US Pharm. 2012;37(6):HS11-HS13.
Systemic lupus erythematosus (SLE) is an autoimmune
disease that may affect nearly any organ system in the human body. The
autoimmunity present in patients with SLE causes local inflammation and
tissue damage, and it may present with a variety of symptoms depending
on the organ system involved. When this disease affects the kidney, it
is termed lupus nephritis. The condition is often associated with
poorer outcomes and is of particular interest for this reason. Even
with the many recent advances in treatments for lupus nephritis, 10% to
15% of treated patients will still progress to end-stage renal disease
(ESRD) and require dialysis or transplant.1
The incidence of SLE is strongly related to race, gender,
and socioeconomic status. The prevalence of SLE is much higher in women
than in men (up to 12:1 in adults), and the African-American population
is up to 10 times more likely to develop the disease as compared to its
white counterparts.1 Approximately 35% of adults diagnosed
with SLE also present with clinical evidence of nephritis at the time of
diagnosis, with 50% to 60% of patients developing nephritis during the
first 10 years of disease.2 If renal involvement is present,
African Americans have been shown to have poorer outcomes as compared to
white patients or those of Hispanic descent. Independent of race, low
income has also been shown to be a risk factor for the development and
progression of lupus nephritis.3
Declining renal function, as measured by increasing serum
creatinine and blood urea nitrogen with concurrent decrease in measured
or calculated creatinine clearance, is one of the first signs of lupus
nephritis in SLE patients. The American College of Rheumatology (ACR)
defines lupus nephritis as persistent proteinuria >0.5 g/day or
>3+ by dipstick, and/or cellular casts including red blood cells,
hemoglobin, granular, tubular, or mixed.2 In order to verify suspicions of lupus nephritis, a renal biopsy must be performed.2
Lupus Nephritis Classification
The World Health Organization (WHO) originally classified
lupus nephritis based upon histological characteristics of a renal
biopsy. The WHO classification was revised by the International Society
of Nephrology and the Renal Pathology Society (ISN/RPS) into six classes
(TABLE 1). Patients often progress from one classification to
another, and treatments will differ according to the severity and extent
of the disease.4
The goal of treatment is to both improve kidney function
and delay the onset of kidney failure. Patients who present with ISN/RPS
class I or class II mesangial disease generally have good long-term
outcomes, and treatment with either an angiotensin-converting enzyme
(ACE) inhibitor or angiotensin receptor blocker (ARB) is recommended for
any patient with proteinuria ≥0.5 g/day, with the primary goal being
the prevention of the progression of nephritis.2
Focal or diffuse lupus nephritis (ISN/RPS classes III-IV)
confers a much greater risk of progression, potentially to ESRD, and
requires more aggressive treatment with immunosuppressive medications.4
Treatment regimens generally include an aggressive induction phase in
which the goal is to induce complete or partial disease remission over
the course of a few months. This is followed by a maintenance phase in
which lower doses of immunosuppressive agents are used to maintain
remission and prevent flare-ups.
There have been some small observational studies
suggesting that antimalarials may reduce the risk of renal flares,
improve maintenance of remission, and reduce the risk of progression to
ESRD in addition to reducing the risk of thrombosis. The current ACR
guidelines recommend the addition of hydroxychloroquine to the regimens
of all SLE patients with nephritis (TABLE 2).2,5-9
Cyclophosphamide Induction Therapy
Traditionally, cyclophosphamide combined with
corticosteroids has been the standard for induction therapy.
Cyclophosphamide, a synthetic antineoplastic drug chemically related to
the nitrogen mustards, is often used in chemotherapy regimens targeted
against a variety of malignancies. It exerts its antineoplastic and
immunosuppressant effects by cross-linking DNA preferentially in quickly
dividing cells, such as cancerous cells and leukocytes.10
The combination of cyclophosphamide and corticosteroids
as induction therapy has been proven effective in randomized controlled
trials and was shown to be more effective than corticosteroids alone.
Patients treated with methylprednisolone plus monthly “pulse” dosing of
IV cyclophosphamide, followed by quarterly injections, were more likely
to achieve and maintain remission as compared to those treated with
cyclophosphamide or methylprednisolone alone.11,12 Daily oral
cyclophosphamide may also be used for induction therapy; however, IV
pulse therapy is preferred due to the decreased cumulative exposure to
cyclophosphamide and a lower incidence of cytopenia.13
While this combination is effective, patients treated with
cyclophosphamide and methylprednisolone for induction therapy in lupus
nephritis are at an increased risk of adverse drug events as compared to
those treated with methylprednisolone monotherapy. Adverse events
include amenorrhea (43% vs. 7.4%), cervical dysplasia (7.1% vs. 0%),
herpes zoster (21% vs. 3.7%), and infection (32% vs. 7.4%).11
In an attempt to avoid these complications of therapy,
trials of lower-dose cyclophosphamide have been studied for induction
therapy. The Euro-Lupus Nephritis Trial compared traditional high-dose
therapy, dosed monthly for 6 months followed by quarterly dosing (0.5
g/m2 initially, then adjusted based on white blood cell count
nadir), with low-dose therapy (500 mg every 2 weeks × 6 doses followed
by azathioprine maintenance therapy of 2 mg/kg/day).14 After a
41-month follow-up, there were no significant differences in rate of
treatment failure or incidence of renal flares between the two groups.
