Giant Cell Arteritis - Nicholas J. Volpe

Hello and welcome to the SOE webinar neuro-ophthalmology series. My name is Nicholas Volpe, and I'll be talking to you about giant cell arteritis from a beautiful Friday morning in Chicago. I'm excited to speak on this topic because not only will we review the classic presentations of giant cell arteritis and the importance of this diagnosis in all neuropathic conditions, but also I'll have the opportunity to share some new approaches to diagnosis and of course the new opportunities for treatment with tocilizumab. I have no financial disclosures relevant to this presentation. I receive equity ownership in a company that works with OCT, but I will not be discussing that. So first and important is to consider the context of this condition and who gets it. This condition is almost exclusively in the northern hemisphere populations of Anglo-Saxon origin. Lighter skinned individuals are more prone to this condition. There are certain HLA types that have shown up in different populations. It may be related to where more older patients are, but there very well may be an environmental factor either related to infectious agents or possibly sunlight that contributes to the development of the disorder. Notably, the incidence is increasing. The exception to this, of course, here's a series of patients that were recorded by myself and a number of other co-authors that identified giant cell arteritis in patients of African-American or Black descent. Interestingly, this group had a higher incidence of headache and eye pain and a lower incidence of typical jaw claudication, which I'll discuss in a moment, which is one of my most important predictors of patients who have temporal or giant cell arteritis. Risk factors: by far the most important is older. This diagnosis is on the top of your list in any patient, particularly over age 75, but even as you get older into the 80s and 90s, any type of neuropathic presentation, whether it's vision loss or double vision, should have temporal arteritis in the differential diagnosis. Definitely the possibility that some type of triggering arterial disease—there are some reports that suggest that smoking is a risk factor that allows a potential for instance viral pathogen or other entity to trigger the inflammatory response in the blood vessels. One epidemiologic study showed that former pregnancy is protective, and there have been a number of interesting reports and populations in which the listed entities—parvovirus, bird keeping, adenovirus, RSV, and others—might be risk factors for this condition. Symptoms: of course headache. Headache is an unusual symptom in an elderly patient that doesn't have headaches, so as soon as you elicit a history of headache, you have to consider temporal arteritis. Two-thirds of the patients have new headaches, but actually because our diagnostic threshold and our sensitivity to this condition and its unusual presentations, the actual prevalence of headaches is decreasing because people are recognizing the disorder under other circumstances. Usually the pain is in the scalp and over the temporal arteries, and it could be mild or severe. Occasionally it's intermittent, but most of the time it's persistent. And again, as I mentioned, jaw claudication—which is not TMJ, it's not 'I open my mouth,' it's when I chew, I progressively get more pain in my jaw, my throat, my tongue as I'm trying to eat, for instance chewing a piece of meat. Importantly, many and most patients, as we think about how we distinguish this from non-arteritic ischemic optic neuropathy—those that develop arteritic ischemic optic neuropathy—the vast majority have prodromal symptoms. Unfortunately, that majority is only 75%, and there will be 25%, which I'll talk about in a minute, of patients who really are presenting with isolated neuro-visual presentations that actually have occult giant cell with the absence of other symptoms. The classic ones as mentioned: the headache, scalp tenderness, and jaw claudication. Fever, weight loss, malaise, polymyalgia symptoms, muscle pain—those are all important systemic symptoms. And of course, anybody who has double vision for a few hours and it goes away, transient vision loss and it goes away, and then goes on to develop a more catastrophic event with this type of ocular prodrome has giant cell until proven otherwise. About 50% of patients will present with visual symptoms. The most common of course is vision loss in the setting of ischemic optic neuropathy, but about a third will have transient vision loss prior to developing their event. These, in my opinion, are some of the most critical patients to try to recognize in your practice that are presenting with vision that recovers in the backdrop of temporal arteritis, because these patients can potentially be saved. Double vision and eye pain are other symptoms. In patients that we call occult GCA—again, these are patients who don't have a lot of other systemic symptoms—it can represent between 20 and 25%. The sed rate and C-reactive protein are often abnormal but maybe less abnormal, again presumably because the disease is less widespread in terms of its symptoms. Obviously these are all visual presentations. In this classic paper by Hayreh, you can see again about a third with amaurosis and 100% with some type of vision loss, most commonly ischemic optic neuropathy. Perhaps one of the most important clues in the patients with vision loss to the fact that it's arteritic or giant cell based is that vision loss is almost always severe. As you can see from this bar