RWCS Fellow Cases B Save

Hi, I'm Jack Cush, I'm here at RWCS twenty nineteen in Maui. We're going over the poster sessions with the fellows and I'm here with Allison Wilden. Allison, where are you from?

I'm originally from Indiana but I'm training in Milwaukee, Wisconsin at Medical College of Wisconsin.

Okay, you've got a really interesting poster here which I think would confuse most doctors and that is GPA as a diagnosis but ANCA negative. Tell me about the case.

Yeah, that's correct. So we had an unusual case of atypical demographic in a gentleman with limited GPA limited only to the lungs and was ANCA negative. He presented with about four months of this dry cough and then about a month of this pneumonia that wasn't responding to broad spectrum antibiotics or antifungals, had a completely negative infectious workup, and just wasn't responding so we had a very broad differential diagnosis and we were working him up, and eventually got a biopsy which showed, demonstrated granulomatous inflammation in the lung and vasculitis consistent with GPA.

Was it a transthoracic needle or you went for tissue?

He went for tissue, he had a wedge biopsy.

Okay, good. Up until that point describe like how sick the patient was. What was his main symptoms? Were respiratory and that's it?

Respiratory, he had progressive shortness of breath and cough eventually by the time he presented to us he was requiring oxygen and he was febrile, he was tachycardic, he ended up intubated after his wedge resection as well.

So is this a case where when the pulmonologist don't know what to do they call a rheumatologist and that's how you got involved?

That is correct.

And were there other clues that this was going to be an inflammatory and not an infectious disorder?

No, not really.

I mean he had no

other manifestations of GP. He had no renal disease or rashes or any other manifestations that would suggest a vasculitis other than these lung infiltrates that wouldn't resolve.

Uh-huh. And so once you did the biopsy, then what did you institute as far as therapy?

So we started him on pulse dose steroids and cyclophosphamide cyclophosphamide as well as plasmapheresis.

Why that?

That's the standard of care at our institution for this disease.

Okay, so you're not using rituximab?

We do, in fact we're planning to use rituximab for his maintenance therapy.

Basically the bottom line here is that if you really think you have the diagnosis but you don't have the ANCA, you have to go for tissue?

I think so. I think you have to have a very high level suspicion in these cases when you can't explain what's going on with the patient and keep a broad differential, and you can't rule out GPA based on the absence of an ANCA.

Yeah, that's an important teaching point. Can you talk a little bit about the diagnostic criteria and how the diagnosis should be made?

Sure, so part of the problem is we don't have great diagnostic criteria. We have the old 1990 criteria for the classification of Wegener's granulomatosis. We're Correct, we're a little bit behind. And they created before ANCA testing was available. Currently there's a study being undertaken by a combination of VULAR and ACR to create new better diagnostic criteria for vasculitis.

That will be really important, especially diagnosis like this. How much after the diagnosis, what's the history after, how was the patient done?

Yeah, so he responded very well to treatment. He was extubated within a week and at this point he is finishing his cyclophosphamide and his lung function seems to be back to normal. Doing well.

He's out of the hospital?

He is out of the hospital. Yes.

Interesting case. Thank you very much for bringing it.

Thank you.

Hi, I'm Doctor. Rachel Tate coming to you from RWCS twenty nineteen and today I'm here with Doctor. Anna Lafian who's one of our really amazing fellows this year. I'm really proud of them. And she's gonna tell us about her poster.

Anna, where are you from?

I'm actually from Loma Linda. Well, I'm from Los Angeles, but I'm doing my fellowship at Loma Linda University.

That's awesome. Well, we're really glad you made the trip to come see us. So tell me about your poster.

Alright. So Should I grab this from you? Alright. To start off with So I'll just present the case briefly. We had an 18 year old, previously healthy Hispanic 18 year old female who basically presented for two weeks of progressive nausea, vomiting, and intractable hiccups.

She then was intubated for airway protection because she had seizing at the outside hospital and was transferred to our facility for higher level of care. So at that point, we had an MRI that basically showed edema from the medulla all the way to the conus, started to get autoimmune workup, she had a lumbar puncture, so her lumbar puncture was consistent with lymphocytic pleocytosis. The NMOs of the CSF, aquaporin-four actually came back high titer as did the serum aquaporin-four. At that point obviously we hadn't waited for these studies to come back because that takes quite a while, but had suspected given the extensive transverse myelitis, we had suspected NMO spectrum disorder and actually started her on pulse dose steroids for five days. We also started plasmapheresis and rituximab also.

