Dr. Patrick Nachman & Treating ANCA Vasculitis with Rituximab

What should patients know about treatment with rituximab for ANCA vasculitis? What do physicians consider when starting a patient on this medication? Dr. Patrick Nachman and Dr. Ron Falk discuss these details in this podcast. Dr. Nachman is the Covington Distinguished Professor of Medicine in the Division of Nephrology and Hypertension at UNC, and he also serves as the Deputy Director for the UNC Kidney Center.

Dr. Patrick Nachman & Treating ANCA Vasculitis with Rituximab click to enlarge Patrick Nachman, MD / Photo by Chris Polydoroff

"Our nursing staff is very well-experienced in giving these medications. They monitor the patient very carefully. There’s a careful protocol to start the dose slowly..The patient is monitored for a little while after the infusion is completed. So we take this very seriously. But by and large, patients really feel very little side effects from that first dose.

-Dr. Patrick Nachman 

Falk: Hello, this is Ron Falk for the Department of Medicine at the University of North Carolina. Welcome to the Chair’s Corner.

Today we welcome Dr. Patrick Nachman who is the Covington Distinguished Professor of Medicine in our Division of Nephrology and Hypertension. He also serves as the Deputy Director for the UNC Kidney Center. Patrick Nachman specializes in the care of patients with immune-mediated kidney diseases, or glomerular diseases, and he leads numerous clinical trials that investigate treatment options for a number of these conditions. He is very well known for his work on ANCA glomerular nephritis or ANCA-associated vasculitis.

Today our focus is going to be on the treatment of ANCA vasculitis with a drug called rituximab—or Rituxan. Welcome, Patrick Nachman.

Nachman: Thank you.

Falk: Let’s start by thinking about a typical course of treatment for a person who has newly-diagnosed disease. You and I see many of these patients in our Thursday glomerular disease and vasculitis clinic. Imagine then, you have a person who walks in and has kidney disease, and perhaps lung disease and it’s an aggressive process. How would you start therapy? What would you do?

Nachman: The classic approach to starting therapy for an aggressive form of vasculitis involving the lung and kidney-or the kidney alone, typically it starts with what we call an induction phase of treatment which usually includes using relatively large doses of corticosteroids by vein and then by mouth.

Falk: That would be pulse Medrol, or methylprednisolone by vein, or oral prednisone. Or if you’re listening from Europe-prednisolone.

Nachman: That’s correct, and how much of the intravenous methylprednisolone is given depends from center to center, from continent to continent. The dose and the length of treatment of prednisone is also, to some degree variable from center to center, and certainly is a focus of ongoing research. But the important thing that we have learned over the years is that corticosteroids alone are not enough. Typically patients are given other immuno-suppressant medications.

Traditionally the drug that has made the biggest impact on patient outcomes and survival has been cyclophosphamide and that can be given either by mouth daily or by vein. More recently, over the last several years, rituximab has been introduced as an option for the induction phase of treatment of vasculitis.

Falk: Who, then, would you use cyclophosphamide on, and what patient would you start on rituximab?-- And then there are some patients you consider both right off the bat.

Nachman: Rituximab has been introduced as an option several years ago and it has been pushed to the forefront by a large randomized control trial called the RAVE trial, where patients with ANCA vasculitis were randomized to a treatment of rituximab versus the more traditional approach of using cyclophosphamide. That trial showed that there was really no inferiority of the rituximab approach compared to cyclophosphamide. And has really promoted the use of this medication for induction treatment.

It is important to remember how the patients were selected to participate in the trial. Most significantly, that trial has excluded patients with very severe kidney disease, very severe kidney failure, or patients who had very severe lung involvement to the point where they were, for example, in an intensive care unit needing respiratory support.

In general, our approach has been to offer rituximab in patients with relatively mild to moderate severity of disease. The data for its use alone in patients with very severe disease, either very severe pulmonary disease or very severe kidney disease is just not yet available.

Falk: By severe, you’re talking about individuals who would have a rapid decline of kidney function.

Nachman: To the point that they need dialysis.

Falk: Or even somebody who has milder disease who is advancing in front your nose. Or somebody who is bleeding in their lungs.

Nachman: This is it, as you mentioned, a little earlier. Sometimes we start the treatment and the patient who’s very severely ill and has received a first dose of cyclophosphamide and is really not improving fast enough clinically and not stabilizing enough clinically, we have been in situations where we have given both medications in sequence.

