Centre for Rheumatology, Department of Medicine, University College London, London, UK.
Correspondence to: C. Gorman. E-mail: clgorman{at}btopenworld.com
Introduction
Renal disease is one of the most severe manifestations of systemic lupus erythematosus (SLE), with up to two-thirds of patients having renal involvement at some point during the course of their disease [1]. The range of manifestations is wide, from asymptomatic proteinuria to rapidly progressive crescentic glomerulonephritis. Patients with the worst prognosis usually have diffuse proliferative changes on renal biopsy (WHO class IV nephritis). These patients have an 1148% risk of end-stage renal failure (ESRF) within 5 yr [1]. This risk is heightened in Black patients who have particularly poor outcomes despite therapy [2].
The aims of therapy for lupus nephritis are to preserve renal function by initially inducing remission of nephritis and then preventing subsequent renal flares. Because therapy depends on potent immunosuppressive regimes, these aims must be balanced against the risks of treatment-related morbidity. This is the conundrum upon which our debate is based.
Our department is a tertiary referral centre for SLE. We currently employ the standard National Institutes of Health (NIH) high-dose intravenous cyclophosphamide (CYC) regime for treatment of proliferative lupus nephritis [35]. However, recent evidence has proposed that regimes using lower cumulative doses of CYC may be as effective but lead to fewer adverse events. This debate, which took part in our department on 24 June 2004, reviewed the evidence for both types of regime with the aim of deciding whether our departmental protocol should be changed.
Proposition: low-dose cyclophosphamide is superior to high dose for treatment of lupus nephritis
High-dose intravenous (IV) CYC is associated with two major disadvantages. The first is the occurrence of sustained amenorrhoea. Multiple studies have shown that this occurs in 23 to 41% of patients receiving a total of 15 intravenous pulses of CYC [3, 4, 6, 7]. Secondly, high-dose IV CYC is associated with a significant infection rate. Up to 25% of patients receiving high-dose CYC can develop herpes zoster reactivation, pneumonia or urinary tract infections [38]. The proposition argued that low-dose IV CYC offers similar efficacy to that of high-dose IV CYC but without the associated disadvantages.
The first study supporting the use of low-dose CYC was published by Houssiau et al. in 1991 [9]. In this small (n = 17) retrospective study, patients were treated with 500 mg of IV CYC every week for either 3 or 4 weeks and followed up for a median of 15 months. Patients were also given oral prednisolone 0.4 mg/kg/day, tapering by 5 mg per month to 10 mg/day. One week after the last dose of IV CYC patients were commenced on oral immunosuppression using azathioprine or cyclophosphamide. The effectiveness of the regime was demonstrated by a significant reduction in anti-double-stranded DNA (dsDNA) antibody titre and oral prednisolone dose. Only two patients developed ESRF requiring continuous peritoneal dialysis. No patients developed a significant decline in their neutrophil count 10 days after receiving low-dose IV CYC, and only one patient suffered severe sepsis. This retrospective study suggested that low-dose CYC was well tolerated and beneficial in the short term.
A larger retrospective study came to essentially the same conclusion. Ninety patients with a number of different autoimmune disorders were treated with low-dose IV CYC. Of these 90 patients, 43 had lupus nephritis. Patients were treated with weekly infusions of 500 mg CYC for a median of six pulses per patient. If complete remission was achieved, patients were commenced on azathioprine; if partial remission was achieved, patients were given IV CYC 500 mg every month. Follow-up was for a median of 56 months. Results from this study revealed that 33/43 patients (75%) with lupus nephritis achieved complete or partial remission. A significant reduction of patients erythrocyte sedimentation rate (ESR), anti-dsDNA antibody titre and proteinuria was observed. Only 7.8% of patients had serious infections during the follow-up period. No cases of premature ovarian failure were seen in 40 pre-menopausal women [10]. The impressive safety profile of the low-dose IV CYC regime was supported in a study of 37 patients with neuropsychiatric SLE: only 5.4% of patients developed herpes zoster and no patients developed leucopenia, cystitis or amenorrhoea [11].
Clearly, retrospective studies alone may not constitute sufficient evidence to support a change in the accepted protocol for treatment of lupus nephritis. It was recognized that a randomized trial making a direct comparison of low-dose and high-dose CYC regimes was essential. The Euro-Lupus Nephritis Trial (ELNT) was carried out by a multicentre European group and published in 2002 [12]. Ninety patients with lupus nephritis were treated with three pulses of intravenous methylprednisolone (IV MP) after which they were allocated to one of two groups.
The high-dose group received IV CYC 0.5 g/m2 every month for 6 months. The dose of CYC was increased by 250 mg according to the nadir white cell count. These patients then received two further pulses of IV CYC 4 months apart. The low-dose group in this study received 500 mg IV CYC every 2 weeks for a total of six infusions. Both groups were given azathioprine (2 mg/kg/day) after remission was induced. Baseline clinical, serological and histological characteristics in both groups were similar. The majority of patients were White and had class IV nephritis. Follow-up in this study was for a median of 41 months.