We did the weekly three seventy five milligrams per meter square dosing. She had great response. She was extubated after two days. She started to actually have I think I may have failed to mention also after she got transferred to us, became she had paraparesis, basically couldn't move her limbs. So she started to have sensation and movement, all of that.

And then within a month and a half, she was up and walking.

So, Anna, sometimes this can look confusing, especially to someone who doesn't see this normally, and if you're rheumatology. Tell me about potential for infection. Was there ever a thought process that this could be an infectious process for this patient?

Absolutely. So, we took care of this patient in collaboration with neurology and neuro ICU. However, the initial thought per them was actually that this was probably a viral infection and so she was being treated with antivirals throughout the course of our treatment as well because these things, again, the studies don't come back for some time. However, that thought kind of dwindled off after we found this diagnosis and then when she was seen for follow-up in our clinic, we actually had further records from the outside facility prior to her transfer and we found this. So her West Nile virus in the CSF was positive, the IgG was positive.

And so that just led me to wonder that that was probably her trigger, like the viral trigger that set off the NMO spectrum disorder in this severity.

So, given that information, do you think that this is It's not a common case, but do you think that there could be an infectious etiology that almost, like you said, triggers this for other patients? And, should we be looking for other infectious opportunities for our patients and making sure that we're treating them, we're treating the patient, not just potentially one thing.

Absolutely. For me, I think it was just really fascinating because ever since starting fellowship, every lecture that I've been through, really do hear like, that there's a genetic component that takes up 10 to fifteen, ten to 20%, and then there's an environmental component which is made up by viral triggers and other exposures and things of that nature. And I always wondered what that viral trigger was. And, you know, we read about cases reported of EBV and other viruses that can trigger things, but it was so fascinating to potentially have a theory about this case and what it could have been.

Well, I think this is a great case and it really does highlight what we need to be doing as clinicians and treating our patients. Thank you so much Anna for coming. We're glad you're here. Hopefully you'll come back next year and we'll have a follow-up on our patient as well. But, check us out on roomnow.com for further information and come join us in Hawaii at RWCS twenty nineteen.

Hi. I'm Jack Cush. I'm here at RWCS two thousand nineteen in Maui. We're looking at the posters that the fellows brought to the meeting. Lot of interesting ones.

I'm here with Leanna Wise. Leanna, where are you now?

I'm in Los Angeles training at LACUSC Medical Center and Keck Medical Center.

Excellent. So you have this case of something that I'm really interested in that is NDA5 and association with dermatomyositis. Tell us something about the case.

So this is a 62 year old woman who came to our institution. She had been complaining to a few outside providers of some kind of nonspecific symptoms mild dyspnea, some arthralgia, just generally not feeling well and was getting a workup as outpatient. But after about two and a half months, her symptoms all started to worsen and she developed worsening dyspnea, a diffuse rash and some other symptoms as well. At that time she saw a dermatologist and rheumatologist and received a tentative diagnosis of dermatomyositis, but unfortunately before a further workup could happen, really decompensated from a respiratory standpoint. By that, I mean that she eventually had multiple admissions for supplemental oxygen and eventually was started on high dose steroids.

She was then transferred to our institution for higher level of care and at that point, the diagnosis of MDA five dermatomyositis was pretty set in stone. Because these patients are so, usually so sick and present so severely, we kind of threw a lot at her. So we ended up giving her additional steroids including, a course of three day course of pulse steroids, cyclophosphamide, IVIG, plasmapheresis, and even a tacrolimus drip. And the purpose of all this was because her lungs looked so bad. So that was really the driver for our treatment.

So, let's go back a little bit. So, you only get the MDA-five after a diagnosis of dermatomyositis is on the table, Correct. So, the rheumatologist, dermatologist made the diagnosis based on skin labs, what?

So, so interestingly her labs were not very characteristic for dermatomyositis. So she had a normal CK, normal adalase and a very transient kind of waxing and waning elevation of her AST ALT but she did and we didn't see the rash because she had so much steroids by the time she came to us, but she apparently did have a very faint shawl sign V sign and maybe some rash on the extremities, but nothing that screamed dermatomyositis, but the outpatient rheumatologist, was astute enough to still suspect it and that's what prompted her to order that panel.

So ordering a panel, you've got the MDA-five. Correct. In your reading about MDA-five, what's the association? Why is that something rheumatology can know about?

