Chapters Transcript Video Demystifying the MABs: Immunomodulators for the Treatment of Rheumatic Conditions Good morning everyone. Uh I'm really pleased to introduce my colleague and one of my personal mentors uh Doctor Eric Lawson as this morning's ran round speaker. Uh Doctor Lawson is an associate professor of pediatrics and pediatric rheumatologist at the University of California San Francisco. She completed her undergraduate studies at the University of Michigan, followed by medical school at Washi in Saint Louis and then completed her pets residency at Seattle Children's followed by her pediatric rheumatology fellowship here in 2012. She thereafter joined the faculty in 2013. She provides care to Children, teens and young adults with chronic rheumatic disease at both the Mission Bay and Children's Oakland campuses. Uh Among her many hats and accolades. Uh Doctor Lawson is an accomplished clinical researcher with over 40 publications at least as of this morning when I last checked. Uh her main research interest is in improving the long term outcomes and access to care for individuals with childhood onset rheumatic diseases with a focus on health disparities. She's also a dedicated medical educator and currently serves as the program director for the U CS F pediatric Rheumatology Fellowship, and the pediatric clerkship director for the School of Medicine. I am really looking forward to hearing her talk today uh titled Demystifying The Mabs Immunomodulators for the treatment of rheumatic conditions. And I will pass it off to Doctor Lawson. All right, thank you, Doctor Soulsby and thank you all so much for inviting me today. So I have to admit when I was asked to give a talk on immunosuppressing drugs for grand rounds for a very broad audience, I felt a little nervous. Now, I have a talk on this that I give every July to our brand new Rheumatology fellows at Stanford and U CS F. Um And it's incredibly packed and super dry and I'm not giving that talk today. Um So what I've tried to focus on um for us today. Oh, whoops. And here's my disclosure. Um What I've tried to focus on today is really the broad concepts to help um non rheumatologists better understand why we treat with the drugs we treat and how the drugs correlate with the path of physiology of the underlying diseases. Um So, not trying to get you to memorize the name of every TNF inhibitor or the exact thing of NIH Protocol Cytoxan. Um But to really understand some of the concepts behind what we do. So we're gonna start off talking about some definitions and basic concepts with regard to immunomodulation. And then we're gonna go through three cases and use that to demonstrate some of these ideas. Um And then both uh at the end, but also integrated into these. Um, I've tried to include tips for pediatricians who are caring for immunosuppressed Children. Um to make sure that those of you who are um on the general pediatric side, uh taking care of these kids um have a sense of where uh you should be engaged and uh what you can do to help these patients. All right. So, immunomodulator is 101 immune modulation is a change in the immune system that is caused by agents that can either activate or suppress its function. An immunosuppressant is a drug that partially or completely suppresses the immune response in order to treat conditions caused by immune over activation or disregulation. And an immunos stimulant is a drug that increases the immune system ability to fight off infections or other diseases. So, these are given, for example, in the treatment of some cancers. So, the next really important definition for us are disease, modifying antirheumatic drugs or dmards. And these are defined um in the context of rheumatoid arthritis as drugs that alter the course of disease. And what does that mean? So it means that function of the joint improves by decreasing the amount of inflammatory synovitis, the amount of inflammation inside the joint. And also importantly that you're able to prevent or significantly decrease the progression of structural joint damage. These are slow acting drugs for the most part, there are some exceptions, but mostly they take effect over weeks to months. Um And these are used really across the board in almost all of our rheumatic conditions, not just rheumatoid arthritis, um but also all of our P DS traumatic diseases and just to put it into context, I included this picture here of late rheumatoid arthritis deformities. So this, I am so pleased to say in our current era, you know, we'll talk more about this, we don't see this very much. Um But in the absence of a dard this, these are the kind of joint deformities that you can end up with uh with long term chronic arthritis. OK. So there are also lots of non DMAR drugs that we leverage and these are important because they work for the most part faster than our dear, they provide faster symptom relief, but they do not prevent joint damage. Um And some of the important categories for us here are nonsteroidal anti-inflammatory drugs. Um The three that I use most often are ibuprofen, naproxen and Meloxicam and we'll get into some more detail on those later. Um Also corticosteroids, of course, the favorite and least favorite drug of all rheumatologists. Um and for analgesics, um acetaminophen is helpful as well. It's worth mentioning that for patients who have chronic inflammatory conditions with chronic not acute pain, opiates should really be avoided in the long term. They can actually worsen chronic pain. And of course, um dependence is a real risk when you're dealing with the kind of pain that's not gonna be gone in a day or two. Um, so within the DMARD category, there are a few different buckets to distinguish between we have. First of all our con conventional dmards and these are also known as synthetic or traditional dmards. The thing to remember about these is they're for the most part, small molecules, they can often be taken