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Ladies and gentlemen and Chairman. The primary systemic vasculitides can target all the different elements of the vascular tree and between them can cause necrosis and inflammation of blood vessel walls.

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But this afternoon I’m going to focus on those primary systemic vasculitides that commonly cause glomerular disease and which are commonly associated with the presence of anti neutrophilic cytoplasmic antibodies or ANCA, as shown here.

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Now these disorders normally start with a focal segmental necrotising GN and if untreated, they will progress often quite rapidly to a crescentic nephritis which is often pauci-immune.

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So what then is the need to treat acute vasculitic GN? Well, one point is because the acute lesions heal by causing a cellular scar and this then leads to the loss of functioning renal tissue and by implication it suggests that early treatment will reduce damage and improve the long-term outcome.

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But is indeed there any evidence for this? Well, there are published studies generally with small numbers of patients which suggest that early treatment is beneficial but I’d like to show you some data from a 20 year cohort study which we undertook in Birmingham which involved 390 patients. Now, this cohort had a median age of 64 and a median creatinine of 343 at presentation. They were all followed up for at least two years.

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Now one of the important outcomes for prognosis was the percentage of normal glomeruli in the renal biopsy at presentation. As you can see here, when there was more than 75% of abnormal glomeruli present, it was very unusual for these patients to reach ESRF over a 10 year period. Whereas if there was less than 25% of abnormal glomeruli, many progressed to ESRD. This suggests that earlier treatment will have prognostic benefits.

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Similarly if one looks at the creatinine at presentation again patients with lower creatinines had better outcomes. If we look at the 10 year outcome, patients who presented with a creatinine less than 120 had a low probability of reaching ESRF, whereas nearly 40% of those whose creatinines were greater than 450 were to reach ESRF within 10 years.

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So not rocket science but all suggesting that early intervention is going to be beneficial. So if we are going to intervene what aetiological mediator or pathogenic mechanisms do we want to target with therapy in order to reduce renal damage?

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There is indeed direct evidence now that the ANCA vasculitic  glomerular nephritides are autoimmune diseases and that the anti neutrophilic cytoplasmic antibodies themselves may contribute to injury. Evidence for this comes from studies in man where the placental transfer of ANCA-IgG was associated with vasculitic nephritis in the neonate. Indicating that the IgG itself is pathogenic. Similarly in animal models a transfer of MPO-ANCA was sufficient to induce vasculitic nephritis in naïve mice.

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So what therapeutic targets might we want to focus on?
If we were to know what the aetiologic agents were that were driving this process, we might want to try to eliminate them. But unfortunately in the vast majority of patients we simply do not know. In a minority of patients we do know that drugs can cause an ANCA-associated vasculitic nephritis, drugs such as the antithyroid drug propylthiouracil and indeed that withdrawal of the drug in those circumstances can lead to resolution of the disease. But for the most part we have to fall back on trying to target the pathogenic mechanisms underlying these autoimmune diseases.So we may want to target the cells of the innate immune system, the neutrophils and monocytes that are known to carry the target antigens of the ANCA antibodies. Or we might want to target the endothelium which is both a target for and a facilitator of inflammation. Alternatively we might want to consider targeting the adaptive immune system, the B cells, the antibody-producing plasma cells, T cells, the antigen presenting cells which likely all permit and sustain an autoimmune response. Now in practice what this is meant is that we have fallen back on using blanket immunosuppressive therapies; prednisolone and cyclophosphamide. These drugs have wide toxicity profiles and cyclophosphamide the toxicity there is related to the total cumulative dose.

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What I’d like to suggest to you is that the standard induction therapy that we have ended up with is to use a combination of prednisolone and IV pulses of cyclophosphamide with steroids being used in relatively high doses to start off with and tapered fairly rapidly with cyclophosphamide dosage being adjusted to age, renal function and white cell count. Accompanying these drugs with various partner prophylactic agents.

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So what is the evidence that this intermittent pulse therapy for use of cyclophosphamide is any better than daily oral cyclophosphamide. The evidence for this came in the first instance from a metanalysis which suggested that pulse cyclophosphamide was as good an inducer of remission as daily oral cyclophosphamide but possibly at the expense of a higher rate of relapse. So this led on to the CYCLOPS trial which is a randomised prospective controlled trial run by the European Vasculitis Study Group or EUVAS.

