 So I'm going to continue the talk on rheumatologic, ophthalmologic diseases, and this one is probably much more common than the one that Tom was talking about. So I'm going to talk about temporal arthritis. And in recent times, the residents have been getting quite a few calls from either the primary service or the ER regarding whether or not their patient has temporal arthritis. And I've discovered that sometimes this patient may or may not even have any ophthalmologic symptoms or neurologic symptoms. So at first, I was kind of annoyed. But in preparing for this talk, I've confirmed that temporal arthritis is a disease that's, at least in the literature, shared between rheumatology and ophthalmology. And so my job today is to equip you with some information about temporal arthritis and hopefully to make sure that you're not annoyed when you get called about patients, possibly with temporal arthritis who don't necessarily have eye symptoms. So we'll review the basics of temporal arthritis or giant cell arthritis, review some ophthalmologic presentations of giant cell arthritis, and then finally give you some updates on the antibiotic treatment study. In terms of the history of temporal arthritis, it is a relatively new disease described mostly in the last 100 years. And the only hint of some description of this disease in ancient times is this picture on the tomb of an Egyptian pharaoh who has a picture of, well, the tomb has a picture of a harpist who looks really sick and may have some thickening of his temporal artery and may be blind as well because of his kind of looking into space glance compared to the other people. And so that's kind of a stretch, but it does reflect the fact that this is possibly a newer disease. It was first described a little over 100 years ago by Hutchinson. He described a man that had such a painful scalp that he couldn't put his hat on. And then 50 years later Horton described two cases of patients with giant cell arthritis systemic symptoms and he described it in a weekly Mayo Clinic conference. And then later described five more people and interestingly none of them had eye vision symptoms. So he and his colleagues, well, there's multiple names that have been proposed and probably the only one that's stuck is giant cell arthritis. But he and his colleagues ended up trying to find out there's an infectious cause. They ground up bits of positive biopsies and injected it into five healthy controls. They were aged matched and none of these controls ended up getting the disease. And then the last patient that they injected it into it wasn't in the scalp. The other five were into the scalp. The last patient, they injected it into her vein. And she did develop symptoms of fevers, malaise, elevated ESR. But because the other five didn't develop the symptoms, they concluded that it wasn't an infectious process, but rather some type of autoimmune process. By definition, temporal arthritis is an immune mediated vasculitis of the medium and the large vessels. And the vessels that are most vulnerable are the vessels of the cranial bed. And these include the superficial temporal artery, the vertebral artery, which is not depicted here, the ophthalmic artery, and the posteriori artery. And in autopsy studies, so just to get yourself acquainted with this picture, I guess the black vessels here are the ones that are most commonly affected in giant cell arthritis, and the gray ones are medium affected, and then the white ones are the least affected in giant cell arthritis. And so as I said before, the most common vessels affected include the superficial temporal, the vertebral, the ophthalmic artery, and the posteriori artery. And you'll find that this high incidence of occurrence in the vessel actually stops abruptly after it hits the dura. And the same thing happens with the central retinal artery. There's a medium amount of vulnerability, and then once it hits the dura, she loses some of its vulnerability to the vasculitis. And so the question is, why does this occur? And it has to do with histology. So we can kind of look at the artery and see that there's different layers to the artery. There's the intima, the median, adventitia. And arteries actually contain elastin. There's, I think, elastin in all three layers. And so in the vertebral artery, before it hits the dura, it actually is thicker, and it has a lot more elastin. So a lot more elastin in the tunica media and the tunica edentition. Here the elastin is darker staining. And then once you hit the dura, there's a lot less elastin. And so the amount of elastin actually correlates with how vulnerable the vessel is to vasculitis. And when you talk about temporal arthritis, you have to know that age matters. And there's a peak prevalence between 70 and 80. It is much more common in northern Europe. It's well-described in Scandinavian countries. And when you look at Europe, when you go from north to south, there's a decline in incidence. There's also a higher prevalence in women, so the ratio is three to one. And in population studies, and so this is a population study from Olmsted County, Minnesota, they not only found that the rate of giant cell arthritis is increasing over time, they also found this kind of cyclical pattern to things. And this average is out to be every five years. And because of this cyclical pattern, they have proposed that there could be some environmental trigger that is going on. And they have tried to match it with flus that have kind of a cyclical pattern. So there's a lot of viruses