graph, 20/200 or worse for the vast majority of patients. In fact, if you have count fingers, hand motions, light perception vision in someone with ischemic optic neuropathy that you're trying to decide whether it could be arteritic, almost always favors arteritic when the vision loss is severe. Remember that the vision loss can also affect the retinal circulation. Perhaps one of the more important points I'd like to make is that if you're not finding significant fundus findings—in other words, swollen optic nerve or artery occlusion—but you do have catastrophic vision loss in an elderly person, the presumption there is that this is posterior ischemic optic neuropathy and that is giant cell until proven otherwise. So 80%—and I showed a different slide a little earlier that it was about 90%—there's a combination of optic nerve and retinal ischemia presentation. I'll show an example of that that's almost always giant cell arteritis. Less than 10% but a significant minority will have this posterior ischemic version, and again a frank ocular ischemic syndrome can develop in a small percentage of patients. Here's a nice and recent summary patient paper about the various findings and symptoms in a cohort of giant cell arteritis patients. You can take a minute and look carefully at these slides in terms of the prevalence of the symptoms, but you can see that things like the new onset of headache and scalp tenderness, temporal artery tenderness—those are present in a significant number of patients in the 70 to 80% range in this particular series. Interestingly, about 40% reported fever, so a fever of unknown origin in an older patient is an important symptom to consider. But again, what I want to emphasize here is that these people generally have other symptoms in addition to their neuro-visual presentation. And then in this very nicely demonstrated pie chart, you can see how things break out in terms of the presentations of vision loss, strongly favoring anterior ischemic optic neuropathy as the most common scenario. In this case, unlike non-arteritic ischemic optic neuropathy where we're a little less sure exactly what the mechanism is, here we know that we're dealing with catastrophic infarction of the posterior ciliary vessels or ophthalmic artery leading to optic nerve ischemia. Here are some nice examples of ischemic optic neuropathy: very pale swelling typical of giant cell. Here's a posterior ischemic optic neuropathy with a cotton wool spot. This is a classic presentation for giant cell arteritis. I'll talk about this again in a minute, but the use of fluorescein angiography to demonstrate choroidal non-perfusion can be a critical diagnostic aid in working through these patients. In my experience, the giant cell arteritis examination often either has this very classic presentation or sometimes there's a paucity of findings in patients with vision loss. So once again, here I show some classic examples of chalky white swelling. Here's that simultaneous ischemic optic neuropathy with branch retinal artery occlusion. Here's posterior ischemic optic neuropathy with just a cotton wool spot. And here's a patient with just some feathery cotton wool spots and maybe a suggestion of choroidal ischemia on exam. So these are all patients that had severe vision loss in the setting of giant cell. In terms of making the diagnosis, as mentioned, the demographics: older women who are lightly pigmented—that's the most common population. Remember the prodromal symptoms as listed: jaw claudication and scalp tenderness. The abnormal artery on exam. Remember that the most potent predictor of not having temporal arteritis is in fact the low sed rate, but unfortunately somewhere between 15 and 20% of patients with giant cell will have a normal sedimentation rate, so you don't get off the giant cell train so to speak in making that diagnosis just because of the sed rate. I would urge you to think about ordering the sed rate with a pre-test probability suspicion and decide what you're going to do based on the sed rate before you separate results—before you even order it. So if it's less than 50, I'm not going to do anything. If it's between 50 and 75, I'm going to treat them and biopsy. If it's 100, I'm going to admit them to the hospital. Some thinking: 'What do I do? I've got the sed rate.' Think about what you're expecting to do based on the test result. So again, various studies show normal sed rate in up to 20% of patients. There is some indication that more sed rate elevation suggests more active disease. The C-reactive protein and platelet count also ordered as complementary tests, and helps with false positives and negative sed rate. Obviously the combination of sed rate and C-reactive protein being both elevated puts your probability in the 90% range. As mentioned and demonstrated in these photographs, this entire choroid is not perfused. This one has lobular non-perfusion areas. I use fluorescein angiograms quite frequently in the distinction of visual presentations of temporal arteritis because even in some with amaurosis or just some transient visual symptoms with paucity of findings, don't underestimate the importance of fluorescein angiogram. Here's a contribution I made earlier in my career about temporal biopsy. Before we had alternatives, which I'm going to talk about in just a minute, the rule was everybody gets two biopsies. In my experience, we do unilateral biopsies and only follow with a second when there's a high clinical suspicion and a negative on the first. We don't do simultaneous bilateral biopsies. In fact, based