All In The Family (8.23.2024) Save

It's 08/23/2024. This is the RheumNow podcast. Hi. I'm Jack Cush with rheumnow.com. This week on the podcast, the challenge of lupus nephritis, perplexing skin problems that rooms have to deal with.

Yeah. You don't know Jack about tick two, and I wanna talk about the value or wasted time with family history. Oh, that's a good one at the end. We're gonna begin with GPA and the role of prophylaxis with Bactrim, Septra, Trimethoprim, Sulfamethoxazole, TMP, SMX. This is a study, I think we talked about this from at ACR in 2023, finally hits the publication, this past month, nine nineteen patients with GPA who receive or don't receive prophylaxis.

I think the number was thirty one percent receive prophylaxis with TMP SMX. And while you're doing the TMP SMX prophylaxis for the purpose of preventing PJP, the main readouts on this were overall less outpatient infections, like twenty percent less significant. Overall, serious infectious event rates, and that's like fifty percent less and that also was significant. And yeah, there were less PJP events, there were thirteen PJP infections, and they were all occurred in the people who did not receive TMP SMX prophylaxis. So I think these numbers are big because if you think about it, these are GPA patients, they're getting a lot of immunosuppression, they're getting a lot of steroids, have highly inflammatory disease, and infection is a big problem and a big problem as far as mortality, morbidity, and that's all above and beyond the risk of Pneumocystis, Uroveci infections.

So these numbers and this practice are really encouraging. I want to talk about lupus because we talked about that before, open with lupus, it's always a good idea. A review of many different sources looked at preconception predictors of adverse pregnancy outcomes in lupus, and it turns out it's everything that you probably know, but I think it bears repeating. Lupus activity, a bad and this is for preconception evidence of these factors. It's bad enough when they occur during pregnancy, but if at preconception, you shouldn't be getting pregnant.

That's lupus activity as measured by sleeti, lupus nephritis, chronic hypertension, and evidence of the antiphospholipid syndrome. These are all good predictors of adverse pregnancy outcomes. A meta analysis of patients, with lupus nephritis and their starting dose looked at what happens based on starting dose and what are the predictors? So this is 50, studies that were in the meta analysis over three thousand lupus nephritis patients and they looked at two starting doses twenty five milligrams as a starting dose of prednisone versus sixty milligrams and not surprisingly a higher starting dose of sixty milligrams was associated with a higher rate of complete response. Thirty five percent for sixty milligrams versus twenty percent for twenty five milligrams.

But if you go with a higher dose, a higher starting dose of prednisone, you also increase your odds of serious infectious events where it went from three point two percent at twenty five to twelve percent at sixty milligrams, and death, the worst outcome. A zero point two percent risk at twenty five milligrams starting dose versus a two point seven percent risk. So steroids wonderful, but then there's always a heavy downside, and it gets heavier as you go higher. You got to consider you had to weigh the pluses and minuses when you're making those really tough decisions. I don't know how you weigh serologies in staging your patients and staging risk, but there was a nice systematic review of anti Smith antibodies or SM antibodies, 17 studies.

Overall, they showed that a real had a really high specificity and you know that it's maybe only second to double stranded DNA with a 90% specificity. It's not seen in the majority. In fact, it's seen in the minority patients. Interestingly, it's primarily seen or mostly seen in African American patients. But what they showed in here that I wasn't probably too clear about was that Smith antibodies by themselves are associated with higher degrees of lupus activity.

And that even you can see in some patients with the highest degree of lupus activity, had higher titers of SM antibodies. However, the presence of SM antibodies did not predict the risk of or presence of lupus nephritis. Interesting. Lastly, not lastly, but next interesting is a skin disorder. Actually, more than a skin disorder, vexus, as you know, described a few years ago as a unique somatic mutation leading to disorders that we confuse with a number of different things and look like Behcet's and other things.