So it is it's present in, anywhere from five percent to about thirty percent of dermatomyositis patients, but it can have a very heterogeneous presentation. The studies that have come out of Asia, it's associated with rapidly progressive ILD and that's what scares us the most is that these patients may have some mild dyspnea on exertion, but it really escalates fast and they become very, very sick to the point of, we're unable to kind of rein in the underlying process. So not only is it associated with ILD but can also have pretty significant cutaneous findings including, mouth ulcers and, ulcerative lesions throughout the body, which are very unique to MDA-five and not to the other dermatomyositis subtypes.

My patients have had really severe ulcerative finger lesions and a few, that was the reason they presented. Other ones I've had were sort of like yours. It was a big lung presentation and really fell into the hands of the pulmonologist and sort of very late, the rheumatologists get involved at that point. There's a lot of lung damage and that's the problem, identifying them late. There's a significant morbid if not more Yeah.

Risk of

I think also to complicate the picture is a large percentage of these patients are clinically amyopathic. So in the Asian populations, MDA five is very strongly associated with lack of myositis. In The US population, the association is not as strong, although our Caucasian patient did not have myositis.

When do you think the rheumatologist should order an MDA five?

I think if the picture is very confusing. I think if this screams full blown dermatomyositis, I think it's just an extra lab test that won't change your management. But like this patient, she had just such vague symptoms and she just started to worsen quickly. And I think if you're not certain what's happening and the patient's getting sicker, I would rather have more information to know how to approach these patients. But again, she just had such a vague picture when she came in to the outside, rheumatologist, the outside dermatologist, and I think the MDA five helped to at least start treatment sooner rather than later.

So I thought and I would then go back. I agree that kind of when you're really stuck and you've already had your evaluation, you don't know where you're gonna go next. It might be a part of a panel, but certainly people who have this lung presentation, which is not that common in myositis, dermatomyositis, or even worse, ulcerative lesions or ulcerations, like you said, that might be a good reason to also go to the test. So, what's happened to the patient?

Unfortunately, she passed away. So we tried a lot for about a month and she eventually was on ECMO, high settings of ECMO that we weren't able to wean down and her primary team, the ICU team, was able to wean sedation and actually have a goals of care discussion with her.

Yeah. And and you know what? That's a lousy ending, but you know what? It's pretty common with

this Yeah.

This subset, this MDA fives, their lung disease and they call it like the as you say, in Southeast Asia, call it rapidly progressive, but I have probably, I don't know, six patients and yet the same outcome. Two died and they died from their lung disease.

Yep, yep, unfortunate.

So early identification, really aggressive therapy, and knowing about MDA five. Cool case. Thanks.

Yeah. Thank you.

Alright. Watch more posters from RWCS. Hi. I'm Jack Cush. We're here at RWCS two thousand nineteen in Maui.

Great meeting. Even better are the posters brought here by the the fellows. I'm here with Mike Putnam. He's a fellow at?

I'm at Northwestern in Chicago.

Excellent. Your what year is last year?

I'm at second year, but I'm staying on for a third research year, so I'll around a little longer.

Superb. Superb. Mike is the host of the Evidence Based Rheumatology Podcast. Check it out on iTunes or on wherever you get podcasts. I listen to them.

It's great. Mike, tell us about this poster. I think it's kind of interesting. You attempted to look at control trials in the rheumatology literature. What was the purpose?

What was your objective?

So I had a couple things I was curious about. One was over time have quality of trials changed? And then a couple other things related to whether industry funding or not industry funding affects the quality of trials and how big the effect sizes in the rheumatologic literature were. And so I kind of assessed a couple of questions.

So what was your choice? What trials were you going go to? Obviously you could choose millions and not just in rheumatology, so what did you hone down to?

So I decided to narrow in on randomized controlled trials that specifically assessed a pharmacological intervention against a comparator, whether that's placebo or an active comparator such as another medication.

And are these rheumatology trials?

Yeah, I looked at the top three rheumatologic journals, the Annals, Rheumatology and Arthritis and Rheumatology. Uh-huh. Yeah. Then I looked at nineteen ninety eight, 2008 and 2018. I just read every single randomized controlled trial in those years.

So different diseases, different drugs?

Yep. All sorts of diseases and all sorts of drugs. So

why did you do a cross section like that as opposed to let's just say focusing on PSA trials or RA trials?

Yeah. Good question. I thought about doing just RA and doing more years, but I felt like getting a broad swath of the rheumatologic literature would kind of let me be more generalizable.

Okay, that's interesting. So what was your takeaway? What did you find or did you find anything surprising?