like perinfluenzovirus, EBV, chlamydia, other things that have been proposed to be a trigger for these cycles. So I just wanted to take a jab at the pathogenesis. And so thinking is that there's some type of virus or antigen that is triggering inflammation of the arterial walls. And the first thing that happens is that there's activation of dendrocytes. And then the dendrocytes, once they're involved, they spit out chemokines. And then the chemokines in some way actually causes fragmentation of the elastic lamina. So it brings us back to this elastin issue. And then once this fragmentation starts, this cascade starts with hyperplasia and then ultimately occlusion of the vessel. And when you occlude the vessel, you get symptoms. And so when you're taking a history, most common symptoms in giant cell arteritis by far are a new headache and jaw claudication. And the new headache can be this temporal artery, temporal pain, but the headache can be elsewhere in other places as well. And the jaw pain isn't just pain in the jaw, it's pain when you're chewing. And then also PMR symptoms are basically kind of arthritic symptoms in the proximal joints. And I was surprised to find that there are a couple of symptoms that are super high yield in diagnosing temporal arteritis. So common symptoms that have higher likelihood ratios of suspected temporal arteritis was diplopia and jaw claudication. That's come up multiple times in the literature that if there's good clinical correlation, if there's double vision or jaw claudication, that really helps you out. In terms of signs and exam findings, everything revolves around the temporal artery. So there's high likelihood ratios if they've got a beaded temporal artery, they have a prominent or enlarged temporal artery, they've got a tender temporal artery or they have an absent temporal artery pulse. I don't think I've ever palpated somebody's pulse. And then of course, one of the signs that's very helpful is an elevated ESR above 50. And the upper limit of normal for ESR usually is defined at 50 millimeters per hour. But to be more accurate, for men it's actually the age divided by two, and for women it's age plus 10 divided by two. Unfortunately, the ESR isn't always helpful. And approximately 5 to 10 percent of the time, you may have biopsy-proven temporal arteritis, but actually have a negative ESR. And so then you have to kind of, you know, use your history-taking skills. And there's other markers that can be helpful, including a CRP, which is more sensitive. And IL-6 is technically the most sensitive, but it's not commercially available and probably not as specific as the other two. In addition, you can have temporal arteritis without an elevated ESR based on the American College, the American College of Rheumatology criteria. So this was made in 1990. And all you need is three of these. So any three of this, you could potentially have three knots with elevated ESR and still have a yield of sensitivity of 93.5 and a specificity of 91.2. So I talked about diplopia being a very important question when somebody has good reason to have temporal arteritis. In terms of vision loss, by far the most common etiology is anterior ischemic optic neuropathy. So in this study of 63 or 64 eyes, by far people had swelling of their optic nerve indicative of an anterior ischemic optic neuropathy. And not only does this anterior ischemic optic neuropathy have swelling of the nerve, I tried to find one that showed pallor of the nerve. So there's a pallid swelling to it, not just plain swelling. And about 50% of people with temporal arteritis with anterior ischemic optic neuropathy will have this milky, chalky, white appearance to the nerve. So treatment of this disease, as you all know, includes steroids. And up front, it is IV or high dose PO steroids. And this is a long term treatment. So you start at one meg per gig per day for at least a month. And then as long as the patient is stable, they're tapered slowly over a course of six to 12 months. And I think this range is even wider, meaning that a lot of rheumatologists drag this out a lot longer. The prognosis from a vision standpoint, lots of numbers or big range, but the prognosis is between five to 34% can have recovery of vision. And this is recovery of two lines on the Snellen chart. However, if you start out at NLP, your recovery is probably pretty minimal. And so now I want to present some things that I think Dr. Katz had presented on earlier this year and what had been presented at NANOS. So the data that was presented previously was that there has been a strong association between giant cell arthritis and the strain of bacteria called Birkeldaria. And so previously it's been described that the Birkeldaria DNA has been found in the walls of patients with giant cell arthritis compared to controls who don't have the DNA in their walls. And so we've also found that an ELISA-4, this bacteria is found in patients with temporal arthritis and not in patients with control. And then this is another graph that depicts patients with giant cell arthritis and they're ELISA-titer for the strain of Birkeldaria. And you can tell from here that they have a much higher level than controls. And I think Dr. Kenig actually tested his blood and his value was about 50 picograms per milliliter just to give you a reference. So although I don't have time to go into some of the basic science research, we have been able to isolate the organism in vitro and show that it can activate giant cells and then activate giant cells by