This is a cohort of one hundred and twelve Vexis patients that were studied and they specifically looked at skin involvement. And it turns out that skin involvement was a common phenomenon seen in eighty three percent of patients and it was tended to be seen early on in most of those patients. When you looked at the pathology, when that was available in about half the patients, they were either leukocyte clastic vasculitis in a third, neutrophilic dermatosis in a third, and perivascular dermatitis in thirty percent. What they I think the main point of this paper was, well, one, the skin manifestations responded really well to steroids, over ninety percent, ninety two percent responses to these skin findings, right? But they did show that there were, specific, UB, I'm sorry, somatic mutations that were associated with different skin findings.

So specifically, the p Met forty one leucine variant had a higher association with what looked like a sweets sweets syndrome kind of dermatitis. That was seen in eighty two percent of people with that leucine variant. If you had a valine variant, a p Met forty one valine variant, that had a higher risk of other manifestations, including more than half of patients with vasculitis like lesions. So again, I think we're learning more about Vexis, we're learning more about treatment. Interestingly, in this report, the use of an IL-one inhibitor was associated with really bad IL-one inhibitor injection site reactions and even evidence of, I think, ulcerative or necrotic lesions.

So but I think that we need more research on Vexis. Again, I think a risk was something like one in four thousand men over the age of 50 may have this variant. I haven't seen it yet, but then again, I haven't been looking for it. Alopecia areata, Alopecia universalis, the major advance in recent years has been the use of JAK inhibitors. Know, the original research started with baricitinib.

Baricitinib was the first to get approved and now a number of the other JAKs are falling in line either with research or soon FDA approval for this. The real question is, as you know, JAK inhibitors do respond, response to them is really pretty brisk, right? For things that we use it for. Is it that way for this hair loss? When I've used it, and I've used some baricitinib, I've probably used more tofacitinib.

Oh, I know he was using them off label before they were approved. Kind of a slow response, but you definitely start to see skin, hair growth within a month and an invisible hair that the patient was proud of within twelve weeks. The question is, if you have to stop a JAK inhibitor and someone who has alopecia areata or universalis, when is it that they start to lose hair again? And this happened with me in, a few women. Can remember one really well where she had to stop, wanted to stop, she fully had regrowed totally no hair, nowhere, no eyebrows, no underarm hair, no pubic hair, nothing.

And, and on to facitinib, she got all her hair back. It was just miraculous. But then she got married, then she wanted to have a baby, and then she got pregnant. And the question is, what do you do? Well, she stopped her, JAK inhibitor, and guess what?

Lost all her hair right quick. Well, there was a research study, that was put reported this week, a sub study of the registration trial called BRAVE-one. And in that study, eighty percent of the people who stopped their baricitinib had loss of hair and that was compared to eight percent, loss of hair or worsening, in those who continued the baricitinib. So clearly a big time loss. So I think it's important that you count and it does, by the way, happen pretty quick, like within weeks, you start to lose the hair.

The other important part of this sub study was that when you reach, if they get treated with a JAK inhibitor and then you stop and then they start to lose all their hair again or they go bald again, How can you regain the response? And yes, the vast, vast majority of people did regain response. And I think that's kind of cool and really good information. While we're on the topic of skin disorders, I don't know about you, but I see have seen a fair number of patients with hidradenitis suppurativa where I'm largely managing the skin disease, although they may or may not have musculoskeletal features that may accompany that. And what I did not know, because I don't think I'm as well trained in HS, is that tobacco use and smoking is a risk factor for developing hidradenitis suppurativa.

In this particular study that I pointed out this week from Korea, fairly large cohort study, looked at six million people in the population, three thousand seven hundred had a hidradenitis suppurativa and they had data on their smoking history and they basically found compared to people who continued to smoke, there was significantly less risk of incident hydradenitis suppurativa in those who quit smoking. So if you were a smoker and you quit, you actually lowered your risk of hidradenitis suppurativa. Turns out that again, same thing, people who didn't smoke had much less risk than people who did smoke, but the bottom line was there is a value in patients quitting. What they did not study, what I would like to know is that if you have hidradenitis suppurativa and we're treating you, if I stop your smoking, will you get better? Will you be easier to treat?

