Case 3: Treatment Options
In this video, Craig Gordon, MD, nephrologist at Tufts Medical Center and associate professor of medicine at Tufts University School of Medicine, discusses the treatment options in this case of ANCA-associated vasculitis:
Editor’s note: The following is an automatically generated transcript of the above video.
“So let's look at the KDIGO approach to treatment. And this is from the executive summary. You could see upon making the diagnosis of ANCA-Associated Vasculitis, the next step is to assess the degree of disease activity. This is both in the kidney and elsewhere. And assuming that there's organ involvement from ANCA-associated vasculitis, and of course from a nephrology perspective that this is always the case when we're involved, our focus is going to be on induction of remission. And KDIGO feels there's three reasonable general approaches to this.
The first of which, and this is not in any specific order, is rituximab (Rituxan, Genentech) with either a glucocorticoid taper or avacopan (Tavneos, ChemoCentryx). And I'm going to talk a lot more about avacopan because this is new information in the last few years. I'll talk about that a little bit later in the talk. But avacopan is a C5A inhibitor that will inhibit terminal portions of the complement cascade and result in reduction in inflammatory mediators being recruited to the inflammation, in this case in the kidney and elsewhere. Second, and there's no preference of one of these over the others is cyclophosphamide (Cytoxan, Bristol Myers Squibb), again with a glucocorticoid taper or avacopan. More details to follow about that.
And the third of which is rituximab as well as cyclophosphamide. It's a dual therapy combined with a steroid taper. There's mention of plasma exchange, that's opening up a little bit of Pandora's box, but I'll talk about that a little bit later in a few slides. I'm not going to spend much time today on disease control and then maintenance therapy. But just so we don't miss this point, it's important to recognize that when you're in the maintenance phase, one can continue with rituximab infusions, scheduled basis or switch to azathioprine. And I'll come back to all of these in a little bit more detail a little bit later on.
So KDIGO provides some information on which circumstances might favor the use of rituximab versus cyclophosphamide. So you can see here on the left that rituximab is preferred at the extremes of ages. So among children and adolescents, among premenopausal women and men concerned about fertility due to the known issues with cyclophosphamide, but also on the other end of the age spectrum. So older and frail adults, and so for those of us who've been around for a long time, we recall the old days of cyclophosphamide causing a lot of infectious problems. And at least the perception is that among these older individuals, rituximab might be safer. In individuals where steroid sparing is particularly important, there's a little bit more evidence for rapid steroid tapers with rituximab.
And then finally, in individuals with either relapsing disease or at risk of relapsing disease, including those who are PR3 positive ANCA disease are probably people who rituximab should be preferred. You can see it's a smaller list where cyclophosphamide is preferred. And this is largely in situations where you don't have access to rituximab for whatever reason. And then finally, this important point about how to manage really bad, severe GN cases with markedly elevated creatinine over four, where there's really a paucity of data on rituximab, and therefore a lot of experts feel that there's a little bit more support for the older treatment regimens of cyclophosphamide. And lots of people do tend to pull the trigger on cyclophosphamide in this type of circumstance.
So let's dive in a little bit to some of the specifics of these regimens. So you could see here again from KDIGO are the regimens that can be used for either oral or IV cyclophosphamide. You can see the details here about dosing. They're available in the KDIGO guidelines if you need to refer to that to make decisions. There is some age-related reduction in dosing and GFR related-reduction in dosing, both for the oral or the iv. Turning to rituximab, KDIGO feels that the two generally used regimens are both acceptable for the use of induction. This includes the rituximab 375 milligrams per meter squared, weekly times four weeks or equally the one gram administered at week zero. And then two weeks later, 14 days later, at week two.
Turning to the combined rituximab and IV cyclophosphamide regimen, this would include either the four weekly infusions of Rituximab combined with IV Cytoxan. If you look carefully, it's a comparable regimen to the beginning of the regimen given here in the second column under IV cyclophosphamide or rituximab one gram dosed at day zero and then two weeks later combined with IV cyclophosphamide. And look carefully, this is 500 milligrams every two weeks for six weeks. Essentially the Euro lupus protocol for cyclophosphamide, MMF, some people like to use in this circumstance, you could see at relatively high doses. And then avacopan is raised as an alternative to steroids. Avacopan again is a C5A inhibitor. It's dosed 30 milligrams twice daily and can be used in combination with rituximab or cyclophosphamide induction, and is used as a means to more rapidly taper or completely avoid the use of corticosteroids. And I'll provide you some information on this because you don't get completely away from steroids with this regimen.
I think it's important to recognize that one really important change in the management of many glomerular diseases, but in particular ANCO-associated vasculitis, is to really try to reduce the exposure to prednisone and other corticosteroids. So these are the reduced corticosteroid regimens used in the PEXIVAS trial, which looked at both plasma exchange but also compared reduced to standard dosing of steroids. And you could see here three columns divided by weight, but even in the people with a weight greater than 75 kilos, you could see the steroids are tapered down to 20 milligrams of prednisone by week seven to eight. Below this value is the level where many people would even stop PTP prophylaxis. So this is a quite rapid removal of steroids. And if you look four or five months down the line at all three weight groups, the dose is down to five milligrams with the idea of potentially tapering even below that, obviously in subsequent weeks. So again, and this is a really important message for nephrology as well as rheumatology, I do in my practice see some resistance to this. We should really be tapering steroids much faster than we're used to in this condition. So let me just briefly talk about plasma exchange.