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Now this trial has not yet been published but essentially it was organised to target patients with generalised untreated ANCA-associated vasculitis that had renal involvement with creatinines between 150-500µmol/l. Patients were randomised to receive either daily oral cyclophosphamide or pulse cyclophosphamide until remission. Then the cyclophosphamide was continued in both limbs for a further 3 months. After that the cyclophosphamide was discontinued and patients were continued on azathioprine. 149 patients were entered into the study and followed for 18 months.

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So on an intention-to-treat analysis the proportion of patients reaching the primary endpoint with 9 months disease free survival was actually equivalent between the two limbs of the trial. Furthermore, the proportion and remission at 6 months was also the same in both limbs of the trial. The time to remission as assessed by a Kaplan-Meier survival analysis was also no different between the two limbs of the trial. So there was no difference in any of these endpoints.

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What about relapse? Now the study wasn’t powered to look at there specifically but there were 17% of relapses in the intermittent pulse limb and 8.2% in the daily oral limb but this was not statistically different and there was no significant difference in the time to relapse between the two arms of the study. I don’t have time to show you the data but in the daily oral limb there was a non-significant increase in adverse events.

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So the CYCLOPS study suggests that pulse cyclophosphamide is as effective as daily oral cyclophosphamide but as it is associated with an approximately 50% reduction in the total cumulative dose, remember that’s what relates long-term to toxicity, then the pulse regime is probably safer.
What about other ways of inducing remission? Well, methotrexate has been shown to be effective at least for patients who do not have renal disease. Currently mycophenolate is being tested against cyclophosphamide in the MYCYC trial which is currently recruiting. So hopefully in a few years time we’ll have further information on whether mycophenolate is an alternative to cyclophosphamide for induction of remission.

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So far I’ve talked about patients with moderate renal involvement what about patients with severe disease where creatinines were greater than 500 µmol/l at presentation or patients had lung haemorrhage. Here the recommendation is that these patients should receive plasma exchange as adjunctive therapy to the prednisolone and cyclophosphamide with at least seven 4l exchanges being performed over 14 days as plasma exchange appears to be more effective than pulses of methylprednisolone in this setting.

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The evidence for this comes from the MEPEX trial where patients were randomised to receive either 3 IV pulses of 1g of methylprednisolone or plasma exchange in addition to daily oral cyclophosphamide and prednisolone with cyclophosphamide being switched to azathioprine after 6 months. The endpoints were renal independence at 3 and 12 months.

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This study has been published so I shall just show you some data on the primary endpoint and as you see here, the renal recovery in those patients receiving plasma exchange was much better than those who received the pulses of methylprednisolone suggesting that plasma exchange is probably more beneficial at achieving renal independence at 12 months.

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So having got patients into remission what then? How do we maintain remission? The recommendation is that we switch patients to the less toxic drug azathioprine from about 3-6 months and maintain them on this agent together with low dose steroids.

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The evidence for this recommendation comes from the CYCAZAREM trial which was the first EUVAS trial to be published. In this patients all received daily oral cyclophosphamide for the first 3 months and then in the standard limb this being the standard in the mid ‘90s when the trial was designed was based on the NIH regime and all the patients in the standard limb received 12 months of cyclophosphamide. The others were switched to azathioprine at 3 months and all patients were then continued up to 18 months.

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The primary endpoint in this trial was the rate of relapse. As you can see, there was no difference between the two limbs of the study suggesting that the lower dose of cyclophosphamide with early conversion to azathioprine was probably justified and probably safer long-term.

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So once patients are in remission they need to be monitored because this disease can relapse. You need to look out for recurrence of the clinical symptoms and signs of the disease, keep an eye on renal function and monitor for example, acute phase markers. But in the metanalysis there are some 22 studies there was no recommendation achievable in terms of the value of serial ANCA monitoring and this was largely due to methodological shortcomings in the study. So at the present time we do not recommend that you alter your therapy on the basis of a change in the ANCA titre on its own.