My supposition based on this data is that that is true, but that really was not part of this particular study. Another study on another skin disorder that I like, you know, Still's disease, refractory Still's disease, a meta analysis of JAK inhibitor use. I've talked about this in the past. I'm a big believer in JAK inhibitor use, especially for treatment of cytokine storm or macrophage activation syndrome. In this meta analysis of nine studies and only thirty five patients, they did show, and the JAK inhibitors that were looked at were mostly tofacitinib in seventeen patients, baricitinib in fourteen patients, ruxolitinib in four patients, and upadacitinib in one.

When they combine them, they were able to achieve remission with a JAK. And these are people who largely had refractory disease. So you can imagine what they're refractory to more than steroids, probably even biologics, but half of them were able to achieve complete remission. In the one study that they looked at with ruxolitinib for patients, a hundred percent of them had remission. A third get partial remission with a JAK and one fifth have no response or lose effect.

So again, I think it's important to know that this is an option, but again, they're not going, they probably have different indications other than being just refractory as to why they were getting a JAK inhibitor. Was it just for the fever and the rash? You know, it, I don't think it was for the most of these were not for arthritis, okay? That would make sense, but I think we're talking about systemic disease, febrile disease and complications of stills like, macrophage activation syndrome. Another meta analysis this week of 40 studies, twenty one thousand psoriasis patients looking at PASI 90 responses looked at what predicts a poor response to a biologic.

And in this study of psoriasis patients, not PSA, that being older, being a smoker, having a high BMI, especially a BMI of greater than thirty and prior biologic use predicted that you weren't gonna do as well if you started on a biologic. They were looking at a a real I guess as I said, this is 40 studies, a variety of different biologics, all of which you're familiar with. So that's the patient who you're more likely to have problems in managing and by the way, you know, the amount of lowering of response, you know, it's 60, almost 60% when you had prior biologics, almost forty percent with a high BMI, about twenty percent reduction with steroids. So these are important factors in managing these patients. You may remember ACR23, we talked about a new TYK2 inhibitor called taq two seventy nine.

I think it comes from the drug company Takeda. It's got a name now. It's called zazocitinib. Zazo, I kinda like that name. It's kinda it's got some spark to it.

It's a new TYK2 inhibitor being studied, not yet approved for use in psoriasis or psoriatic arthritis. At ACR twenty twenty three, Alan Kivics Alan Kivics and colleagues talked about its efficacy in PSA and it clearly worked at the two highest doses. So in this study from April Armstrong in patients with just psoriasis, two fifty nine patients with moderate severe plaque psoriasis, they either got placebo, I think it's the doses were ten or five is a low dose and then fifteen and thirty milligrams. The two highest doses had a PASI 75 response rate of sixty eight, sixty seven percent more than two thirds versus a 18% placebo response and again primary endpoint on responses were twelve weeks. So just like other JAK inhibitors or TIC inhibitors, they work relatively quickly.

This is yet another TYK2 inhibitor. There are other TYK2s that are in development. Right now we have only dacravacitinib that is in use for psoriasis and psoriatic arthritis. Looking at the drugs that we use to treat psoriasis and psoriatic arthritis and spondyloarthritis, there is a number and an interesting report this week about hepatitis B reactivation when you're using these drugs IL-seventeen, IL-twelve twenty three, IL-twenty three and JAK inhibitors. So a meta analysis of many different studies showed that patients who have chronic hepatitis B, meaning that they are B surface antigen positive or have detectable double stranded, double stranded, hep B DNA titers show really, high rates of reinfection.

So chronic HBV, the reinfection rates were like fourteen percent. And, but if you had a cold or resolved infection, these are B surface antigen negative, but they are B core antibody positive, that's resolved infection. They had lower rates, four to five percent and that's about the rate, you know, two to four percent seen with other biologics like an RA with TNF inhibitors. So, the bottom line though is the chronic infection shouldn't be getting any of these biologics, and this is again B surface antigen positive patients without being on prophylaxis and without being co managed by a hepatologist. I personally don't believe that a resolved infection with core antibody positivity only needs to be on prophylaxis, especially if they are surface antibody positive, meaning that they basically have immunity.

