Slide 1

Thank you for this introduction. I would also like to thank the organisers and the scientific committee for giving me the opportunity to share with you some recent data about the use of rituximab in idiopathic nephrotic syndrome in native kidneys.

Slide 2

Many treatments have been tried for idiopathic nephrotic syndrome but coming back to a few months ago one can say that anti-B cell therapy wasn’t the most rational therapy to be tried. Indeed even though the pathogenesis of idiopathic nephrotic syndrome is not yet fully understood many data seems to lead to a T-cell mediated disease and little is known about B-cell implication in such a disease. Rituximab is a monoclonal chimeric antibody directed against CD20 which is specific for early B cells. The role of CD20 is still not known as – is described. Well established indications of rituximab are for B-cell tumoral diseases and some autoimmune diseases like rheumatoid arthritis. Moreover, rituximab could be effective for other autoimmune diseases like ITP or Lupus.

Slide 3

First cases of idiopathic nephrotic syndrome treated with rituximab were accidental as rituximab administered for other purposes ITP or post transplant lymphoproliferative disease led to a dramatic improvement of the underlying nephrogenic disease. Based on these 3 first published cases a growing interest rapidly came over the years for rituximab for idiopathic nephrotic syndrome either before or after transplantation.

Slide 4

From now on I will divide my talk into parts. First cyclosporine dependent nephrotic syndrome and then cyclosporine resistant nephrotic syndrome.Let’s begin with cyclosporine dependent nephrotic syndromes.

Slide 5

To date only 8 cases have been published. Most of them were children and presenting with MCNS. The dosage of rituximab was far from homogeneous but rituximab was considered to be effective in all cases leading to a reduction or a complete remission of proteinuria in all patients treated during a proteinuric period and a stabilisation of the disease activity and a sparing or a withdrawal of other immunosuppressive treatments in all treated cases. No adverse effects were described.

Slide 6

Based on this conclusion we drew from the published literature a paediatrician from le Societé de Nephrologie Pédiatrique Network decided to use rituximab as a rescue therapy for severe cyclosporine dependent nephrotic syndromes.

Slide 7

I will now present our experience. The idea was to use rituximab in order to avoid kidney transplantation or severe side effects of calcineurin inhibitors. SNP members agreed to use rituximab for severe idiopathic nephrotic syndrome. Patients must have presented with immunosuppressant sensitive nephrotic syndrome, conventional agents must have failed to control the disease activity and patients must have experienced a long-term dependence on calcineurin inhibitors or severe side effects.

Slide 8

The design of the study wasn’t very rigid given this open and rescue context but the aim of the proposed guideline was to use rituximab as a sparing treatment for other immunosuppressive drugs that had become toxic for these patients. Thus most patients received rituximab during a protein free period with at least one other immunosuppressive treatment.
As this study took place in France and not in a more disciplined country several patients were not treated according to these guidelines. This weakened the results of our study to some extent but at the same time it brought some interesting data I will discuss.

Slide 9

To date 57 patients are included in this study. 34 of them at follow up are sufficient enough to analyse rituximab efficacy. I will then focus my talk on these 34 patients for the next coming slides. Most patients presented with MCNS. 2/3 were boys. Rituximab was infused for a mean disease duration of 9 years. With an age at rituximab ranging from 6-18. The mean follow up after the first rituximab infusion was 13 months.

Slide 10

Rituximab was infused during a proteinuric period in 12 patients. It was infused with other immunosuppressive treatments for all patients but 3. Those with rituximab changed with time and – and ranged from 4 to an infusion of 375 mg/m2. Complete B cell depletion was obtained for all patients from whom it was tested independently of the proteinuric state of the patient or the total dose of rituximab infused.

Slide 11

Given the efficacy criteria you can read here rituximab was considered to be effective in 82% of cases. But let’s have a closer look at these results.

Slide 12

When rituximab was infused during a proteinuric period, it led to a complete remission in 5 cases. No patient who received rituximab alone was induced in a complete remission and all the 6 failure cases of rituximab were observed in this proteinuric patient group.