The other form of treatment that is considered in those cases is called plasmapheresis where the patient’s blood is run through a filter to remove the offending autoantibodies that drive the inflammation.

Falk: The ANCA themselves. The idea then is those individuals who you need to have the medicines to work promptly—cyclophosphamide is still the drug of choice. Rituximab can take two or three months to fully work, and so if you need to have a drug work more quickly, in addition to steroids, then in fact cyclophosphamide may be better. But for a large number of patients, rituximab is excellent induction therapy.

Nachman: That’s correct.

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Falk: If a patient is feeling nervous about getting their first treatment-this is an infusion, what is called a biologic drug, what do you tell a patient who’s anxious about their first dose, to make them feel better? What kind of side effects do you describe?

Nachman: The immense majority of patients really tolerate rituximab infusions very well. The thing that we worry the most about is that in a very small minority of patients— less than ten percent—there can be an allergic reaction to the first dose. What we do use routinely, is the patient receives their first dose in a monitored setting. They receive a dose of intravenous methylprednisolone dose to decrease the risk of an allergic reaction, and other medications, such as diphenhydramine—or an antihistamine medication. 

So if this is really a very sick patient who’s in the hospital already receiving their first dose, these things are going to be done automatically. If the patient is not hospitalized and they’re receiving their first dose in an infusion center, he or she will receive these medications to decrease the risk of an allergic reaction, and our nursing staff is very well-experienced in giving these medications. They monitor the patient very carefully. There’s a careful protocol to start the dose slowly and the patient is monitored every fifteen, twenty minutes. The rate of infusion is increased progressively. The patient is monitored for a little while after the infusion is completed. So we take this very seriously. But by and large, patients really feel very little side effects from that first dose.

Falk: And usually if they’re developing a reaction, one could just slow down the rate of administration. That said though, the side effects of rituximab short-term and long-term are like any other immunosuppressive drug. Every single trial that it’s been compared to, the adverse events are equivalent to oral cyclophosphamide or azathioprine.

Nachman: In terms of the risk of infections, this is common to all immunosuppressants. In the very short term, the difference in side effects between rituximab and cyclophosphamide, cyclophosphamide is more likely to cause nausea and vomiting for a day or two after an intravenous infusion. That’s quite uncommon with rituximab. 

Falk: How do you pick the dose?

Nachman: That’s a good question. The traditional dose of rituximab was inherited from the oncology cancer treatment realm, where the dose classically used was 375 mg per meter squared body surface, weekly for four consecutive weeks. The RAVE trial that I mentioned before used that approach. As we have gained more experience using this medication, we have moved towards a simpler protocol where we give two doses two weeks apart. I have not seen a trial that compares one dose to the other. The two doses two weeks apart is just easier and more convenient for the patient. 

Falk: And side effects of one are really no different than the side effects of the other. When someone has had an adverse event—or has had a reaction to the infusion, does that mean they’re going to have a reaction the next go-round, or does it really mean that the drug should be used more slowly, infused more slowly next time?

Nachman: It depends on the severity of the reaction. Certainly, if it is a convincing allergic reaction, we avoid using the medication altogether again. If it is a very mild reaction that went away by slowing the rate of infusion, I do not think this would be a reason to give up on that approach. Certainly someone who has had hives or a more serious allergic reaction, I would shy away from using the medication again. 


Falk: If you go forward for several months, these patients are typically on tapering doses. Prednisone or prednisolone over twelve, sixteen weeks or so and then the drug can be tapered down, if not off. In contrast, if you have somebody who’s been given cyclophosphamide, you have to repeat the dose of cyclophosphamide. If it’s given by vein, then in about a month perhaps less, and then perhaps again at month three. The rituximab treatment, you hope, has an effect that doesn’t require another round of rituximab within those first four to six months.

Nachman: That’s correct. The big question right now, is what is the frequency of dosing of rituximab in the more long-term or maintenance phase of treatment of the disease. The last couple of years, we are learning to see if we can use rituximab for maintenance treatment of vasculitis. There are a couple of protocols that are being investigated. One of them that has been studied in a large study in France used a dose every six months. There’s an ongoing trial across all continents where they’re studying a dose every four months. Your point is very well taken—classically the course of cyclophosphamide required treatment for anywhere from three to six months, whereas rituximab ideally we can just do the induction dose. That dose appears to inhibit or deplete the target lymphocytes for anywhere from six to twelve months.

Falk: The way of determining then if rituximab has worked—at least working with respect to getting rid of circulating B lymphocytes or what are called CD19 or CD20 lymphocytes is a blood test, right? 

