Friday, December 3, 2010

High Maintenance

Many nephrologists will have faced “interesting specialty, shame about the evidence-base” jokes in the past. However, following a profusion of randomised controlled trials in lupus nephritis, we are now entering an era where we can integrate data to make truly evidence-based treatment plans.

The latest randomised trial to appear is the MAINTAIN study. This was designed to assess whether MMF is superior to azathioprine (aza) in the maintenance phase of treatment of biopsy-proven proliferative lupus nephritis. For the most part, recent studies in lupus have focused on induction treatment, with an emerging consensus that MMF and IV cyclophosphamide (IVC) are at least equivalently efficacious with a favourable avoidance of ovarian failure associated with MMF.

MAINTAIN was an open label study of 105 patients who were followed-up for 48 months. All patients received induction treatment with steroids and IVC before being randomised to either MMF or aza regardless of renal response to induction. The primary endpoint was time to renal flare (defined as either development of nephritic syndrome, a 33% climb in serum creatinine or 3 fold increases in urinary protein); secondary end points were set as the numbers of severe systemic and benign flares, those withdrawing steroids and those achieving renal remission.

The headline result was that whilst fewer renal flares (25% v 19%) were seen in those treated with MMF this, and all secondary end points, did not differ significantly.

So what is important and original about MAINTAIN? Well, recent publication of the 10 year results of EUROLUPUS has shown the effectiveness of aza as a maintenance therapy. Therefore, given that MMF is about 15 times more expensive than aza and carries a reasonable burden of side effects, some feel it should be demonstrated to be superior to justify its widespread usage.

The trial was performed in Europe with a huge Caucasian predominance. This is likely to be relevant given the racial disparity in MMF response demonstrated during the induction phase of the ALMS trial. ALMS was designed to compare MMF and IVC as induction therapy for 24 weeks and then saw re-randomisation of patients to MMF and aza. Black and Hispanic patients responded better to MMF. The maintenance phase results of ALMS are now available in abstract form and show that MMF was superior to aza in preventing a composite end point of death, renal damage, and renal relapse. This difference between MAINTAIN and ALMS may be a result of the fact that in ALMS only patients who had achieved a renal response at 6 months were included in the maintenance phase, or because a composite end point was used in ALMS, or, more simply, because ALMS was larger (227 randomised patients v 105 in MAINTAIN).

So what more do we need for trial evidence in lupus? Some long term data focused on ESRD and death would be helpful. Especially if it focused on those patients both induced and maintained with MMF. One thing is for sure though, the days of expert opinion guiding treatment of glomerular diseases is receding fast.

Tom Oates M.D.

1 comment:

Anonymous said...

Why hasn't ALMS maintenance been published yet? Or these results were interim and follow-up is ongoing?