Cytotoxic therapy of lupus nephritis: recent developments

Frédéric A. Houssiau1, and Michel Jadoul2

1 Departments of Rheumatology and 2 Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, B-1200 Bruxelles, Belgium

Keywords: cyclophosphamide; lupus nephritis

Introduction

Until recently, the primary goal of most therapeutical trials in lupus nephritis (LN) has been to avoid treatment failure, namely death, end-stage renal disease (ESRD) or doubling of serum creatinine (DSC). Fortunately, these poor outcomes have become relatively less frequent, particularly due to the early detection of kidney involvement by regular follow-up in specialized institutions. As an alternative goal to the prevention of treatment failure, prompt achievement and long-term maintenance of remission with less drug-induced morbidity should become the primary treatment objectives. Such an ideal goal is, however, difficult to achieve for several distinct reasons. Firstly, LN is a heterogeneous disease, the prognosis of which is influenced by many variables such as race, gender, socio-economic status, presenting features, initial renal pathology, the occurrence of renal flares, the presence of extra-renal disease, the presence of antiphospholipid antibodies and as of yet unknown factors. Secondly, we still partially ignore the pathophysiological pathways operating in LN, thereby precluding a more specific—and hopefully less toxic—immunointervention. Besides the well known pathogenic role of anti-DNA antibodies, interleukin-10, CD40/CD40-L and B7/CD28 interactions, other mechanisms implicated in the initiation and relapses of LN will hopefully be unravelled in the next decade. Thirdly, few controlled trials have been performed in this field, mostly due to the rarity of the disease and the need for long-term follow-up. Accordingly, the literature contains more reviews, comments and editorials (including this one!) than prospective controlled trials.

The gold standard: the NIH regimen

Most patients with proliferative LN are currently treated with a long-term, high-dose, intravenous (i.v.) pulse cyclophosphamide (CPM) regime, combined with glucocorticoids (GC), based on the results of three prospective, long-term, controlled studies performed by the National Institutes of Health (NIH) group. The first NIH study demonstrated that patients given oral GC and a long-course, high-dose, i.v. pulse CPM regimen had a lower rate of ESRD after a follow-up of 5 years, compared with those given GC alone. In contrast, patients given GC and either oral CPM or oral azathioprine (AZA) or a combination of oral AZA and oral CPM had a similar outcome compared to patients given GC alone. Most importantly, however, the i.v. CPM regimen was not found to be superior to the other regimens, including use of a cytotoxic drug [1]. The second NIH study, performed in patients with severe LN, indicated that patients given a long-term course (30 months) of pulse CPM treatment (but not those given only a short-term course (6 months) of CPM pulse therapy) had a lower probability of doubling their serum creatinine compared with patients given a short-term course (6 months) of i.v. methylprednisolone (MP) pulses. The outcome of patients given a short course of i.v. CPM did not differ from that of patients given an extended course, except for the rate of exacerbation, a not unexpected finding given the absence of long-term maintenance cytotoxic therapy in the short-course group [2]. The third NIH study demonstrated the superiority, in terms of achieving remission, of a combined i.v. MP and CPM pulse regimen, compared with monthly i.v. MP pulses alone [3]. Extended follow-up on the completers showed that the proportion of patients who doubled their serum creatinine was lower in the combination group than in the CPM group [4].

Taken together, the pioneering work from the NIH group demonstrated the importance of long-term follow-up studies in LN, and the superiority of an extended course of CPM over oral or i.v. pulse steroid therapy. Several investigators have, however, raised concerns about the indiscriminate use of the so-called ‘NIH regimen’ to treat all LN patients [57]. First, a recent meta-analysis of all randomized trials in LN failed—as did the NIH studies themselves—to demonstrate that an extended course of i.v. CPM was superior, in terms of renal outcome and survival, to other regimens using a cytotoxic drug(s) [8]. Secondly, high-dose i.v. CPM treatment is highly toxic. Thus, up to 25% of patients develop Herpes zoster infection, up to 26% suffer from severe infection and up to 52% of women at risk have ovarian failure [13,9], a dire side-effect in young women whose life expectancy has dramatically improved over recent decades and who, therefore, soundly wish to preserve, as much as possible, their childbearing potential. Thirdly, clinically milder cases of biopsy-proven proliferative nephritis, for whom less aggressive treatment regimes might be justified, are now frequently diagnosed due to the prompt assessment of early renal involvement.