Nachman: It is a blood test. What that blood test tells us is that the target lymphocytes have been depleted by rituximab. There’s a very tiny minority of patients who just don’t deplete in response to the medication. One of the research questions that are ongoing now clinically is whether we can use that blood test to determine when we should re-dose rituximab in the future for maintenance therapy. That question is not fully answered yet.

Falk: All B-Lymphocytes are not the same. There are some B lymphocytes that are destined to become antibody-producing plasmablasts and plasma cells. Others are regulatory B lymphocytes that you would like to have control the immune response. Rituximab gets rid of all kinds of B cells. You’d really like the B regulatory cells, if you could measure them, to return and repopulate, and the potentially harmful B lymphocytes stay away.

Nachman: That is also a question that we have addressed. In a relatively small number of patients we are looking to investigate more formally whether there are certain B cells—phenotypes or types of B cells that can help us anticipate which patients are more likely to have a relapse and need further immunosuppressive therapy, and differentiate these patients from patients who are less likely to relapse, and maybe perhaps be able to be followed expectantly, without continued long-term immunosuppression. 

Falk: What do you do when a patient is given rituximab and their disease is just not getting better, by month one, or two, or even month three? So you’re sitting there with a patient in the clinic and it’s twelve weeks into the course of their disease and it’s clear they still have very active disease?

Nachman: This is a tough situation. If the patient is clearly not getting better, or is getting worse, then we would intervene with an additional medication. The combination of rituximab and cyclophosphamide has been used together and in fact, in the oncology world they are routinely used together. But also in the vasculitis world there has been a small study called RITUXVAS which has used a combination of rituximab and cyclophosphamide. So for patients who are failing to improve, or who are having more severe symptoms, we would introduce medication number two. If it’s cyclophosphamide, we can add rituximab, and if we started with rituximab we can add cyclophosphamide.

The other possibility is thinking about introducing plasmapheresis again to remove the offending ANCA antibodies from the circulation. 

Falk: By and large most patients end up doing remarkably well, whether they’re treated initially with cyclophosphamide or rituximab. Fully eighty-five, ninety, ninety-three percent of patients end up getting into remission by month four, five, or six, and then the maintenance question that you’ve already addressed is the real active question. 

Falk: What should a patient expect with respect to adverse side effects within those first six months? Whether they’ve gotten cyclophosphamide or they’ve gotten rituximab?

Nachman: By far, the biggest concern is the risk of infections. The risk of infections is highest in the first three to six months. Certainly with cyclophosphamide. And that actually may be driven just as much by the dose of the corticosteroids in addition to rituximab or cyclophosphamide. This is the one take-home message that patients should keep in mind, which is, they are now unable to fight infections normally. If they do develop symptoms suggestive of bronchitis or pneumonia, or severe headache or fever, or urinary tract infection, they should seek immediate attention, so we can identify and treat the infection as promptly as possible.

Falk: They’re garden variety infections, most of the time—garden variety meaning common bacterial and viral infections.

Nachman: They’re common bacterial infections. In our retrospective analysis, the most common infection is pneumonia, and the most common offending agent is staphylococcus. There are also rare, or uncommon infections that we occasionally encounter. 

Falk: But prednisone, or corticosteroids are probably just as involved in creating this basis for immunosuppression and infection risk than either the cyclophosphamide or the rituximab. As a matter of fact, trying to stop the prednisone, hopefully by week sixteen or certainly by month six, is an important way of decreasing that risk of infection.

Nachman: That’s correct. We are also finding out that the very high doses upfront could be contributing to this increased risk of infections and other complications that we see with corticosteroids. Corticosteroids are wonderful, anti-inflammatory drugs—they work very fast, they quelch this inflammation that we see upfront very fast and frequently the patient feels much better after the first few doses. They have an ugly flip-side which is risk of infections, diabetes, fluid retention, cataracts, bone loss—so this is another field where the vasculitis and glomerulonephritis community is putting a lot of effort to try to find the right balance between the dose that’s going to give as much benefit while minimizing the risk of adverse events in the short and long run. 

Falk: Let’s talk for a moment about the cost of these treatments. They’re both financial costs and personal costs—individuals not being able to work. Rituximab as the infusion is an expensive medication, which may be different depending upon insurance plans, but there is a real out-of-pocket cost for the co-pay for this biological drug.