Yeah, so we found, we looked over ultimately, 85 trials wound up making the cut. Over time, not a lot changed. There was a small increase. Those statistically significant sensitivity analysis and intention to treat, but an overall quality scale did not show any differences. Industry funding was interesting.

Industry trials tended to be better. They're more likely to use blinding, they're more likely to use patient reported outcome measures, and they're more likely to use an attention to treat analysis. And on a quality scale, they were more likely to be And so I found those are the main differences between those two variables.

And that makes sense because their objectives are to get their drugs FDA approved, and the FDA rules and guidelines on doing the right trial are pretty standard, pretty well known, and other people that do trials don't necessarily have to hold themselves up to that standard. So interesting.

Yeah. Think it's an incentives thing where the incentive for industry is to run good trials so that they can get the FDA to approve the drug. Absolutely. The incentive does cut in a way that I think is a little bit less optimistic. So in 1998, almost half of our trials included an active comparator.

So methotrexate against a TNF. By 2018, it was only one in ten. And so a lot of what we're doing these days is comparing an active drug against placebo as opposed to a drug against another drug. And I think we're losing out by not doing those kinds of trials because there's a lot of times when you want to know what should you give for myositis And we don't

I'll give you my perspective on this as someone too old in that the reason that was going on compared to say the drugs in 2008 and 2018 are newer drugs and there's a lot of new drugs being developed and hence the objective is just get it to market, get FDA approved and there you'll to do placebo controlled trials. In 1998, that's when infliximab and itanercept started and Arava was started at that time. But up until then, there wasn't a lot of drugs. If there were studies happening, it was 1998, these would have been studies that were done before 1998. Yeah.

People are looking for the answers for the currently marketed drugs. And so you're more likely to see these head to head comparisons. In the life cycle of a drug, you start out with a lot placebo controlled trials and then maybe over time you get into more comparator trials. But I agree with you. I think comparator trials are what people are asking for now because sometimes you're faced with a A, B or C decision and the placebo is not one of those choices.

Yeah. It's usually not a good option. Right.

So

Yeah. I think optimistically, a lot of this is us being a victim of our own success, which is a positive finding.

It's a good problem to have, right? It is. I'm always confused by funnel plots. Tell us what that was about.

This is a fun one. Let me walk you through Yeah. So on the on this axis is the precision of the trial. I used the number of participants in the study as a surrogate for that. So around here is about 500 participants and around here is zero.

Mhmm.

And then some trials report absolute risk reduction. So that's the blue dots. And then some percent improvement, that's the green dots, and I overlaid those on each other so the scale is the same. And so a trial here has five participants and a 50% absolute risk improvement. So what you see from this chart, which I think is relatively striking, is that small trials have a much larger percent improvement or absolute risk improvement.

And so you see a large effect size with smaller studies. And as your N goes up, and hence the precision of the trial improves, you see a smaller and smaller effect trial. So it's kind of a reminder to not trust trust small trials. And the second thing is that there's a there's a total lack of negative trials.

That's the reporting bias.

Yeah. I think I think there's two takes that are both reasonable. The first is that there's an incredible amount of reporting bias and that we're just publishing positive trials and that all these negative ones either don't happen Mhmm. Or they get censored somehow or the journals aren't interested. A more optimistic take is that by the time you get to a randomized controlled trial, you're probably testing a therapy that you think works if you're gonna spend all that money.

And so the pretest probability of success is actually a little bit higher. And so if that's true, then we would expect you know this to be the center of the funnel plot as opposed to zero. And so maybe this little mound here is what's happening. It depends on you how squint at it.

What about those crazy outliers out there? Are those the most successful trials in rheumatology?

Yeah. Like this one right here was phenomenal. Yeah. There's a couple with large effect sizes that were large and yeah. Mean, every once in while you do hit a home run that in a large large randomized controlled trial you see this is a 50% improvement, you know.

Alright. So having studied this over 09/2018, what's your advice to pharma when they're making up their next three trials for the next three years?

You know, that's good a question. And this kind of goes back to what I was saying about incentives. You know, I think pharma is responding to incentives that are appropriately driving the creation of good trials. I think the onus is on us as clinicians to try to fill the gaps that these incentives aren't driving. So I think that doctors need to be running these comparative effectiveness trials to see whether we should be using Imuran or CellCept for myositis and things like that.

I think that would be a good direction to go. I mean, 84% of the of RCTs are funded by pharma. And so trying to find more creative ways or cheaper ways to fund trials ourselves, think, is actually my my take home solution.

