CME Slides Forum - C. Pusey

A joint Congress by ERA-EDTA and ISN

LUPUS NEPHRITIS: CLINICAL TRIALS AND NOVEL THERAPIES

Charles Pusey, London, UK

Chair: Leishi Li, Nanjing, China

Francesco Paolo Schena, Bari, Italy

pusey

Dr Charles Pusey
Faculty of Medicine
Imperial College
London, United Kingdom

Great, thanks very much indeed Vicky and I’d like to thank the organisers for asking me to speak at this conference. I’m going to cover quite quickly a range of clinical trials and novel therapies in lupus nephritis.

You’re all familiar with the ISN Renal Pathology Society classification of lupus nephritis ranging from minimal mesangial change through mesangial proliferative to class III or class IV i.e. focal or diffuse proliferative, class V which is membranous and class VI which is advanced sclerosing. When you’re considering the results of trials you need to consider what class of lupus nephritis was included. Most of the trials described evolve to both class II and IV, some additionally involve class V.

Now the treatment of class III and class IV has been widely influenced by the long-term NIH studies with which you’ll all be familiar. Their results a show a clear advantage of additional cyclophosphamide over prednisolone alone. In addition, they’ve shown that combining cyclophosphamide and methylprednisolone is superior to IV cyclophosphamide alone and these results are shown here showing that cyclophosphamide and methylprednisolone alone give the best long-term outcome compared to either cyclophosphamide alone or methylprednisolone alone.

So this combination of two very unpleasant drugs, cyclophosphamide and corticosteroids has become kind of accepted practice and one of our major aims or one of my major aims is to eliminate all these unpleasant drugs and try to treat lupus nephritis in a kinder way.

So one question is can the cyclophosphamide dosage be reduced while maintaining efficacy?

Addressing this question has been the Euro-Lupus Nephritis Trial which is a multicentre trial across Europe comparing an existing high dose cyclophosphamide regimen similar to that used by the NIH with a new low-dose cyclophosphamide regimen involving 500 mg of cyclophosphamide IV given every 2 weeks times 6. After the completion of the induction therapy each of these regimens was followed by azathioprine.

If we compare the high and low-dose treatment, there was absolutely no difference in the failure to respond in the two groups.

Similarly there was no difference in the incidence of renal flares or relapses during the 5 years of the study.

However, there was a slight tendency towards more severe infections in the high-dose group than in the low-dose group which is rather as you might expect. So the answer is you can use a lower dose cyclophosphamide regimen than the classical NIH studies.

The same group went on to report a long-term follow up of their work. I think only last month they released their follow up paper following these patients up for 14 years. Again looking at the major outcomes here there was no difference in death on long-term follow up

and there was no difference in the development of ESRD on long-term follow up. Although the follow up maintenance treatment was a bit varied it does show that taking a low-dose approach does not cause a problem to the patient in the longer-term. So if people would still like to use cyclophosphamide for whatever reason I think the lower dose regimen is acceptable.

Mycophenolate mofetil, I’ll be talking about a fair bit because there are a number of trials it’s moving into first line therapy. Cyclosporine and tacrolimus are probably going to become acceptable for membranous lupus nephritis. Leflunomide is used in rheumatology, it’s not used much by nephrologists in Europe certainly though there are reports of its use coming in from the Far East. IV immunoglobulin has been shown to be effective in one small controlled trial quite a long time ago but it’s the type of treatment that I think many of us would use if we were concerned that a patient with active disease also has active infection. We’re trying to avoid other immunosuppressions and it may well be that it has a distinct role there. As you heard in an earlier talk, it does very interesting things in modulating the immune system. Rituximab, I will mention again in more detail and other biological agents.

This is something we’ve all thought probably would be the case but fortunately this trial was released in I think last month or this month’s Journal of the American Society of Nephrology comparing the use of prednisolone, cyclophosphamide and cyclosporine in patients with class V lupus nephritis. The regimens used were prednisolone alone, an IV cyclophosphamide regimen or standard cyclosporine.

Interestingly there was no difference between the cyclosporine and the cyclophosphamide regimens both of which showed a better induction of remission in lupus nephritis than prednisolone alone. So that’s very reassuring so to induce a remission in nephrotic syndrome, in lupus nephritis you don’t need cyclophosphamide you can use cyclosporine.