activating dendritic cells. And then Dr. DiDomenico, who's a hematologist and did a lot of this research, was able to induce a vasculitis in mice with this bacteria. And then she treated them with steroids and antibiotics. And treating them with both steroids and antibiotics seemed to help the mice do better than having them just be treated with steroids alone or without anything. So I want to describe a pilot study and the purpose of the pilot study was number one to find out if treating patients with antibiotics was safe and to use this information to build upon a later larger study. So inclusion criteria for the pilot study on human subjects was that they had to have a positive biopsy for giant cell arthritis. And they were enrolled either through the rheumatology or neuro-ophthalmology clinics. And they had to have a positive Birkeldaria, ELISA titer. And if they met the inclusion criteria, they were placed on minocycline or doxocycline for 30 days and then put on a steroid taper. It was either an individualized taper or a six month long taper. And then they were followed for whether or not they had relapse and if they had any side effects from antibiotics and then their inflammatory markers were followed as well as their Birkeldaria lipopolysaccharide titer. So in all we've enrolled six patients, I'll describe five of them because one of them is still getting treated. So in total there's been three males and three females and their average age is 80 and they've all had a biopsy that confirms giant cell arthritis. The first case was an 84 year old man with a new diagnosis of giant cell arthritis. His presentation was central retinal artery occlusion with light perception vision only alongside headache and jaw pain. And just take note that his initial titer was 538 which is high. So because of that he was enrolled in a study in place on an antibiotic for 30 days. And he's been followed for 16 months and in that time he's had no relapse and he's been tapered off his steroids completely after a total of 10 months. But he did have one side effect from steroids and that's avascular necrosis. He's been asymptomatic but this was found on bone studies. So this is a graph that depicts his ESR levels in red and his Birkeldaria lipopolysaccharide titer in green. And then this gray bar represents his treatment, the time frame that he was treated with minocycline. And you can see that both the titer of the bacteria and the ESR drops in conjunction with his remission status and after treatment with antibiotics. Case two is an 88 year old woman. She presents previous enrollment with a left frontal stroke and scalp tenderness. She actually had some question of whether or not she had genital arthritis in her past. But her presentation prior to enrollment was basically a stroke and scalp tenderness. And she had elevated ESR in a positive biopsy and again her titer was elevated at 521 picograms per milliliter. And she was treated with antibiotics. At month four after enrollment she did have a relapse and that's this asterisk right there. Her relapse with scalp tenderness, weight loss and elevation in ESR as you can tell from the rise in ESR right here. And so her prednisone was promptly increased from 10 milligrams to 20 milligrams. And because her Birkeldaria lipopolysaccharide titer never really dropped, if you remember the other patient dropped a lot lower, it never really dropped because of that Dr. Curry, her rheumatologist actually gave her another course of minocyclin. Just to see if it could come down and it did and it seemed to also match her ESR level. So next case is a 61 year old woman again presenting with the genital arthritis relapse. Her presentation was actually painful in cold hands when driving and she was found to have bilateral subclavian occlusions. And because of that she needed a write-up or extremity bypass and her carotid and brachial artery biopsies were sent to pathology and it showed up with giant cells. And so her, before enrollment, her Birkeldaria titer was also elevated at 513. She was put on minocyclin and she's been followed for about 10 months and in that time she did have a relapse that included jaw pain. And because of that her prednisone was increased. The interesting thing about her story is that number one she never really had elevated ESR throughout the time that she's been followed or at presentation. And she kind of constantly had left upper extremity pain with exertion. So it's kind of hard to tell if she was, you know, having smoldering disease. And so here with this ESR in red it just kind of reflects, so it's about 20. We just have to take off 1-0. But the ESR has been about 20 to 8 to 10 the whole time. And despite her relapse right here the ESR kind of stayed the same all the way through. However the Birkeldaria lipopolysaccharide titer has always been high. So it started out at 500. It didn't drop too low. Dropped about 300. And then you wonder if this number right here before the relapse was trying to hint at potentially her potential to relapse. But it's hard to say. And so case four is an 80-year-old man whose presentation was anterior ischemic optic neuropathy. And he was followed by Dr. Warner for about nine months where there was multiple attempts made to bring his steroid dose below 20 milligrams. I think there were like three trials to get him below 20 milligrams and every time he would have recurrence of vision symptoms. And he unfortunately also had severe osteoporosis with compression factors from the steroids and a bout of pneumonia which