So that's just my belief, but it's up to you. If you're comfortable with that, do as I do. If not, then get a a a a hepatologist involved or use concomitant, you know, etanovir or any kind of drug that would suppress reactivation. A study of a longitudinal and I think this might be the RISE registry because it comes from Dan Solomon, but it didn't say RISE registry, but it's 32,000 RA patients followed longitudinally, show something really interesting and that is these thirty one thousand plus patients with RA followed for a hundred and forty eight thousand patient years. So it looks like on average, I don't know, five years of follow-up at least shows serially higher disease activity was associated with a progressive decline in the estimated GFR.

What? And that was associated with higher degrees of renal function, and they specifically looked at CKD stage three a, which was a GFR of less than 60 cc's per minute or, a CKD three b of less than 45 per minute, you know, divided by meter squared, whatever. Turns out that patients in high disease activity had twenty seven percent higher risk of stage three a and they had a almost a double or ninety three percent added risk for three b. Now I'm not I wasn't aware that RA activity by itself is a risk factor for CKD. There was an abstract at EULAR that I looked at along with my colleagues.

We debated making it into a big story or a big issue. We didn't think it had enough data. It might well have been this report from Solomon and colleagues. So we weren't sure about this, but there may be a story here and of course the decline in renal function may not be from these activity, it might be that you're using more drugs that may have more nephrotoxic effects or renal effects like nonsteroidals. But I believe in the abstract that you are that we saw it wasn't a nonsteroidal effect.

Anyway, interesting and something you should be looking at. Let's end with a discussion of family history. We're all trained the same way. We're all trained to ask the question about, you know, what's your family history? You know, for everything, what your mother and father die of, are your family siblings have?

We get we lapse into crazy discussions of my aunt on my uncle's side who was married to someone and they had lupus. I don't know what the heck that means. I pay no attention to that. You know, immediate first degree relatives may have some bearing. This is a study done by the CDC credibility, right?

Using an NIH database called All of Us. Yeah, it's called the okay, the AU, All of Us registry, and they ask the question, do you have a family history of arthritis, osteoporosis, or carpal tunnel syndrome? In fact, they actually ask of seven different kinds of arthritis, including fibromyalgia, lupus and RA, etcetera. And what they came up with that in patients who positively indicated they had a family history of arthritis, osteoporosis, carpal tunnel, that the patient, the that was being asked the question had a three point six to seven point six fold higher odds of having the same condition. What?

And that they had a zero point seven lower versus twofold odds of having a different arthritis condition. The strongest association between a family history and having OA was a family history of OA and the prevalence of OA, which had an eightfold higher rate, the same for lupus. A history of lupus was associated with a higher prevalence of lupus and odds ratio of six point three. So this sounds compelling, except I've been saying for years, history, Bah humbug, useless. I strongly believe that family history has utility and predictive value in when there's a history of gout, spondylitis, ankylosing spondylitis, DIP in women, DIP OA in women, and maybe I can be convinced for a marginally important effect for lupus and RA.

But they came up with a lot of stuff. The problem is that it's the CDC using the NIH data set. The NIH data set is actually 450,000 people, of which they selected only a 156,000 people because only thirty eight percent of them had complete family history data. Does that represent a selection bias in a skew? I think it does.

Then we compound this issue by asking those 157,000, do you have these disorders? So it's recall bias on your family history, which is notoriously wrong. Honestly, does your patient Sally somebody who has got a history of some, you know, you know, arthritis condition gonna be right when she says, I think my aunt had, you know, blank. And you know, rheumatoid is thrown around like it's a nickel when it's really should be a manhole cover. You know, everybody's wrong about family history of rheumatoid because it's being diagnosed by people who don't know how to diagnose arthritis in the first place, don't know how to use lab tests.

This study is hampered in my opinion by all kinds of biases and I'm still holding true to my belief that there's a limited value to family history. Now, if you're a young rheumatologist, prove me wrong. Go with what you've been taught by your mentors that ask that question, document that issue, study this, put an ACR abstract out, I'll come by and congratulate you. But I think I wanna know from you, you know, people with gray hair, who are contemplating the tsunami of retirement. What do you think about this, the utility of family history?

I'd be interested in your comments in the notes underneath this on the website. You can go to the website, check out these citations and more. I really like your family. I may not like your family history. We'll talk next week.

Bye.