However, what was not so good was that the incidence of relapse of nephrotic syndrome was much higher after cyclosporine than after cyclophosphamide. As you’ll all know, in many other forms of nephrotic syndrome where calcineurin inhibitors are effective they do tend to show this tendency to early relapse? So you either need to keep on treating longer or you think of some other form of maintenance.

So to mycophenolate mofetil, is that an effective alternative to cyclophosphamide in proliferative lupus?

The earliest study really came from Hong Kong comparing prednisolone together with MMF versus prednisolone and cyclophosphamide orally for 6 months followed by azathioprine.

Most of you will know this data already complete remission was the same in MMF and cyclophosphamide limbs as was partial remission and relapse. There was the tendency towards more infections in the cyclophosphamide limb. However, this study formed the early basis for the belief that MMF was effective in induction therapy.

This was followed up by a trial in America published in the New England Journal and this was a trial comparing MMF 1g, TDS quite a big dose compared with cyclophosphamide between 0.5-1 g/m² monthly. One particular point of this trial based on the ethnic mix of the group studied was there was a high proportion of African-American patients.

If we look at the results of this study, it looks as if MMF induces a higher number of complete remissions, similar numbers of partial remissions but overall when you add these together an overall higher incidence of complete and partial remissions. This really led on to other studies of MMF in the belief it might be even better than cyclophosphamide and one of these that just reported again last month I had read all these slides in the last week because there are so many studies that are getting published all the time.

This was the Aspreva Lupus Management Study or ALMS trial and this compared patients who all got the same standard prednisolone regimen and then they either had MMF orally or IV cyclophosphamide for the first 6 months i.e. for induction. The idea was that after those 6 months they would be re-randomised to compare MMF with azathioprine in maintenance. It’s the early study, the induction study that was reported by Gerald Appel just recently.

As you can see, the response rate was identical MMF 56% overall, cyclophosphamide 53%, the number of complete remissions was similar but complete remission was very tough, it was normal creatinine and proteinuria less than 0.5g in 24 hours.

The serum creatinine targets, the urine protein targets were the same and there was no significant difference in adverse events. Now, because of the requirement to satisfy the FDA, this was powered as a superiority study so the aim of this study was to show that MMF was superior. For this reason many commentators have said well this trial has actually failed because it failed to demonstrate what it set out to do. I don’t agree with that I think it is a very successful trial that chose a very large number of patients across various centres, that MMF is as effective as cyclophosphamide. Therefore, if you believe in avoiding the side effects, very well known side effects of cyclophosphamide, this is an encouraging study it suggests you can safely use MMF instead. The other interesting bit was when this was analysed, the response rates were seen by racial group involved. We can see that the only group in which there was a significant difference in which MMF induced more remissions than cyclophosphamide was in the other group and others in fact include mainly black and Hispanic races. So it could be that in certain ethnic groups for whatever reason of their immune system or biology MMF seems to be more effective.

Well, the earliest study of this was published by Contreras and it used an induction regimen of cyclophosphamide in all patients. They were then randomised to a maintenance therapy either with IV cyclophosphamide, azathioprine or MMF.

The results showed that in terms of maintaining the patient free of a major clinical event either MMF or azathioprine were considerably better than cyclophosphamide and again, this is good news because many people thought we need to continue cyclophosphamide for maintenance 3 monthly or however roughly it was. In fact MMF and azathioprine are more effective.

When we look at the relapses occurring, again here it looks as if MMF is better than either azathioprine or cyclophosphamide although it’s only significantly better than cyclophosphamide. So it looks as if MMF is good for maintenance too.

The study I described to you earlier from Hong Kong by Chan et al. was extended to look at a follow up period and it included the original patients he had in his first study plus he added some more such that there were 30 or so in each group. MMF induction and maintenance although in his earlier study you’ll remember some were swapped to azathioprine compared with cyclophosphamide followed by azathioprine.

Again, in terms of relapse free survival there was absolutely no difference suggesting that MMF was perfectly reasonable maintenance therapy.

Finally, what’s the role of new biological agents in the treatment of lupus nephritis?

You’ve heard an awful lot about these from the previous speaker so luckily I won’t need to dwell on them. In terms of the B lymphocyte just to remind you some of what Doctor Diamond talked about, you can eliminate these or some subsets of these with antibodies to CD20 or CD22. You can inactivate them perhaps by engaging the B cell receptor with DNA multimers. You can block their activation via blocking BlyS/BAFF signalling and you can inhibit T cell costimulation via CD28/B7 or CD40-CD40 ligand. So there are a lot of potential places, all of these have been looked at and exploited, all of these have been found to be effective if you can try with an experimental model to show they’re effective and none of them are proven in human disease which I think is the message you received a little bit earlier.