orally and they are less targeted than our biologic dmards. What this means is that they often have more side effects. So these are medications for the most part that we figured out empirically how to use them in um rheumatic diseases. Um And examples can include methotrexate, hydroxychloroquine leflunomide and ari in contrast to this, we have our biologic dmards. So while somebody just happened to figure out that, you know, these other drugs were useful in rheumatic diseases, biologic dmards are different and that these are drugs that were actually designed based on our advancing understanding of immune pathways to interrupt those very specific pathways. Um So instead of figuring out that a drug helps the condition, you actually understand the condition and then design the drug to have the effect that you want. Um And these are drugs that have totally revolutionized our field in amazing ways over the past 20 years. Um These are large molecules and therefore they have to be given by injection or infusion. If you eat them, you'll digest them and then they won't work the way they're supposed to. Um And because of this really targeted pathway specificity, they don't have the kind of side effects for the most part that some of these other drugs have. Um, the side effect profile is often better. Um There is a risk that your body's immune system will actually develop an immune reaction to these large molecules. They'll recognize them as foreign, this is known as immunogenicity. Um And we're gonna talk a little bit about some of these naming conventions because I know the names of these drugs are impossible. Um But two big categories to think about are your receptor blockers. And that's the suffix step. So an example of that is the Tanner the or you may know it umbrella which is a TNF inhibitor and monoclonal antibodies which are actually full IgG antibodies have the suffix mab for example, Glia um A K A symphony and that's another um uh TNF inhibitor. So let's talk a little more about how about the names of monoclonal antibodies. So over here, um on the left, you have the 100% urine antibodies. These are made from mouse antibodies and they have the suffix OAB and we don't use any of these drugs. They have a high potential for immunogenicity and they don't, don't work as well in humans. Um But we do have a bunch of chimeric antibodies that are part mouse and part human that we use. Um with the suffix IAB and a couple of examples of that are riTUXimab, which is an anti um CD 19 anti B cell agent. And um Infliximab which is a TNF inhibitor. We also have humanized antibodies that are greater than 90% human. Um They have the Sui Zuma and the examples of those are obita, which is another anti B cell agent and Tosya, which is an anti IL six. And finally, we have our fully humanized antibodies. And examples of that include Adalimumab, which is a TNF inhibitor and Canakinumab, an IO one inhibitor. So now hopefully, when you see these really confusing names, you can understand a little bit more what they mean. All right. And then the last category I'm gonna mention are targeted synthetic dmards. And these are the newest category. Um these uh the category of these that we use uh currently are the Janus Kines inhibitors or Jack inhibitors. Um These work by preventing cytokine mediated gene expression in immune cells. So you can see uh jack inhibitors work here to block this Jack sta pathway, which is important in inflammation. It is a small molecule and can be taken orally but is targeted the way biologics are. So it's um been a real breakthrough to have an option for a drug uh that is targeted like a biologic but doesn't need to be given by an injection or infusion. So, Toid was first approved for rheumatoid arthritis in 2012 and for JI A in 2020 other drugs that are out there include Bei Roxy Aid and CII. All right. So now we're gonna move on to some cases. This is a four year old little boy who shows up in rheumatology clinic with a cheap complaint of limp, been going on for about four months, kind of gradually getting worse, worse in the morning. And at the end of the day, parents notice he's having a little bit of a hard time picking up his toys. He's not wanting to run the way he used to, but he's not complaining about pain, he's sleeping well and he's eating well. Um So you examine the patient and you find quite a bit of arthritis. He has swelling in both his wrists, both his elbows, his ankles and his knees. Labs are significant for elevated white count, a mild normocytic anemia and elevated platelets. His inflammatory markers are high crate and crp his rheumatoid factor and A N A are both negative. Um And you get quantum urine testing knowing that you may be starting immuno suppression in him and you wanna check his tuberculosis status and that's negative too. You also get a baseline x-ray of the affected joints um to assess for any kind of bony damage and you see some effusions are noted but no bony abnormalities. So no joint damage right now. So this is juvenile idiopathic arthritis or ji A defined as arthritis of one or more joints. Ji A in order to be juvenile, you have to have onset of symptoms before the age of 16 and it has to last for at least six weeks. So this is a chronic arthritis. Always important to remember that JI A is a diagnosis of exclusion. So you wanna think about infection, malignancy, trauma, other rheumatic diseases like lupus, um or reactive arthritis as possible causes. And just to remind you, this is what a nice normal joint looks like here with a smooth cartilage and um normal amount of synovial fluid. This is an arthritic joint here. So you can see that cartilage starts to get kind of raggedy. You can get narrowing in this joint space and then you have this inflamed synovium here. So big hyper feed synovium and extra fluid. Um Another finding that we can see sometimes on x-ray as well is this bone density loss? So you see something called