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But what patients will relapse? Will those who have ever been cANCA positive of PR3-ANCA positive as against to P-ANCA or MP-ANCA positive appear to have a much higher likelihood of relapsing as do those patients with diagnosis of Wegener’s rather than microscopic polyangitis and of course, with time there is an increasing increment in the numbers of patients relapsing. The graphs show data from EUVAS studies showing here that patients with Wegener’s are more likely to relapse as are those who have a cANCA or PR3-ANCA.

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So if well over 50% of our patients are going to relapse at some point how can we try to maintain remission and reduce the chances of relapse? Well, there are 2 trials which have attempted to address this. The IMPROVE study, a EUVAS trial has compared the use of mycophenolate for azathioprine for maintenance of remission. This study has recruited and is currently being analysed and hopefully the preliminary data will be available later this year.

Slide 26

So it’s all very well then to try to treat acute disease early and avoid chronic disease, to try to get our patients into remission and prevent relapse. But another problem that we have then is the toxicity of therapies particularly cyclophosphamide and prednisolone. Although the CYCAZAREM and the CYCLOPS trial have shown that we can safely try to reduce the amount of cyclophosphamide that we are using we still have a problem. You can see here that the toxicity was particularly high in patients with severe disease and this is data from the first 3 EUVAS trials collated.

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Furthermore, mortality tended to go with infection. So there’s clearly a need for drugs which have a better toxicity profile.

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So we need novel therapies particularly for when patients fail on conventional therapy either because of toxicity or because of resistance. In such circumstances we would recommend that patients are referred perhaps to a specialist units and then anti-T cell therapies or perhaps some newer immune suppressing drugs such as deoxyspergualine or novel biologicals may be indicated. Now, recently controlled trials have been targeting the anti-B cell and the anti-TNF biologicals. In particular, with the anti-B cell agent rituximab the RAVE study is in progress in the US and the RITUXVAS trial has recruited in Europe.

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Now, RITUXVAS has compared a CYCLOPS type induction regime with a regime involving the use of rituximab partnered with 2 and only 2 pulses of cyclophosphamide, a single dose of methylprednisolone and a very rapid steroid taper. Now this trial has recruited and again hopefully the data will be available later this year.

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But what I can show you is some data from a small study from Ulrich Specks at the Mayo clinic where rituximab was administered to 10 patients. The top graph shows a BVAS score which is a score of disease activity and as you can see, the use of rituximab was associated in all these patients with a rapid achievement of induction of remission generally within 4-6 weeks. This was accompanied by B-cell depletion in all patients. In the first 24 patients that we treated in Birmingham for vasculitis all of these patients who had had problems of one sort or another with standard regimes entered remission within 4-6 weeks and the median duration of remission was 13.5 months and all achieved B-cell depletion. As in the published study we too saw a slow fall in ANCA titres. So, rituximab is causing a lot of excitement at the moment and it may well become an important inducer of remission for primary vasculitic disease. But we need the data from the randomised prospective controlled trials to be sure about that.

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What about the anti-TNF agents? Well, 2 have been tested in vasculitis. A monoclonal antibody called infliximab which targets both cell bound and soluble TNF and etanercept which is a soluble recombinant TNF receptor fusion protein which just targets soluble TNF.

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The WGET study was a randomised prospective controlled trial looking at the use of etanercept in Wegener’s and no effect was demonstrated when this was added to standard treatment. Infliximab was used in a pilot study of 32 patients in the UK to treat ANCA-associated vasculitis and although some benefit was demonstrated this was at the expense of a high instance of infection. So currently anti-TNF therapies do not appear to be centre stage for treatment or primary treatment of patients with vasculitis.

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Finally, don’t forget about patients with end stage renal failure, renal transplantation is an extremely good treatment for these and with good renal and patient survival and you can use standard transplant suppressive regimes for these patients. Relapses can occur and these maybe either renal or non renal but in general the graft survival is good. However, as a word of caution it’s generally better not to transplant patients until they’ve achieved a clinical remission although you can safely transplant patients when they remain ANCA positive.

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So finally, I’d just like to thank all my colleagues in EUVAS without the concertive efforts for many, many colleagues we would not have been able to report on the trials I have described this afternoon. Thank you for your attention.