They have been reviewed quite nicely in a recent article in Rheumatology so I don’t need to go in to them. Clearly rituximab, antiCD20, epratuzumab, antiCD22, B cell activation via something called abetimus which is a multimeric DNA molecule that cross links immunoglobulin receptors. Belimumab which is an agent that antagonises BAFF. Blockade of T cell costimulation, abatacept and belatacept are like CTLA 4Ig, they block CD28/B7 and there’s an IDEC compound, Biogen compound, these block or these antagonise CD40 ligand. TNF blockade you’ve heard about with either antibodies to TNF or soluble TNF receptor. There are early studies using an IL-10 monoclonal antibody. Finally people are starting to look at complement inhibition with eculizumab which is the antibody to C5.
So all of these approaches as I say can be shown to have an effect biologically in different animal models. All of them are entering early phase clinical studies, so I’m not talking about many years in the future I’m talking about these are ongoing studies.

At the moment none of them have shown to be of proven benefit. So I think that we’ll just watch this space. There’s a little more published about rituximab. This is one brief report again in last months’ Clinical JASN showing 20 patients either refractory, in relapse or as first line therapy showing a 60% response rate which is not bad for this group of patients. B cell depletion was associated with response, failure to deplete was associated with black ethnicity and also with severe hypoalbuminemia.

This is obviously additional therapy. We’ve taken a slightly different approach and I’ll just show you two slides. We’ve taken an approach of using rituximab and methylprednisolone 2 weeks apart and maintenance therapy with MMF alone with no oral steroids this is because we’ve now eliminated cyclophosphamide from many of our regimens, let’s try and eliminate steroids as well or at least the high-dose element of them. In this we got an overall response rate of 79%, 11 complete and 12 partial.

Protein creatinine ratio in the urine improved significantly as did serum albumin in the blood. If we look at how our patients did compare with the MMF limb of the ALMS trial I know this is not the valid thing to do scientifically but just out of interest it looks like there are more responders and more remissions.

However, I’m sure most of you in this room won’t have escaped the fact that Genentech has announced on their website that their study of rituximab on a background of MMF and steroids did not show any significant benefit. I haven’t actually heard this presented or seen it published or anything but it’s just up on the website it says it doesn’t seem to be of benefit. However, bear in mind that in this study rituximab was an add on, on top of MMF and steroids which is already very effective therapy. So I think we ought to wait and see what the paper shows before we’re absolutely confident of what the results.

So I’d like to wind up by saying I think recent studies have shown MMF is as effective as cyclophosphamide for inducing remission in lupus nephritis class III and IV. I think either MMF or azathioprine are as effective as cyclophosphamide for maintaining remission. You have to take your choice based on whatever parameters you use, cost perhaps might be one thing. Rituximab, maybe I should have changed this I think it probably is still worth investigating but the results of the Genentech trial do suggest it’s not of additional benefit compared with conventional therapy. However, it may have a role if you’re trying to eliminate other therapies as in our own studies where we’ve cut down on steroids. So it might have a role in being steroid sparing and we might be able to learn how to use both it and the other biological agents more scientifically as you heard in an earlier talk just administering at any random time point and seeing what happens is perhaps not the best way to do it. We actually need to think what stage of the disease’s pathogenesis we’re dealing with and target these biological agents more thoughtfully in the future. Thanks very much for your attention.

Chairman: This presentation is open for discussion. Could you state your name and institution?

Question: My name is Doctor Turi from Hungary. When can you stop the maintenance therapy in an SLE patient? I’ve been following for more than 20 years a couple of adult patients who were children when I started their treatment but when I asked Stewart Cameron how can you decide to stop for instance every other day steroids or some other things, what is the indication? How can you be sure that you can stop that? Because sometimes I experience that everything started at the beginning even after 15 years.