A challenger: the Euro-Lupus regimen

As an alternative to the extended course of i.v. CPM, 10 years ago we proposed a sequential use of cytotoxic therapies to treat proliferative LN, namely a limited course of i.v. CPM as remission-inducing treatment, followed by the administration of a safer cytotoxic drug, such as AZA, as a long-term remission-maintaining therapy [10]. Interestingly, a similar approach has been (and indeed is being) tested in vasculitis patients in the CYCAZAREM and REMAIN trials launched by the European Vasculitis Group [11]. In addition, to reduce the toxicity of i.v. CPM further, we have been using a low-dose (LD) i.v. CPM regimen (six fortnightly pulses of 500 mg) as remission-inducing treatment. This approach, supported by retrospective analyses [10,12,13], has now been tested in a controlled study. The Euro-Lupus Nephritis Trial (ELNT) is a prospective European-based multicentre randomized study designed to compare a high-dose (six monthly pulses and two quarterly pulses, with doses increased according to the white blood cell nadir) and a low dose (six fortnightly pulses of 500 mg, providing a cumulative dose of 3 g) i.v. CPM regimen as remission-inducing therapy for proliferative LN. In both arms, AZA was used as a long-term cytotoxic drug to maintain remission.

The results of the trial indicate: (i) that there was no significantly greater cumulative probability of treatment failure (absence of primary response, DSC or GC-resistant flare) in patients given a LD i.v. CPM regimen vs those receiving a HD regimen; (ii) that the kinetics of the initial response did not differ between the two groups; (iii) that the cumulative probability of reaching renal remission was similar; and (iv) that the number of flares did not differ. Severe infectious side-effects were half as common in the LD group, although the difference was not statistically significant [14]. These data suggest that even a low cumulative i.v. CPM dose of 3 g prescribed as remission-inducing therapy may achieve good clinical results. Thus, we would question the current practice, based on the NIH trials, of treating all lupus nephritis patients with an extended course of i.v. CPM.

Several differences in patient populations and in study design between the ELNT and the NIH studies should be emphasized. First, most patients included in the ELNT did not suffer from clinically severe kidney disease. Although all patients had proliferative glomerulonephritis, only 22% of them presented with renal impairment, and 28% with nephrotic syndrome. It should be stressed, however, that these patients were, by definition, representative of those currently treated in our Lupus Clinics. Moreover, few Black or Afro-Caribbean patients, whose prognosis is poorer, were included in the ELNT, a figure contrasting with the high percentage of Afro-Americans randomized in the NIH studies. Finally, the duration of the HD i.v. CPM regimen prescribed in the ELNT was shorter compared with that of the North American studies and, as a consequence, the cumulative i.v. CPM dose was lower, thereby precluding strict comparison.

Although the results of the ELNT should be only cautiously extrapolated to other LN populations with different ethnic backgrounds or disease severity, the many advantages of the Euro-Lupus regimen should be emphasized. A 500 mg CPM pulse can be administered, with excellent immediate tolerance, on an out-patient basis as a 30-min infusion, without the need for i.v. antiemetics and forced hydration, thereby considerably reducing the costs of therapy, and possibly the cumulative dose-dependent long-term toxicity.

Future directions

Optimal maintenance therapy and successful treatment of refractory cases remain two critical issues. Thus, 25% of the patients randomized in the ELNT experienced at least one flare, mostly renal, while they were treated with AZA, indicating that other remission-maintaining drugs should be tested in lupus nephritis. As already mentioned in another Editorial Comment recently published in Nephrology Dialysis and Transplantation [15], the newly developed immunosuppressive drug mycophenolate mofetil, a non-competitive reversible inhibitor of inosine monophosphate dehydrogenase [16], is promising in this respect, given its superiority over AZA in reducing the incidence of acute rejection episodes after renal and cardiac transplantation [17,18] and its successful short-term use together with high-dose GC in Chinese lupus patients suffering from proliferative glomerulonephritis [19]. The European Working Party on Systemic Lupus Erythematosus has recently launched a new trial, MAINTAIN (for maintainance therapy), aimed at comparing MMF and AZA, in terms of efficacy and toxicity, as remission-maintaining treatment of proliferative LN, after a short-course of LD i.v. CPM therapy. Those investigators interested in joining MAINTAIN are welcome (e-mail: houssiau{at}ruma.ucl.ac.be).

For refractory cases, a topic well beyond the scope of this short Editorial Comment, novel cytotoxic treatments are currently under investigation, such as HD immunoablative therapy with or without haematopoietic stem cell transplantation [20], not to mention the use of biological approaches such as anti-IL-10 antibodies [21], CD40/CD40-L blockade [22] or B7/CD28 blockade.

Acknowledgments

The authors are most grateful to the members of the Euro-Lupus Nephritis Trial Group and to Dr Graham R. V. Hugues (St Thomas' Hospital, London, UK) for introducing the LD i.v. CPM regimen as remission-inducing therapy for lupus nephritis, and for stimulating the investigators of the European Working Party on SLE to embark on a controlled trial.

Notes

Correspondence and offprint requests to: Frédéric A. Houssiau, Department of Rheumatology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, B-1200 Bruxelles, Belgium. Email: houssiau{at}ruma.ucl.uc.be Back

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