Ep 100: A 46-Year-Old Man with Vasculitis

Harrison's PodClass provides engaging, high-yield discussions of key topics commonly found on rotational and board exams in internal and family medicine. 

Transcript

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 [Dr. Shapiro] This is Dr. Samantha Shapiro, executive editor of Harrison's Principles of Internal Medicine. Harrison's Podclass is brought to you by McGraw Hill's AccessMedicine, the online medical resource that delivers the latest trusted content from the best minds in medicine. And now onto the episode.

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 [Dr. Handy] Hi everyone. Welcome back to Harrison's Podclass. We're your co-hosts, I'm Dr. Cathy Handy.

 [Dr. Wiener] And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine.

 [Dr. Handy] Welcome to episode 100, a 46-year-old man with vasculitis.

 [Dr. Wiener] Cathy, today's a really special day for Harrison's Podclass as you know. First of all, it's our 100th episode together, and second, we're thrilled to welcome the newest Harrison editor, Dr. Carol Langford, to discuss today's patient. So let me tell you about your patient. He's a 46-year-old man who, six months ago, presented to the hospital acutely with hemoptysis, diffuse nodular pulmonary infiltrates, and glomerulonephritis. Work-up revealed a positive serologic study for antibodies against cytoplasmic antineutrophil cytoplasmic antibodies, or ANCA, and he was eventually diagnosed with granulomatosis with polyangiitis. Treatment was initiated with high-dose glucocorticoids and daily cyclophosphamide with an excellent clinical response. You are ready today to have the patient transition from induction therapy with his rituximab to maintenance therapy with azathioprine. Which of the following blood tests would you check before starting azathioprine? Option A. is ANCA titers; B. cryoglobulins; C. CYP3A4 genotyping; D. glucose-6-phosphate dehydrogenase enzyme levels; or E. thiopurine methyltransferase enzyme activity.

 [Dr. Handy] All right, well, the answer is E. So prior to initiation of azathioprine, thiopurine methyltransferase, an enzyme involved in the metabolism of azathioprine, should be assayed because inadequate levels may result in severe cytopenias.

 [Dr. Wiener] So you'll dose your drugs differently based on the results of that assay.

 [Dr. Handy] Correct, and patients can certainly have significantly more toxicity.

 [Dr. Wiener] Okay, so we know the answer is E. What about the other answers?

 [Dr. Handy] So ANCA titers can be misleading, that's option choice A, and should not be used to assess disease activity. Many patients who achieve remission continue to have elevated titers for years. Results from a large prospective study found that increases in ANCA were not associated with relapse and that only 43% of patients relapsed within one year of an increase in ANCA levels. So a rise in ANCA by itself is not a harbinger of immediate disease relapse and should not lead to reinstitution, or an increase in immunosuppressive therapy.

 [Dr. Wiener] Okay, what about option C, which is CYP3A4, or option D, which is testing for the G6PD enzyme?

 [Dr. Handy] CYP3A4 is one of the cytochrome P450 enzymes and it's important in drug metabolism. It's actually the enzyme that's inhibited by grapefruit juice. So while it's important for the metabolism of many drugs, azathioprine is not metabolized by that enzyme, so it's not relevant here. G6PD is an enzyme vital for stabilization of the red blood cell membrane and its deficiency is the most common genetically transmitted enzyme deficiency. It's transmitted in an X-linked recessive fashion, so men are typically at risk. While most people are asymptomatic, certain foods, drugs, or conditions that provoke an oxidative stress can cause an acute hemolytic anemia in susceptible individuals. So notable among those are fava beans, antimalarial drugs, sulfa drugs, and dapsone.

 [Dr. Wiener] Okay, great. And let's not forget about the cryoglobulins. Why are those not relevant to this case?

 [Dr. Handy] Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins and cryoglobulinemia may be associated with a systemic vasculitis, but it's not relevant to starting azathioprine.

 [Dr. Wiener] Okay, well let's welcome Dr. Carol Langford to Harrison's Podclass. Dr. Langford, before we start talking about this case, can you tell us a little bit about how you became the director of the Center for Vasculitis and Research at Cleveland Clinic, and how you became the newest editor of Harrison's?

 [Dr. Langford] Well, thank you, Charlie and Cathy, for me being here today, it's a great pleasure. And first off, congratulations on the 100th episode of Podclass. congratulations on the 100th episode of Podclass. I've had the pleasure of being engaged in the field of vasculitis for almost 30 years now and began my career at the NIH with Harrison's editor, and began my career at the NIH with Harrison's editor, Dr. Anthony Fauci. And in 2004 I moved to the Cleveland Clinic to become the director of the Center for Vasculitis Care and Research where I work with a wonderful group of colleagues in advancing our mission in patient care, education, and research in vasculitis. I've had the privilege of being involved with Harrison's as Dr. Fauci's associate editor and was thrilled to be as Dr. Fauci's associate editor and was thrilled to be included as a member of the editor team for our upcoming 22nd edition. So thank you.

 [Dr. Handy] Thanks for joining us. So with this patient, do you agree with the treatment plan? And can you talk a little bit about the choice of maintenance therapy here?