Dr. Pusey: That’s a very good question I would certainly say in our rituximab treated patients we do stop immunosuppression after about 6 months probably. But as you know, the B cells recover and the immune process comes back in about a year, so we tend to try to either re-treat with rituximab or maintain low-dose immunosuppression. But I think that’s a different situation. In the normal situation when you’re not using something like rituximab Stewart Cameron’s view would be that life-long low-dose immunosuppression is necessary. I would always try and stop in fact. I would hope that the patient had been in clinical remission for a year at least and I would taper very slowly. If they had a rising titre of anti-DNA antibodies I probably wouldn’t choose that moment to reduce although as you know antibodies are not particularly accurate biomarkers. But if they were in clinical remission and they didn’t look very active immunologically, I would taper them very slowly and we do get a proportion of patients off and we just need to look early to see if they’re relapsing. But I think I would move very much towards trying to minimising the damage we’re doing to these patients long-term immunosuppressive drugs and even steroids that are sometimes regarded as less harmful than others cause immense damage. So I would try and get patients off unlike I think the older approach. It may be that some of the new biologicals will allow us to, once we’ve learnt how to use them properly.

Question: Charles I have a practical question for you. When you have patients with SLE which drugs are first line treatment, second line treatment, third line treatment?

Dr. Pusey: First line treatment for most cases of proliferative nephritis would be a combination of MMF and steroids. If the patient had severe crescentic nephritis with rapidly deteriorating renal function, I would still use cyclophosphamide. That’s maybe a little bit old fashioned but I would still retain more confidence in cyclophosphamide and I would add pulse methylprednisolone. So I think for a very severe crescentic nephritis I would use that. For most cases of proliferative GN I would use a combination of MMF and steroids. As I say, our use of rituximab has been in the context of an open label protocol, so whether we actually choose to continue that protocol we need further analysis to wait and see.

Question: Thank you very much Charles for this excellent talk. I just want to ask how do you start MMF? Usually you up the dose initially in the active form. If you give for example, prednisolone does this act immediately? You need to build up the dose because the dose is large, some people use 2g or 3g. So what is your protocol? I think building up the dose starting with a small dose and see the response. How do you measure the response?

Dr. Pusey: In terms of the dose that we aim at we monitor those mycophenolate levels as we do in transplantation. So we don’t like to talk of dose, we like to talk of the levels we achieve. But in general most of our patients achieve the levels we want, 2g a day. We rarely use 3g a day which seems to be more of an American requirement. In terms of starting in order to avoid gastrointestinal symptoms and putting the patient off the drug all together I always start slowly. So I might start at perhaps 250mg twice a day, 500 mg twice a day, 500mg 3 times a day. Over two or three weeks. It depends how severe they are if they have severe disease I would be more aggressive in starting. But if there is time I would try and increase the dose over the first couple of weeks to minimise gastrointestinal symptoms. That does appear to work because if you whack them on a top dose they’re more likely to get symptoms and perhaps discontinue the treatment.

Question: My name is -- I’m from Pakistan. In fact I want to ask in which class type IV or type V rituximab is also good? Would you like to assess the chronicity or activity index before starting rituximab? In my experience what I have observed in my paediatric patients class IV they do respond to the protocol which you have mentioned but type V or class V, if they nephrotic range proteinuria the results are very poor.

Question: The prognosis was -- in type V with proteinuria in the nephrotic range.

Question: We have started with methylprednisolone pulses and initially 3 pulses followed by cyclophosphamide pulses on a monthly basis. 6 pulses followed steroids and azathioprine or MMF.

Dr. Pusey: Ok so you’re asking about the outcome of the different classes? I mean if we consider III and IV to start with it looks that most studies suggest that III and IV respond equally even if you subdivide class IV into sort of global or segmental variants which it was originally suggested they behave differently but recent studies suggest they probably all behave the same. Class V behaves probably differently and that’s why more people are using things like cyclosporine or tacrolimus. Sorry I should have said actually our first line for membranous would be tacrolimus. I missed out that because it’s less toxic than cyclosporine and just as good so I’d use tacrolimus. So, the therapies are all aimed at avoiding the older more toxic unpleasant drugs. So I agree with your point.

Question: Before starting rituximab do we need to do the activity index or the chronicity index?

Dr. Pusey: I think our pathologists should always do the activity and chronicity index. But I think unless the chronicity index is so high that you think you hesitate about treatment I think it’s of interest in following up the patient with a repeat biopsy which I’d always recommend but I don’t think it would stop you treating if there’s some activity going on.

Chairman: I think we’re going to have to move on but I’m sure Doctor Pussey would entertain questions independently.