So this is a couple points from KDIGO about when to consider plasma exchange. You'll notice that these are practice points, which means the evidence is not strong enough to put out a guideline recommendation. But basically the consideration here is for plasma exchange in individuals with a creatinine greater than 3.4 as well as those requiring dialysis or with rapidly progressive GN with increasing creatinine, and/or patients with diffuse alveolar hemorrhage, right? You could use plasma exchange for diffuse alveolar hemorrhage and hypoxia, even if they don't meet the creatinine criteria. And you can consider plasma exchange for people who meet the renal criteria with or without diffuse alveolar hemorrhage. So in your most sick patients, this is a reasonable thing to consider per KDIGO. More strongly is that plasma exchange should be added for the dual positive overlap syndrome of ANCA-Associated Vasculitis with anti GBM positivity. And about 10% of people with ANCO-Associated Vasculitis will also be anti-GBM positive, and these individuals should be treated with plasma exchange.
So let's turn to avacopan because this may be relatively new to some of you listening. So this is the paper from, now I guess about three years ago, called the Advocate Study. I'm going to show you first before I provide the data here the mechanism of action. So this is from a fairly recent review looking at the three complement pathways, the classical, lectin and alternative pathway. But what we're really thinking, focusing in on here is the terminal complement where C5 is converted to C5B, which ultimately becomes the membrane attack complex and C5A, which is a very potent recruiter of T cells, monocytes, et cetera. And basically what avacopan is doing is it's inhibiting the C5A-induced recruitment of inflammatory mediators. So it's a potentially attractive medication for these severe inflammations like as seen in ANCA-associated vasculitis. And this is why it was studied.
So an Advocate was comparing avacopan to steroids, and it's a phase-three, double-blind randomized trial that compared oral avacopan to oral prednisone in individuals with ANCA-associated vasculitis. So the patients were randomized to either avacopan 30 milligrams twice daily, plus a placebo that was similar to prednisone or a prednisone taper with an avacopan matching placebo. Everyone received induction therapy with the standard types of treatments, either cyclophosphamide or rituximab. And what the authors looked at was two efficacy endpoints, the first being a remission, clinical remission at week 26, and then a sustained remission at weeks 26 and 52. And the latter were tested for non-inferiority as well as superiority. And you can see here, presented on the other side of the document is if you look at avacopan here in this maroon color and prednisone in the gray, you could see some separation of the curves, looking here in the Y-axis as the probability of being free from relapse. And you could see the hazard ratio was 0.46 for this outcome.
So Avacopan was not only non-inferior at 52 weeks, but actually some evidence of superiority compared to steroids. So if you look at this numerically, you can see here at 52 weeks, 66% of individuals treated with avacopan obtained sustained remission at that 52 week mark versus 55% with prednisone. And if you dive down here to the bottom to look at change in EGFR, at week 52, the increase in GFR was 7.3 versus 4.1 when you compare avacopan to prednisone. And this is presented graphically here. You can see at the 52 week mark in gray is prednisone. In this maroon color is avacopan. And you could see the 7.3 and 4.1 change in GFR. And this is just presented the same data via survival analysis. So avacopan looks appealing compared to steroids. From an efficacy standpoint, it's at least as good as far as induction of remission and sustained remission as well.
But what about exposure to steroids? So avacopan, in theory, they were getting no steroids at all, right, per the protocol. But of course, patients who were getting avacopan were given pulse methylprednisolone, like my patient in the hospital as well as on occasion or more than on occasion, frequently, steroids used to mitigate from any reactions to the infusion of rituximab. In contrast, prednisone, you could see the dosing here in adults and adolescents, again, a fairly rapid taper, right? They were down to 20 milligrams by week seven and eight, very similar to PEXIVAS. If you look at the mean total exposure to prednisone or prednisone-equivalent dosing, and gray is prednisone group. You could see it's much more exposure to prednisone earlier on. And the maroon color again is avacopan.
As I alluded to earlier, in the beginning of treatment, people are exposed to steroids whatever group you're in because of the induction approach with IV methylprednisolone as well as infusion related use of steroids. So there's not no steroid exposure, but it's considerably less. And if you look at the area under the curve, it's obviously graphically very different between the two groups. So that's an important finding. But then the question is, is there a benefit to the patient? And so if you look at the two groups here and compare the rate of infections, this was 15.2% with prednisone versus 13.3% with avacopan.
The most common infections were pneumonia and UTI, influenza, et cetera. But when you go further down this side, you could see that the types of infections seen in the prednisone fit for sort of a generalized immunodeficiency induced by the treatments. So you could see occasional cases of aspergillus and fungal infections, herpes zoster, et cetera. And for what it's worth, and again, we're only talking 160 or so patients, there were relatively few of these sort of more unexpected infections with avacopan, suggesting maybe it's a little bit more of a targeted therapy because it's so focused on the terminal end.”