Alright. Mike, great poster. The evidence based podcast. Check it out. More good posters, more good videos from RWCS.

Thanks so much.

Hi, I'm Doctor. Rachel Tate coming to you with Doctor. Nina Narasimhalu from RWCS twenty nineteen in Maui. And Nina has an amazing presentation about her poster, which, you know, the fellows are supposed to bring us a poster that will be really engaging and stimulating, and that's exactly what she's done. So I am sure that Irvine is very proud of you.

But Nina, tell me what brings you here. Tell me about your poster.

Sure. Thank you so much for having me. It's been a blast so far. I have a 33 year old gentleman who presented with bilateral lower extremity swelling, myalgias, generalized weakness, along with progressive shortness of breath that had been going on for about a couple of weeks. He had actually been hospitalized at another hospital and left AMA, ended up coming over to our emergency room for further evaluation.

From our history, we learned that he actually was an active IV drug user using both methamphetamine and heroin, and his last use was one day prior to coming into the hospital. On physical exam, his vitals were notable for some tachycardia. He was also tachypneic. He was saturating okay on room air. On exam, we noticed that he also had this violaceous palpable purpura that you can see on the image here, and the and he had macules as well that were in a retiform pattern.

His labs on admission were notable for anemia and thrombocytopenia, and he also did have some mildly elevated, transaminitis and, a urinalysis with some mild proteinuria. In terms of his imaging that they had obtained in the emergency room, this was all within the span of, like, a few hours. They showed they got an echocardiogram that showed that he had evidence of impending cardiac tamponade. Shortly thereafter, he actually was taken by cardiology, had a pericardiocentesis, had a drain place because they were immediately able to drain a liter of fluid, and then they drained in subsequent days, I think, at least another liter more. Throughout this time, he was having some intermittent fevers.

And given his history of infectious, or IV drug use and then the rash, we were concerned about an infectious endocarditis, some possible infection that was contributing to his current presentation. But as the workup kept coming back negative, then the question was posed, is this potentially an autoimmune process? We started sending off our labs, and, his ANA, double stranded DNA, along with the histone came back positive. He had some hypocomplementemia and then interestingly a positive P ANCA with both MPO and PR3, which we can see in cocaine and levamisole induced vasculitis. His antiphospholipid antibodies were also elevated as well.

So at this point, when we saw, the these labs and in order to further work up the urinalysis, which showed 100 protein, we actually got a twenty four hour urine, which showed 1.8 grams of proteinuria. And so we wanted to get a renal biopsy to determine if this was lupus or an ANCA vasculitis presentation. At this point, the patient admitted to cocaine use, but his last use was actually several months ago, so it seemed that the methamphetamine and heroin was more at the more relevant drug use at the time. We ended up getting a renal biopsy, and we discharged him home on prednisone. He unfortunately had a lot of hospitalizations after that initial hospitalization.

He really didn't come to any of his follow-up appointments. One of his hospitalizations we saw that he had constrictive pericarditis. He had renal insufficiency. We gave him steroids again. We started him on Plaquenil and CellCept, but there were issues of medication adherence.

Then he also had multiple PEs, and we started him on anticoagulation. And so this led us to, you know, further work up what was going on because he had all these positive antibodies, but we know that lovamisole could definitely cause the positive p ANCA and the MPO and p r three, but could also be responsible for some of the other labs. And so from preparing for the presentation, and learning more about the case, I saw that with lovamisole, you can definitely have a positive ANA, a positive double stranded DNA, positive ANCA with both MPO and PR3, and you can also have a positive lupus anticoagulant, many of the labs which he did have. And so some of the key points to take away from the presentation was that more recently, although we cc levamacol with, cocaine, it's now being found in heroin. So in patients that, are using really any types of IV drugs, it might be worth to send off, for a levamosol level, making sure you check a UTox.

You can always check an anti elastase antibody, which is both, sensitive and specific for Livamisole induced vasculitis. But because of, our findings, we really do feel that this patient has a drug induced lupus, antiphospholipid syndrome, and, ANCA associated vasculitis.

Nina, thank you so much. I think this is a really good case because it really does show us that it's important to talk to your patient. We need to know that they're being honest with us, especially when they come into the hospital. Do you find that the anti elastase antibody is something that is easily drawn in a community setting? I think it is.

And, yeah, and I think that that's something we can all look forward to. So anytime you have an atypical presentation of something with multiple antibodies, it's always important to ask about drug use. Thank you so much. I really appreciate it. And I did not know Levamisole was a cutting agent for heroin, so I learned something, well, in addition to everything that you just taught me.