Slide 13

The main effect of rituximab seemed to rely on its sparing effect on other immunosuppressive treatments. Indeed rituximab allowed withdrawal of at least one other immunosuppressive treatment in 25 patients and withdrawal of all immunosuppressive treatments in 11 patients without any relapse during the CD20 depletion period.
When used in association during a proteinuric free period, rituximab was considered to be effective in all patients. Currently, when used alone in a proteinuric period, rituximab was considered to be ineffective in all patients.

Slide 14

A similar study is in progress for adult cases but unfortunately, my time is too short and the study is not advanced enough to give you some precise results but preliminary results seem to be similar to paediatric ones.

Slide 15

Talking about long-term effects of rituximab that are more difficult to analyse. Additional courses of rituximab were performed for most patients in order to induce the prolonged B-cell depletion period. Several relapses occurred during this period but always when CD20 cells had reappeared just before an additional cause of rituximab. As you can see here, no CD20 cell count threshold was predictive of relapse.
Rituximab withdrawal was planned for 6 patients after a 19-month period of B cell depletion. Relapses occurred in 5 of these 6 patients. To date only one patient is free of proteinuria with circulating CD20 cells.
The German experience seems to be better as only 50% of patients treated by Kemper and colleagues relapsed after rituximab withdrawal.

Slide 16

Adverse effects were observed in 40% of cases but most of them were moderate and transient. The most severe were bronchospasm, cardiac arrhythmia, neutropenia and hemostasis.
Induced hypogammaglobuminemia occurred in 6 patients. I must add that a very recently treated patient that does not appear in these results deceased after the first rituximab infusion due to pulmonary fibrosis. The link between the death and rituximab hasn’t been proved yet. But several cases of pulmonary fibrosis in rituximab treated patients have already been published.

Slide 17

Those about cyclosporine-resistant nephrotic syndrome are less numerous.

Slide 18

To date only 6 cases have been published most of them were children. Again the dose of rituximab was far from homogeneous but authors reported efficacy in 5 of these 6 cases including complete remission in these cases and a sparing of other immunosuppressive drugs for all these 5 cases. Again, no adverse effects were observed.

Slide 19

As steroid and cyclosporine resistant nephrotic syndrome are not in the rituximab guidelines of our group, our experience is very limited. Nevertheless, 2 cases have been treated either alone or in association with other immunosuppressive treatments but led to no effects on proteinuria or albuminemia despite a complete B-cell depletion.

Slide 20

As I have shown you, many questions remain about the use of rituximab for idiopathic nephrotic syndrome but one of the big questions is how does it work?

Slide 21

Several hypotheses could be suggested. First of all, the efficacy of rituximab for idiopathic nephrotic syndrome addresses the question of B-cell implication in idiopathic nephrotic syndrome pathophysiology bringing back to daylight some old published data that I have no time to detail here.
Interestingly, a subset of T cells could express CD20 in normal subjects. One can ask the role of such a T cell subpopulation in idiopathic nephrotic syndrome pathogenesis.
Thirdly B cell depletion could have a B-T cell cooperation and then T cell population as recently described for ITP or lupus patients.
Lastly in each treatment it is possible that all the effects of rituximab are not yet known leaving the possibility of beneficial so-called adverse effects for idiopathic nephrotic syndrome patients.

Slide 22

Here are the conclusions we drew from our experience. Despite the fact that our series is the largest published to date, these conclusions remain fragile as there is to date no prospective control data. We have shown that rituximab by itself can induce remission of idiopathic nephrotic syndrome. Rituximab must be a very effective treatment as a sparing treatment for other immunosuppressive drugs.
When rituximab was effective, no relapse occurred during the CD20 cell depletion period but no CD20 cell threshold was predictive of relapse.
Finally rituximab may only be a suspensive therapy for idiopathic nephrotic syndrome.