could have been from being on the steroids as well. So nine months after multiple attempts to get him below 20 milligrams for prednisone he was enrolled in the study. And he was enrolled because his titer was elevated at 590. And he was put on menocycline. And in about seven months he actually finally went below 10 milligrams for his prednisone. And at 17 months follow-up he has not had another relapse. His prednisone does his currently at 1.5 and he might be on that for a long time. And this is his graph of his ESR in red. And you can tell that his ESR also wasn't all that elevated for his age. So 32 was his presentation ESR. And his ESR kind of oscillates in different areas but kind of within the normal range. But his lipopolysaccharide titer drops and then stays low and is more reflective of his remission status than potentially ESR. And this last case is from the VA. He's an 87-year-old man with a new diagnosis of giant cell arthritis and he had sequential anterior schematic neuropathy. And here's that pallid swelling. He had a very elevated ESR with 74 and he had a positive temporal artery biopsy. And it sounds like within a week he had both eyes affected. His case was a little different because he got some heparin because he had such a severe course of the giant cell arthritis. But eventually he was placed on steroids. And again, his Burkle-Daria titer was elevated and so he was treated with 30 days of minocyclin. And at eight months' follow-up he did have a relapse while he was on a little dose of prednisone at one milligram. And his relapse was jaw pain and headache. And his steroids were promptly increased to 20. And once they increased that he had hallucinations and agitation and delirium while at a skilled nursing facility. And then this is his graph. This is his treatment with minocyclin. And you can tell that both the lipopolysaccharide titer and the ESR rise right at the point of his relapse. So this graph shows basically the peak Burkle-Daria titer for each case and the trough Burkle-Daria titer. And in this graph you can kind of tell which ones had relapse. So it was case two, case three, and case five that had relapse. And the two that did not have relapse were case four and case one. And they seemed to have the steepest slope of drop in this Burkle-Daria titer. And then also if you look at the cases that had relapse, the person who relapsed the fastest was the one who had the least drop in the Burkle-Daria titer. So we'll probably need more numbers to kind of sort that out. But the overall conclusions in this pilot study is that there have been so far six patients enrolled. And I guess five of them have completed the antibiotics. And out of those three have had flares. And so you might think that this is quite a lot of flares. And it might be, but when you look closer into how they were treated, they were actually treated with a really fast steroid taper. And most of them were tapered on a plan that was 210 days to be off steroids. And that's quite a lot. And when you look at rheumatologists, they kind of drag things out sometimes to one to two years. So this was a very fast taper. And that's probably why we got some of this signal. And it seemed like the ones that had flares had the smallest drop in the lipopolysaccharide titer after antibiotics. And none of these flares in these three people resulted in a serious complication. None of them had new ophthalmologic involvement. And none of them had any side effects to this antibiotic minocycline or doxocycline. Three of them did have steroid side effects like the avascular necrosis, delirium, and then the compression fractures. And then it seemed like even though the titers dropped, they still stayed elevated after treatment. They never went down to a normal controls level, which is about under 100 or 50 picograms per milliliter. So in conclusion, it seemed like adjuvant antibiotic therapy in patients with giant cell arteritis is safe. Perhaps this Berkel-Daria lipopolysaccharide titer could be a novel marker for monitoring disease. And then many patients with giant cell arteritis suffer from complications, severe complications from long-term steroid treatment between 58 to 86 percent. And perhaps therapy directed at Berkel-Daria, the strain of Berkel-Daria, may help some people taper off of steroids. And in order to answer that question, we definitely need a future study. And the goal is to have a prospective placebo-controlled multi-center trial of patients with steroids and antibiotics versus patients with steroids and placebo. And that's it. So I definitely want to thank Dr. Katz and Dr. Kenig for involving me in their research. And then Dr. Warner and Dr. Degree for helping me with everything. And then I don't think you've met Ivana. I kind of wanted her to talk today, but I don't think we had enough time. So not yet, but their steroids, their titers are high. But I think some of that still needs to be analyzed. Some of them, I don't think I went into it in too much detail, but Dr. Kenig, the rheumatologist, had extended their minocycline for 60 days. So I don't really have the results of that, but he's starting to do that. It's really hard to analyze because they were treated by outside rheumatologists. A lot of them were on methotrexate. And so that has to be accounted for, I'm sure, in the future study. I think just reviewing the charts, none of the rheumatologists here, because we have some of the controls that are treated elsewhere, those have been. But I can't tell you if they're doing worse or better.