on some of these newer techniques—first, Doppler ultrasonography, which was first reported by Schmidt in the New England Journal in 1997—we are using other methods now to increase our sensitivity and ideas about the screening for giant cell without having to do a biopsy. It's a very quick and non-invasive test, and I believe this is the first test that should be gotten on all patients after the laboratory workup when giant cell is highly suspected. It's a very easy finding to make, as demonstrated on these slides: these hypoechoic areas around the artery that are really just demonstrating the thickening and infiltrated arterial wall in patients with giant cell. You can see in various studies when compared to the temporal biopsy as the gold standard, there's a fairly good sensitivity and specificity—it gets into the 80 or 90% range. Of course, nothing being 100%. The only thing that's 100% is a good doctor making good decisions based on the various amounts and types of information that are available to him or her at the moment. When in doubt, we treat these patients and go towards biopsy. Some newer techniques that have been used: functional MRI scans with tracer elements that show inflammation in the arteries. It's exciting that these will be very predictive and sensitive and specific. Actually, MRI scan, as seen in these very elegant pictures, can demonstrate true inflammation enhancement of the superficial temporal arteries. We're finding that we sometimes stumble upon this when an MRI scan is done for a third nerve palsy or some other reason where the suspicion was low, and we'll look for this and then decide to pursue giant cell arteritis based on these findings. I think this is an excellent summary in this rheumatology article by Ponte about the approach, and it very much mirrors my approach with the addition of using fluorescein angiography. This is written by a rheumatologist, so they don't have a visual presentation, but I think this plugs in pretty well in terms of how patients might present to me with a vision loss symptom. You can see using the ultrasound is the first step, and if it's negative and the suspicion is low, you can stop there. Then if it's higher, you can decide on biopsy or one of these other methods. If it's positive and high, I'm done, because that patient—if I'm pretty sure they have it and I get the ultrasound—then I will treat this patient without a biopsy. If it's lower or medium, again potentially using fluorescein angiogram or the other diagnostic tests to help you make a decision. So prompt treatment: of course, anybody who you even think might have this gets treated with steroids and hydration. We use intravenous steroids when vision loss is present based on some studies that suggest that it works more effectively. I think the most important thing is that the steroids get into the patient. So if they're going to have to sit 12 hours in the emergency room waiting to see a nurse or a doctor to get steroids, then you're better off getting them the pills out of pharmacy. Just get steroids into these patients immediately and as quick as possible, long before you make a decision as to whether they definitely have it based on your diagnostic testing. Most patients require treatment for up to two years. There's definitely an increase in fractures and diabetes from the steroid treatment. Until recently, all the alternatives—azathioprine, cyclosporin—work in some patients but no good trials have demonstrated success. And then finally, in the last five years, targeted treatment against IL-6, which is an inflammatory mediator that is upregulated in inflamed arteries in giant cell patients, has been studied and very effectively in the last five years demonstrated in a couple of different randomized clinical trials to be highly effective. This is tocilizumab as an adjunct treatment for the treatment of giant cell arteritis. So this is now becoming standard of care. The question is how and when this care is introduced to patients. So this is not a beginning treatment; this is part of the chronic treatment and a desire to get patients off of steroids sooner. While as an organized community we don't have specific recommendations, it will depend on the rheumatologist that you work with. I am finding that I'm introducing tocilizumab much sooner in the treatment of most patients. There are different professional recommendations in different journals about who should get it. The emphasis, of course, recognizing that steroids go first for sure, and you're not delaying treatment for diagnosis, and then you're introducing tocilizumab particularly in patients who you need to get off of steroids and in whom this can be done effectively and expeditiously. And then another excellent editorial and discussion by Alfredo Sidoon and Lynn Gordon, kind of going back and forth on when and whether it should routinely be used. I don't have an answer for you except to say that I am using it on a more and more regular basis in combination with my rheumatologist and having very much success in getting patients onto lower doses of steroids at a much sooner rate. So with that, I thank you for your attention. Remind you again that the presentation should be suspected in any patient who's over age 70, less so under age 60, but as you get into 75, 85, if you have vision loss, double vision, or any neuro-ophthalmic presentation, you should think temporal arteritis. You should use fluorescein angiography. Don't hold treatment for diagnosis. Think about introducing ultrasound and the other diagnostic methods. Thank you very much.