Thank so much for being here. We've really enjoyed it. And that's all from RWCS twenty nineteen for right now. Check us out on roomnow.com.

Hi, it's Doctor. Artie Cavanagh, RWCS twenty nineteen and we're very pleased to have a number of posters and case presentations and other academic presentations by a really good group of fellows that we're pleased to have with us at the meeting this year. This is Doctor. Hanif who comes to us, from Detroit from Wayne State University Henry Ford Hospital System. Gonna talk to us about a case she has showing the overlap of things we see in rheumatology with some of our other disciplines.

Doctor. Hanif?

Thank you, Doctor. Kawanana. Very nice meeting you and I'm having a great time here at Hawaii with the nice weather which is a shift from the Detroit's weather. So thank you so much for the invitation. So I'll talk about a fascinating case that I had about scleroderma or malignancy.

It was a diagnostic and therapeutic dilemma because the symptoms could be attributed to either malignancy or a scleroderma. So it was a veteran, a 61 year old gentleman, who presented with lightheadedness, dysphagia, dyno phagia. And his symptoms really started about one year ago, and that was a sequela. One year ago, going back, he had Raynaud's phenomenon and he noticed his skin thickening diffusely. At the outside hospital, they did a biopsy that showed morphia or it looked like scleroderma pattern.

Off note, his serologies at that time, ANA was six to one is to six forty. The typical antibodies that you would expect to see in his scleroderma, the SCL 70 and T centromere were negative. What was positive was RNP polymerase three. They also did a CT thorax. At that time, they thought it might be a esophageal duplication cyst.

They did not progress further, and he was enrolled in one of the scleroderma trials at the scleroderma center of excellence at a university hospital for tocilizumab. So in our hospital, when he presented a year later, he had symptoms of ortho orthostatic hypertension. He was not even able to solve his saliva. The imaging showed the CT scan showed diffuse mediastinal hilar lymphadenopathy. Echo was normal.

So in our during the second day of his hospitalization, he had acute respiratory distress, and EBUS was done, and it showed aggressive stage three diffuse large B cell lymphoma, non Hodgkin's type. Off note, all this happened within the year of his diagnosis. He completed his chemotherapy four cycles. He was on Epoch regime. In five months, if you notice the difference in the CT scan post chemotherapy, we can expect the improvement in the mediastinal lymphadenopathy.

But what was remarkable was that his skin tightening significantly improved with the administration of chemotherapy within a span of five months. So we do know that scleroderma patients have increased risk of cancer compared to general population. That could be because of damage from scleroderma as in ILD or Barrett's. The cytotoxic therapy that's used for management could be an insight common inciting agent or genetic predisposition. Of note, the recent immune related adverse effects that we noticed.

And there is a case of scleroderma, reported from the immune related adverse effects by the the checkpoint inhibitors as pembrolizumab. But, in our case, it is a unique subset, that's described with concurrent onset of scleroderma and cancer. There's a group, by led by Shah John Hopkins. He has noticed a striking temporal clustering of cancer diagnosis within the year or within first few years of first clinical signs of scleroderma. In one study, they actually found a five point zero eight fold increased risk of cancer within two years of scleroderma onset in those with positive RNP polymerase three antibodies.

So is it the RNP polymerase three that should be a red flag for us to search further for any other signs of cancer? Because in this study has been replicated in Australia when they noticed at least a fourfold increase in cancer diagnosis within the first five years of signs of scleroderma. So, what they hypothesize is the mutated RNA polymerase three proteins to be immunogenic that initiate anti RNA polymerase three antibody response. So my conclusion and what the take home point would be that cancer induced autoimmunity may occur in a subset of patient with these positive RNA polymerase three antibodies. We may describe scleroderma as a paraneoplastic disease, and these antibody should be a red flag that should warrant more aggressive cancer screening.

In our case, chemotherapy almost resolved skin tightening. Thank you so much.

Excellent. An interesting case really brings to to, into play a lot of considerations that we have with our patients with scleroderma. I guess will you follow this patient because he may actually be cured if you took care of the cancer and that was the cause of the scleroderma.

Unfortunately he passed away last year due to complications of chemotherapy, neutropenic fever, sepsis, septic shock.

Well, that highlights the danger of a very aggressive treatment for scleroderma, made the skin better, but, so it sounds like a bad outcome. But, good learning experience. Thank you so much for the presentation, and thank you from RWCS twenty nineteen.