The ACR guidelines include recommendations for both induction regimens,
with the lower Euro-Lupus dosing being preferred in white patients with
Western or Southern European ethnic background.2
Induction Therapy With MMF
Mycophenolate mofetil (MMF) is metabolized to mycophenolic
acid, which inhibits inosine monophosphate dehydrogenase and in turn
inhibits the de novo pathway for guanine nucleotide synthesis. As
the proliferation of B and T cells is highly dependent on this pathway,
MMF has a potent cytostatic effect on lymphocytes.15
Within the last decade, MMF has been shown in studies to
be effective for induction therapy for lupus nephritis. In a study
conducted in Hong Kong, 42 patients with diffuse proliferative lupus
nephritis were randomized to either oral MMF (2 g daily for 6 months
followed by 1 g daily for 6 months) or oral cyclophosphamide (2.5
mg/kg/day for 6 months) followed by oral azathioprine (1.5 mg/kg/day for
6 months). Both arms of the study also received oral prednisolone
daily. After 12 months of follow-up, there were no significant
differences between the groups in terms of complete or partial remission
rates. There were also no significant differences in relapse rate
between the two arms; however, infections were significantly less common
in the MMF induction group (13% vs. 40%).16
A larger randomized, controlled trial, the Aspreva Lupus
Management Study (ALMS), was conducted to verify the results of some of
the smaller studies.17 Three hundred and seventy patients
with WHO class III-V lupus nephritis were randomized to 24 weeks of
treatment with either MMF (3 g daily) or IV cyclophosphamide (0.5-1 g/m2).
arms were also treated with prednisolone daily. After the 6-month study
period, no significant differences in remission rates or mortality were
seen between the groups. Diarrhea occurred more often in the MMF group
(28% vs. 12%), while nausea/vomiting (37% vs. 45%) and hair loss (10%
vs. 35%) were more common with cyclophosphamide therapy. This study
helped confirm that MMF is a viable alternative to cyclophosphamide
induction therapy, and may confer less risk of toxicity.17
The ACR recommends 2 to 3 g/day of MMF as part of an
induction regimen with pulsed corticosteroids. The 3 g/day dosage is
favored in patients with proteinuria and significant rises in serum
Once remission has been induced, long-term maintenance
therapy should be initiated to reduce the risk of recurrence and
long-term complications of the disease. Various therapies have been
studied for maintenance therapy, including azathioprine, MMF, and
cyclophosphamide, all combined with corticosteroids. One study compared
azathioprine (1-3 mg/kg/day), MMF (0.5-3 g/day), and IV cyclophosphamide
(0.5-1 g/m2) for the maintenance therapy of proliferative lupus nephritis.18
The study involved 59 patients followed over a period of 2 years. After
follow-up, the percentage of patients reaching the primary composite
endpoint of death or glomerular filtration rate (GFR) <60mL/min/1.73 m2
were 20%, 25%, and 55% in the MMF, azathioprine, and cyclophosphamide
groups, respectively. Adverse effects were also significantly less in
the MMF and azathioprine groups as compared to the cyclophosphamide
In order to compare azathioprine to MMF directly, another
study was conducted for maintenance therapy for lupus nephritis. The
MAINTAIN Nephritis Trial was conducted to compare maintenance of
azathioprine 2 mg/kg/day with MMF 2 g/day in 105 patients with
proliferative lupus nephritis.19 After a median 53-month
follow-up, there were no significant differences between the groups in
the rate of relapse or adverse events, aside from cytopenias being more
common in the azathioprine group. The results of this trial show that
both MMF and azathioprine are effective as maintenance regimens for
The ACR guidelines recommend that patients be placed on
maintenance regimens of either azathioprine or MMF. Available studies
are not adequate to determine how rapidly azathioprine or MMF may be
tapered; however, the guidelines recommend 3 years of MMF maintenance
therapy.2 Corticosteroids may also be utilized in maintenance
regimens; however, doses should be tapered over time to reduce the risk
of adverse reactions.
Membranous Lupus Nephritis Treatment
The treatment of membranous lupus nephritis, ISN/RPS class
V, differs from that of proliferative nephritis. Milder disease with
stable kidney function, subnephrotic proteinuria, and the absence of
proliferative lesions may only require treatment with an ACE inhibitor
or an ARB in order to suppress the renin-angiotensin-aldosterone system
(RAAS). For disease that is more severe or includes proliferative
lesions, studies have demonstrated that treatment with a corticosteroid
in combination with either cyclosporine, MMF, or cyclophosphamide is an
effective regimen.20,21 The ACR recommends first-line treatment with MMF and prednisone followed by maintenance therapy with MMF or azathioprine.2
Many other agents are currently undergoing studies for
their role in the treatment of lupus nephritis, including rituximab,
belimumab, and tacrolimus. Additional data from randomized controlled
studies are needed before recommending these agents as first line;
however, the ACR recommends treatment with one of these agents if a
patient fails both cyclosporine and MMF induction therapy.2
Current therapies are quite effective in the treatment of lupus nephritis (TABLE 3
provides counseling points). Cyclophosphamide in combination with a
corticosteroid remains an effective and reliable regimen for the
induction phase of therapy for proliferative and membranous lupus
nephritis. IV pulse therapy reduces cumulative cyclophosphamide exposure
and may confer less risk of toxicity. MMF has also been shown to be an
effective agent for the induction in combination with a corticosteroid,
and appears to have less risk of serious toxicities as compared to
cyclophosphamide regimens. Either medication is recommended by the ACR
as first-line induction therapy for lupus nephritis.2 Once
remission has been induced, maintenance regimens containing either
azathioprine or MMF in combination with a corticosteroid appear to be
most effective, while having the lowest risk for adverse events. The
treatment of lupus nephritis will continue to evolve and improve as new
treatments and data become available.
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