Results from this study revealed a significant decline in serum creatinine, proteinuria, ECLAM scores and oral prednisolone dose and a significant increase in serum albumin and C3 in both groups. Critically, no significant differences in these outcome measures were observed between the two groups. Renal remission was seen in 71% of patients in the low-dose group and 54% in the high-dose CYC group. This difference was not statistically significant. The number of treatment failures in both groups was similar (16%). The ELNT therefore confirms that low-dose IV CYC demonstrates a comparable efficacy to a high-dose treatment regime.
There was a trend for more infections with high-dose CYC, with twice as many infections occurring in this group. This difference, however, was not statistically significant. There was only one case of premature ovarian failure, and this was in the high-dose group. This surprisingly low incidence of amenorrhoea, in comparison to previous NIH studies, may arise from the fact that the cumulative dose of CYC (even in the high-dose group) was lower than in the standard NIH regime.
In summary, the proposition argued that it is imperative to find a way to treat lupus nephritis effectively without incurring the high burden of adverse effects associated with high-dose IV CYC. Several studies have shown that low-dose IV CYC is tolerated well. In particular, amenorrhoea is very rare with this regime but may occur in up to 41% of patients treated with the NIH high-dose regime. The ELNT is the only study to compare low-dose and high-dose regimes and shows unequivocally that there was no difference in renal outcome between the two groups. There is no need to continue using the high-dose IV CYC regime and no justification for doing so.
Opposition: high-dose cyclophosphamide is superior to low dose for treatment of lupus nephritis
The basis of the argument for the opposition focused on the large body of robust evidence to support the efficacy of the high-dose IV CYC regime. The retrospective studies and the single flawed prospective trial supporting the low-dose regime do not match this body of evidence.
The NIH regime has been regarded by many as the platinum standard of therapy for lupus nephritis. The five trials that led to the acceptance of this regime as the standard for reducing the risk of ESRF were conducted rigorously over a period of 15 yr [35, 8, 13]. The NIH regime consists of monthly pulses of IV CYC 0.51.0 g/m2 of body surface area for 6 months. The pulses then continue every 3 months for 2 yr (a total of 15 pulses). The dose should start at 0.5 g/m2 and be adjusted according to the nadir leucocyte count (i.e. increase to a maximum of 1 g/m2 if the count remains above 1500/mm3).
An early NIH study showed no clear advantage of oral cytotoxics over prednisolone in preventing deterioration of renal function at 28 months of follow-up [14]. However, when the follow-up was extended to 7 yr the superiority of all cytotoxics in preventing ESRF emerged. Furthermore, IV CYC was found to be the most efficacious cytotoxic treatment, especially in patients with severe biopsy changes [14]. One hundred and seven patients with lupus nephritis were divided into five treatment groups:
These therapies were continued until clinical remission had been maintained for at least 6 months. Low-dose oral prednisone (1020 mg on alternate days) was given to patients in groups 25 in addition to the medication shown above. Intravenous CYC plus oral corticosteroids (group 5) was found to be more effective in preserving renal function than corticosteroids alone, especially in patients with severe biopsy changes. There was no difference in major infection between any of the five groups, although there was a higher incidence of herpes zoster infection in the CYC groups. Premature ovarian failure was also more prevalent in the patients receiving CYC. However, although haemorrhagic cystitis was observed in the oral CYC group, no cases were observed in the IV CYC group.
When the follow-up of these patients was extended to 9 yr it became clear that renal survival was significantly better in all three groups given CYC than in the group given corticosteroids alone. These significant differences had only become evident at about 56 yr of follow-up, showing the importance of long-term analysis in trials of lupus nephritis. There was no evidence of excess mortality due to CYC [13].
In the next trial, a longer course of IV CYC was found to be more efficacious in preventing renal exacerbations than a shorter course of IV CYC or a 6 month course of monthly IV methylprednisolone (MP). The long course comprised what we now regard as the standard NIH regime, whereas the short course was the initial 6-monthly pulses of the regime only. Sixty-five patients were followed up for 60 months. Their renal disease was more severe than the patients in the previous studies, with all having proliferative changes on their renal biopsies (mostly diffuse proliferative change, i.e. WHO class IV). The patients who received the longer course of CYC experienced fewer renal relapses (10% vs 55%) than the short-course group and were at lower risk of creatinine doubling (15% vs 35%). Although a higher rate of premature ovarian failure was observed in the long-course patients (38% vs 19%), herpes zoster and other major infections were rare and not higher in either treatment group. The authors concluded that although a briefer course of CYC may be effective in preventing renal progression in the first few years of the disease, an extended course is required to reduce the risk of subsequent exacerbations [3].
More recently, 82 patients with proliferative glomerulonephritis were treated with either the NIH regime alone, the NIH regime plus IV MP or with IV MP alone. The outcome, in terms of deterioration of renal function and increasing probability of remission, was superior for both NIH regime groups than for IV MP alone over follow-up intervals of 72 months [4] and 120 months [5]. Furthermore, the combination of IV CYC and IV MP appeared to be more efficacious than IV CYC alone [4, 5].
