ronald J Falk, MD Nothing to disclose Maria Dall'Era, MD Consultant/Advisory Boards: Genentech [Lupus
(Rituximab)]. Gerald B Appel, MD Grant/Research/Clinical Trial Support: Regulus Therapeutics [Alport's];
Bristol-Myers Squibb [Lupus nephritis (Abatacept)]; Genentech [Membranous (Rituximab)]. Speaker's Bureau:
Takeda Pharmaceuticals USA, Inc [Gout (Febuxostat, colchicine)]; Genentech [Vasculitis (Rituximab)].
Consultant/Advisory Boards: Genentech; Takeda Pharmaceuticals USA, Inc; Bristol-Myers Squibb; Amgen;
Mallinckrodt Pharmaceuticals; EMD Serono, Inc; Merck; Pfizer; Genzyme-Sanofi; Omeros; Achillion
Pharmaceuticals [Immunosuppressives (Drugs under development for immunosuppression)]. Richard J
Glassock, MD, MACP Consultant/Advisory Boards: Bristol-Myers-Squibb [Lupus nephritis, FSGS (Abatacept)];
ChemoCentryx [Vasculitis, diabetes (No product)]; Astellas [Nephrotic syndrome (Tacrolimus)]. Speaker's
Bureau: Genentech [Vasculitis (Rituximab)]. Other Financial Interest: Karger [Editor]; AAKP [Patients with kidney
disease]; American Soc Neph [Editorial duties (Blog)]. Equity Ownership/Stock Options: Reata Stock
[Diabetes]. Brad H Rovin, MD Grant/Research/Clinical Trial Support: Biogen Idec; Questcor (Mallinkrodt);
Genentech [lupus nephritis]. Consultant/Advisory Boards: Auven; Alnylam; Biogen Idec; Boeringer Ingelheim;
Centocor; Chemocentryx; Eli Lilly; Genentech; Genzyme; GlaxoSmithKline; ISIS Pharmaceuticals; Mallinkrodt;
Medimmune; Novartis; Pfizer; Roche [lupus nephritis (Anti-CD20, c5a receptor antagonist, acth gel, antiinterferon alpha receptor)]. Albert Q Lam, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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