Low-dose CYC induction, AZA maintenance recommended for lupus nephritis

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Low-dose CYC induction, AZA maintenance recommended for lupus nephritis

Dec 29, 2004 Janis

Brussels, Belgium - Long-term follow-up of patients from the Euro-Lupus

Nephritis Trial shows that induction with the low-dose IV cyclophosphamide

(CYC) regimen used in that study, followed by azathioprine (AZA)

maintenance, is likely as effective as the widely used " NIH regimen " of

high-dose CYC for controlling nephritis and end-stage renal disease (ESRD)

risk in patients with systemic lupus erythematosus (SLE) [1].

Results of the study are published in the December 2004 issue of Arthritis &

Rheumatism.

A high-dose long course of quarterly IV CYC pulse therapy is probably

not justified anymore as remission-maintaining therapy in most lupus

nephritis patients.

" Faced with a patient with newly diagnosed Class 3 or 4 lupus nephritis, a

reasonable choice in 2004 is to prescribe a 3-to-6-month IV CYC course as

initial therapy, in addition to glucocorticoids. Although mycophenolate

mofetil (MMF) is a new star twinkling in the sky, we still lack long-term

follow-up data on patients given the drug as initial therapy. For

maintenance, the choice is currently between AZA and MMF, " lead author Dr

Frederic A Houssiau (Universite Catholique de Louvain, Brussels, Belgium)

tells rheumawire. " A high-dose long course of quarterly IV CYC pulse therapy

is probably not justified anymore as remission-maintaining therapy in most

lupus nephritis patients, mainly because of its gonadal toxicity, except

when the latter concern is not applicable or when anticipated lack of

compliance to daily oral immunosuppressive treatment should be avoided by

the use of IV therapy. "

Long-term data from Euro-Lupus Nephritis Trial

In the Euro-Lupus Nephritis Trial, after 3 IV pulses of 750-mg

methylprednisolone followed by oral prednisolone for 4 weeks, 90 patients

were randomized to induction with a high-dose IV CYC regimen (6 monthly

pulses and 2 quarterly pulses with escalating doses) or with a low-dose IV

CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks). Both groups

then received AZA (2 mg/kg per day). Study end points were renal function

(based on serum creatinine). Kidney biopsies were obtained at baseline in

all subjects and after about 2 years of follow-up in 11 patients in the

low-dose group and 9 in the high-dose group.

After a median follow-up of 73 months, there was no significant difference

in the proportion of patients with permanently impaired renal function in

the low-dose vs high-dose patients (20% vs 23%, p=NS). Similarly, there was

no greater cumulative probability of ESRD or doubling of the serum

creatinine value in the low-dose vs high-dose patients.

Houssiau tells rheumawire that the median follow-up of 73 months shows that

induction with the Euro-Lupus low-dose IV CYC regimen was not inferior to

induction with a high-dose CYC regimen, at least for European patients.

" Outcomes may be different in African Americans. We do not know, " he says.

Houssiau's current approach to induction therapy in lupus nephritis is to

give 3 daily pulses of 1 g of methylprednisolone followed by oral

prednisolone (mostly 0.5 mg/kg per day during one month; then tapered) along

with 6 fixed doses of IV cyclophosphamide 500 mg IV given as a 30-minute

drip infusion once every 2 weeks. " Please note that MMF is an alternative as

induction immunosuppressive therapy, but we lack long-term follow up data, "

Houssiau says. As maintenance, he gives AZA (2 to 2.5 mg/kg per day).

Houssiau tells rheumawire that he is currently coordinating the MAINTAIN

trial comparing AZA with MMF for maintenance therapy in lupus nephritis.

" MMF might be superior to AZA based on the transplant data, but, so far, we

don't know, " he says.

Early response is essential

The investigators also found that achieving an early response to therapy is

key to preventing renal failure. " The 2 predictors [of avoiding progression

to ESRD] were improvement in serum creatinine at 6 months and proteinuria

less than 1 g at 6 months, " Houssiau says.

For the patient whose renal response by 6 months is not adequate, Houssiau

advises first checking patient compliance with treatment. " Also, optimize

proteinuria-sparing measures (such as ACE inhibitors or diuretics) and

blood-pressure control, " he says.

Houssiau emphasizes that the big unanswered question is what the best

regimen is for maintaining remission. He points out that AZA is almost

certainly not the ideal drug, since it is associated with a 35% relapse

rate.

Source

1. Houssiau FA, Vasconcelos C, D'Cruz D, et al. Early response to

immunosuppressive therapy predicts good renal outcome in lupus nephritis.

Arthritis Rheum 2004; 50:3934-3940.