These trials have established the efficacy of high-dose IV CYC in treating lupus nephritis beyond reasonable doubt. The ELNT data are not sufficient to show that a low-dose CYC regime would be equally effective. One reason for this is that the low-dose regime was not compared with the accepted NIH regime: members of the high-dose group were given only eight standard pulses over 12 months. In addition, the patients in both groups of the ELNT did not have as severe renal disease as those in the NIH cohort. Compared with those in the NIH trials [35], the patients in the ELNT had a lower prevalence of proliferative changes on renal biopsy (92% vs 95100%), less proteinuria (mean of 3.0 g/24 h vs 4.04.8 g/24 h) and a lower renal chronicity index (0.8 vs 2.93.3). There were also far fewer Black patients in the ELNT cohort (8.9% vs 2343%). The ELNT patients were followed-up for a shorter period than the NIH patients (41 months vs up to 132 months): thus, differences in the harder outcome of ESRF would be less apparent at this shorter interval.
Although proponents of the low-dose regime cite a reduced rate of adverse events as its major advantage, the ELNT found no statistical difference in rates of any adverse events between high-dose and low-dose regimes. Furthermore, the trial may have been underpowered to detect such differences [15].
We know that premature ovarian failure in patients treated with CYC is related to age and total dose of CYC received. Boumpas et al. [16] compared the standard NIH regime (15 doses) with seven standard doses (0.51.0 g/m2) of IV CYC. Thirty-nine per cent of the patients receiving the 15 doses experienced sustained amenorrhoea compared with 12% of the patients receiving seven doses. Thus, the major advantage of a briefer CYC course would appear to be a reduction in the risk of premature ovarian failure. Now, however, we do have hormonal strategies to prevent this. It has been shown that gonadotrophin-releasing hormone agonists such as zoladex or leuprorelin, commenced 1 month before embarking on a course of CYC and continued until 3 months after completion, can switch the ovaries into a state of hibernation in which they are rendered less susceptible to harm from CYC [17, 18].
The ELNT is the only head-to-head comparison of low-dose and high-dose IV CYC in lupus nephritis. The opposition submitted that this study provides insufficient evidence to claim that low-dose IV CYC is equivalent, let alone superior, to the well-established NIH regime. The results of the ELNT cannot be generalized to patients in all ethnic groups, especially Black patients, or to patients with more severe disease. More strictly comparable controlled trials with longer periods of follow-up would be required to allow such extrapolation.
We should not change the current high-dose IV CYC treatment regime for lupus nephritis, since this regime is supported by exhaustive evidence. The alternative low-dose regime has not been supported by sufficiently long or sufficiently numerous trials to be accepted as an adequate replacement for the NIH platinum standard regime.
Discussion
There was a lively discussion from the floor. Two speakers felt that although CYC has been vital in the treatment of lupus nephritis, the debate between low-dose and high-dose regimes may soon become academic due to the availability of new treatments. In particular, mycophenolate mofetil has been shown to have equivalent efficacy to CYC in one randomized trial [6] and B-cell depletion with rituximab has also shown great promise in an open study [19]. In a recent trial, Contreras et al. [7] induced remission with five to seven pulses of high-dose IV CYC but then randomized patients into three groups treated with oral azathioprine, oral mycophenolate mofetil and the standard NIH IV CYC regime respectively. Patients in the CYC group had higher rates of mortality, chronic renal failure, amenorrhoea, infections and frequency of hospitalization than the other groups. This underlines the fact that the use of high-dose IV CYC in lupus nephritis is increasingly being called into question.
One questioner asked whether unwillingness to change to low-dose IV CYC was an example of physicians being reluctant to change their practice from what has become a comfortable standard. This was rejected by another speaker who stated that, because proliferative lupus nephritis is such a potentially damaging disease, physicians should be cautious in changing a practice that has been rigorously proven until solid evidence shows that that the alternative treatment is superior. In particular, longer-term follow-up looking at the ultimate end-point of ESRF is important. With over 10 yr of follow-up, the NIH regime has been proven to reduce the rate of ESRF. Dr David DCruz (one of the members of the ELNT group) referred to unpublished 60-month follow-up data from the ELNT patients, which shows similar results to the initial data.
It seems unlikely, however, that further large trials comparing the high-dose and low-dose CYC regimes will be carried out. Difficulties include cost, limited ability to recruit patients given that many may be treated with mycophenolate instead, and the complex new regulations governing clinical trials. Some speakers expressed the opinion that it will be increasingly difficult to carry out such trials in the future other than those funded by pharmaceutical companies.
Other speakers expressed the concern that ovarian protection strategies were impractical and thus were not routinely utilized by the majority of centres administering CYC.
It was pointed out that patient choice was vital in deciding which treatment they should receive, especially in today's National Health Service. Patients should receive the appropriate information to empower them to make such decisions. Experience from the USA suggests that some patients may opt for low-dose CYC on the basis that toxicity (especially infertility) may be reduced. It is difficult, however, to be clear how to inform patients on this issue when the evidence on direct comparison of high-dose and low-dose regimes is incomplete, and likely to remain so.
The resulting vote was almost equally divided but just settled in favour of keeping the high-dose IV CYC regime as the departmental protocol:
The authors have declared no conflicts of interest.
References
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