 [Dr. Langford] Yes, so when we talk about the treatment of ANCA-associated vasculitis, we think about this as having two phases, induction where active disease is put into remission, followed by remission maintenance. When we consider the induction part of the equation the decisions are based upon the degree of disease severity, and this is someone who presented with severe disease based upon the presence of pulmonary disease with hemoptysis, and features that may suggest alveolar hemorrhage as well as glomerulonephritis, and in that setting the options would be glucocorticoids combined with either rituximab or cyclophosphamide. As this was a young gentleman the choice of rituximab was made. Now once they have improved and achieved remission, then the consideration is about maintenance agents. And there are a variety of options that we have, which include conventional therapies such as azathioprine, methotrexate, or mycophenolate or rituximab. In randomized trial, rituximab has been found to be associated with a lower rate of relapse compared with azathioprine, but it remains appropriate to still consider these options as rituximab can have other considerations including hypogammaglobulinemia, and certainly, more recently the consideration of vaccine response. So in the case of this gentleman, he chose azathioprine, which does remain a reasonable option.

 [Dr. Wiener] Hey, Dr. Langford, for many of us who are not rheumatologists or vasculitis experts sometimes ordering an ANCA is just one of a large battery of things that we order without really understanding it. Can you remind us a little bit more about what is ANCA and when we should use it, you know, kind of appropriately as a test?

 [Dr. Langford] Yes, so ANCA or antineutrophil cytoplasmic antibodies are one of our more recent serologic tests first described in the 1980s and found to be associated with vasculitis towards the late 1980s and early 1990s. Now, these can be tested for by two different methodologies: our immunofluorescence test, which provides either a cytoplasmic or c-ANCA, or perinuclear or p-ANCA pattern, and then we can also test for antigen-specific ELISA testing looking for proteinase 3 or myeloperoxidase, which are the antigens associated with the vasculitic diseases. Now, certainly, these have the best utility when we are using these in the setting of a patient where there is a suspicion of a small-vessel vasculitis such as, again, someone who presents with pulmonary hemorrhage, glomerulonephritis, or other features that might suggest granulomatosis with polyangiitis, or microscopic polyangiitis, and in the setting of those diseases, the frequency may range as far as from 70 to 90% positivity. However, we do need to still keep in mind that ANCA can be negative in up to 20% of patients when they have early disease or more organ-isolated disease. So the absence of ANCA does not rule out the diagnosis, and similarly, a positive ANCA may not always confirm the diagnosis if we can see this in other settings as well.

 [Dr. Handy] And you mentioned there that there is a spectrum of diseases that are ANCA-associated. Can you tell us a little bit more about those?

 [Dr. Langford] In the most recent nomenclature system the designation of ANCA-associated vasculitis was made, and within that family are considered the entities of granulomatosis with polyangiitis, microscopic polyangiitis, and also eosinophilic granulomatosis with polyangiitis, or formerly known as Churg-Strauss syndrome. Now, although, these are all considered within this family, particularly in the case of eosinophilic granulomatosis with polyangiitis or EGPA, this is, in fact, ANCA-associated in the minority of patients, so only about 40% of patients will be ANCA-positive with the most common being myeloperoxidase positive p-ANCA. So, again, that is something we need to keep in mind within this family.

 [Dr. Handy] And then the treatment, are they all treated the same, or do you approach the treatment differently based on the specific subtype?

 [Dr. Langford] Yes, there do remain important differences in terms of treatment for each of these diagnoses. Granulomatosis with polyangiitis and microscopic polyangiitis have a number of similarities particularly, when we're talking about severe disease where we would use similar features in terms of, again, glucocorticoids combined with rituximab or cyclophosphamide. There are some individual treatments that are used in granulomatosis with polyangiitis, particularly in the case of sinonasal disease where local treatments play a very important role, and also in the setting of subglottic stenosis, but the most important difference would be in the case of EGPA, where the eosinophil plays a very prominent role, and where we see a different range of disease manifestations including asthmatic features, features of eosinophilic disease, and in that setting the role of the eosinophil, and the use of therapies directed towards the eosinophil such as anti-IL-5 approaches, such as mepolizumab play a more important role.

 [Dr. Wiener] Great, well, thanks so much Dr. Langford, and we'll look forward to working with you and seeing you on some future Podclass episodes. The teaching point of this case is that autoimmune vasculitis and in this case, granulomatosis with polyangiitis are complex diseases that can involve multiple organs. The treatment paradigm involves induction with aggressive therapy, and then if and when the patient responds, movement to a less intense maintenance therapy. All of this really should be done given the plethora of new drugs and evolving studies, all of this should likely be done in consultation with a vasculitis expert, such as Dr. Langford.

 [Dr. Handy] And you can learn more about this in the chapter on ANCA vasculitis.

 [Dr. Shapiro] Thanks for listening to Harrison's Podclass. You can listen to this episode and more on AccessMedicine.com which includes the complete Harrison's Principles of Internal Medicine text, Harrison's Review Questions, which complement and expand upon the questions in this episode, and much more. AccessMedicine.com may already be available to you via your academic institution. Check it out.

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