Nachman: So rituximab is now FDA-approved for this indication, and that has really, thankfully, given a lot of patients access to it through their insurance, but as you pointed out, the co-pay can be very substantial and the out-of-pocket expense to a patient can be very substantial. To the point that patients can’t afford just the co-pay.

Falk: That’s something that should be a conversation with your doctor—What should I expect with respect to this medication cost? 

Nachman: We pay close attention to this, because we don’t want the patient to be blind-sided by a big bill that they can’t afford to pay. But I think you’ve alluded to another cost—which is being able to come for two infusions instead of six, over a period of six months is also a benefit in terms of time away from work, and the loss of income during those days. Also, if a patient doesn’t tolerate a medication well, there is added loss of income from days when they’re not feeling well enough to go work. These are factors that come into the decision of pursuing one treatment versus the other, based on what the patient is tolerating best.

Falk: There’s another very effective remission maintenance drug-equally effective for the most part to rituximab for maintenance and that would be azathioprine.

Nachman: Azathioprine is a medication that is taken daily by mouth, and the immense majority of patients have few adverse events, if any. It does not require an infusion. There is one study that has been published last year that suggested that maybe every six months doses of rituximab may have an advantage over azathioprine. This study needs to be confirmed and is being studied in another clinical trial that is currently ongoing called the RITAZAREM trial. So we’ll have either confirmation or refuting of these original data.

Falk: The first study that was done in France—largely had patients with one of the ANCA types—proteinase 3 ANCA, and very, very few patients with myeloperoxidase ANCA, so we don’t know the best remission maintenance in that population.

Nachman: And that is even more true in the sense that we have learned in the past that patients with proteinase 3 ANCA have a higher risk of relapse, so they may need more immunosuppression, whereas patients with myeloperoxidase ANCA who may have a lower rate of relapses may not need as much immunosuppression in the maintenance phase. 

Falk: That begs the question of when do you stop therapy? And if you stop therapy, how do you make sure that you would pick up an early relapse? 

Nachman: That’s really a fundamental question that’s at the forefront of our minds. It’s easy to start treatment. It’s very difficult to know when to stop. What our approach has been over the years, is if the patient has done really well and has absolutely no signs or symptoms suggestive of active disease after a semi-arbitrary period of time of a year or so, then we try to follow the patient by gradually minimizing immunosuppression and getting them off immunosuppression. At that point it becomes very important for the physician and the patient to report and call if they think that they might have symptoms that could be signs of recurrent disease. The patients themselves become actually better than the physicians in sensing early signs of disease relapse. In our experience, because the patients become attuned to their body, and sense early signs of relapse, we tend to catch those relapses early and hopefully "nip them in the bud."

Falk: Interestingly, we’ve had patients who’ve been off of any medicines for over five years, and have done remarkably well, that’s not to say that they have no chance of relapsing, but the relapses seem to be turned around very quickly—within thirty days, just based on the observation that you just made.

Falk: Are there fun, new drugs coming out on the horizon?

Nachman: There are different immunosuppressants that are being explored. One new approach that is really a little bit different than what we had done so far targets the activation of the inflammatory pathway called the complement pathway of inflammation. There are a couple of drugs; one of them is being actively studied in a limited, targeted way is capable of, or we think, is capable of decreasing this inflammatory pathway which we think contributes to vasculitis damage by recruiting more white cells to the site of the inflammation.

Falk: At least in animal studies it has worked very well and in a few humans it has seemed perhaps to have some kind of a response.

Nachman: Early phase trial results are encouraging. A larger phase III trial is anticipated.

Falk: If an ANCA vasculitis patient is looking for more information, you can find it on the UNC Kidney Center web site. A tremendous resource and support for patients is of course the Vasculitis Foundation. The foundation hosts conferences, symposiums, and provides a wealth of education for patients via their media channels. 

Patients can visit the Vasculitis Foundation web site, FaceBook page, and watch patient education videos and webinars on the Vasculitis Foundation YouTube. You should know that Dr Nachman is actually on one of those YouTube videos trying to help people understand their laboratory findings. Patrick, thank you so much for spending time with me today. 

Nachman: Thank you very much. 

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Ron Falk The Chair's Corner is an educational podcast hosted by Dr. Ron Falk, Department of Medicine Chair at the University of North Carolina School of Medicine. 

Previous episodes include topics related to acute respiratory distress syndrome, alpha-gal meat allergy, and autoimmune disease, and feature interviews with Dr. Falk and UNC physicians who specialize in those conditions.