Slide 23

Questions about the correct dosage and long-term therapeutic strategy remain.
I hope that I have shown you some beginning of evidence that rituximab could be effective for cyclosporine dependent nephrotic syndrome but clearly prospective control trials and long-term follow up are needed before considering rituximab as a conventional treatment for idiopathic nephrotic syndrome given it’s rare but sometimes very severe adverse effects.
Clearly the data are too limited to give any firm conclusion about cyclosporine resistant nephrotic syndrome but data from Bagga and others need to be taken into account when treating such patients with an otherwise very severe prognosis.
Lastly, I don’t think that rituximab will be the clue that will solve the idiopathic nephrotic syndrome pathogenesis mystery but certainly it will help researchers and physicians to look in the right direction.

Slide 24

Before ending I would like to thank Professor Ronco and Doctor Bouissou, without them all this work couldn’t have been done. Professor Chauveau and Doctor Guitard who are in charge of the collection of adult cases on behalf of the Societé de Nephrologie. Professor Bagga from India who kindly gave me some further data details from his patients. All the SNP members who participated in this study and of course, the patients and their families.

Slide 25

The last word of my talk will go to a great scientist of the previous century, Snoopy who as everybody knows had every response to every question. Talking about side effects it maybe very close to the link between rituximab and idiopathic nephrotic syndrome. I thank you for your attention.

Slide 26

Chairman: Thank you Doctor Guigonis for this interesting lecture. I think we have some time for questions. Please identify yourself?

Question: I have some concern about this effect in cyclosporine-dependent nephrotic syndrome because you obtained the best results in the patients in whom you will be able to obtain full remission with cyclosporine and the only problem is dependence and if the major effect is the diminishment of cyclosporine dose, the question arises whether if you diminish the cyclosporine dose, you will have the same effect, the same sparing effect which you received with the administration of rituximab. Considering all this data about T cell involvement in the pathogenesis we have to speculate that the effect of rituximab is connected with something unknown because B cells have no documented role in the pathogenesis. So I feel a little bit sceptical that the event of dependence justifies to use such powerful armamentarium in these children.

Dr Guigonis: Yes, I agree but when the patient has a dependence on cyclosporine for many years, we all know that it is very difficult if possible to withdraw this treatment. The severe side effects, fibrosis that maybe these severe side effects could be avoided using treatments like rituximab.

Question: Well, but we also know that we can prolong cyclosporine 1 mg/day for years and I’m uncertain what is safer. Rituximab or with this prolongation very low dose for years.

Dr. Guigonis: The question remains open I agree but rituximab has already been used for many thousand patients for other diseases with relatively safe use but it could be very dangerous too, so the question is what patients need such a therapy? And the question remains open. We have only treated very severe patients for the moment.

Question: One of the problems I think is in the past many investigators were concerned about the long term side effects of cyclophosphamide for example. We have now a good experience and we know that there are some probably thresholds indicating that more than 36g in total, for example, actually exposes to cancer and so on. My potential concern is that we actually inhibit CD20 production for a long period and although they reported good tolerance of the drug I wonder what happens after 5-10 years in these patients. Unfortunately, I don’t think we have any information about this in non-lymphomatose or non-leukemic patients and what is your opinion?

Dr. Guigonis: About long-term suppression of CD20 cells? Long-term experience about the use of rituximab in tumoral diseases is difficult to analyse because there are no long-term experiments reported and patients are treated with other therapies at the same time. The question is really what do we do for the future when we prolong the CD20 cell depletion period? But for these patients that we treated it seemed that there was no other way because they were dependent on high dose cyclosporine treatment with kidney fibrosis at biopsy for most of them and for most patients rituximab was used or nothing is done and wait for spontaneous remission or wait for kidney transplantation. So we decided to use rituximab but the long-term effect from an immunological point of view we don’t know.

Question: Actually, I feel that this is good news that we can rituximab. The problem is how to treat in the long-term these patients. I’m wondering whether rotating cyclosporine corticosteroids and rituximab maybe shorter term cyclophosphamide etc. can in some way allow to obtain remission, a long-term remission for these patients while avoiding the side effects of any single treatment. So, possibly our future strategy should be completely changed. In any case congratulations because you gave us a lot of information and this is important in clinical nephrology.