periarticular osteopenia. And that's actually um a common early finding in uh on x-rays in our ji A patient. All right. So to quickly review our major ji a subtypes, we have oligoarticular ji A which is four joints or less most common in toddlers. We have polyarticular ji A which is five or more joints can affect all ages and we differentiate between patients who are rheumatoid factor positive or negative. We have enthesitis related arthritis which is characterized by axial arthritis. So, hips thor iliac joints um and then tendon insertion inflammation which is emphasis. These patients often have a positive HLAB 27 and this is a condition that is more common in male school age and older psoriatic ji A um can be defined by just psoriasis and arthritis. But even in Children who don't have psoriasis, if there's findings like dactylitis, male pitting and a family history of psoriasis, they may meet criteria for this subtype. And finally, the one that is quite different from the others is systemic GI A and this is a condition characterized by really intense systemic inflammation, fever, and evanescent rash. So, thinking about our patient that has uh more than 45 joints involved but not features of er a psoriatic or systemic. We would call this polyarticular ji A. So how do we treat new onset polyarticular ji A there. So, one important concept that I want you to take away is that all patients with poly ji A do need to be treated with AD R to prevent that progression of disease and joint damage options include a conventional dmard and methotrexate. Um is the one we use most commonly. It can be given orally or subcutaneously biologic dmards. And we have unfortunately no data head to head on which one is best. So we have several options from which to choose. There are TNF inhibitors, IL six inhibitor, Tocilizumab and an anti CTL A four inhibitor, uh anti CTL A four drug Abita that, that prevents T cell co uh stimulation and all of these um have been shown to be effective in JI A. And finally, there's combination therapy with methotrexate plus a biologic dear adjunct therapies are also helpful. So we have options um for additional therapies to resolve symptoms more quickly when we need to. And these can include nsaids, intraarticular corticosteroid injection or a time limited course of prenazone. So let's talk more about methotrexate. This is a true workhorse drug for us. In rheumatology, you can see there's a long list of conditions um for which we use this medication to treat. Um and can include um dermatomyositis or other forms of myositis. For example, in lupus uveitis, scleroderma, both localized and um sometimes systemic chronic recurrent multifocal osteomyelitis or crmo um vasculitis again, localized and systemic and disease. Um So a um aminopterin is a drug that was first used in 1948 to treat childhood leukemia. Um And this is a cousin of methotrexate. It was studied in rheumatoid arthritis and psoriasis in 1951 and found to be effective. Then um they went on to develop methtrexate uh which was easier to manufacture. Um And so it's worth noting methotrexate. Um Most of you probably know is used in the oncology realm as well, but in much higher doses than we use it in rheumatology. Um And that um at those high doses, it works via an antifolate pathway. So you're preventing cell turnover by blocking folate in um our inflammatory diseases. We actually are not trying to leverage that antifolate pathway. We're trying to use a different effect of this drug, which is inhibiting an enzyme called adenine pinna. So, adeno has an anti inflammatory effect by inhibiting this enzyme that breaks down adenine, you increase adenine levels. Um and it can take up to six months for methotrexate to take full effect, so very slow. Um In terms of how we give this drug subq is preferred over po because the efficacy is better and there are fewer side effects and methotrexate can have significant side effects. Now, it's worth noting everyone is so different. I have patients who have been on this drug for years and years and they've never had any side effects whatsoever and have done absolutely great with it. I have other patients who took their first dose and vomited for three days straight. Um So it's important to recognize that this may be a good drug for some people and not for others. I usually tell my patients don't panic if you have a terrible side of, you know, terrible side effects. The first time you take this, we will never give you another dose because we have other options. Um But the biggest side effects that patients complain at home include nausea, fatigue and headache. Other things that we look out for are transaminitis. Methotrexate is a very potent Tagen. And so, uh counseling around contraception is really important and we'll talk more about that later, um to prevent those antifolate effects that we don't want, we actually supplement with folic acid 1 mg daily. Um Some of those antifolate side effects can include hair thinning, um oral ulcers and cytopenias. Um And finally, there are rare reports of interstitial lung disease and possibly increased risks of uh rate of malignancy. It's not entirely clear. Um How well that translates to Children versus adults, uh where there's stronger evidence for that increased malignancy risk. So, how do we decide? Well, first of all, it's important to assess for JIE features associated with poor prognosis because this will lead us to more aggressive initial therapy recommendations. And some of those features can include cervical spine or hip arthritis, RF or CCP positivity and radiographic evidence of joint damage. Share decision making is really important here. So, something that, you know, a place we really have to live in in rheumatology is that we don't have randomized controlled trials to tell us what's the right thing to do all the time. We use a lot of um discussion among our community. We use a lot of observational data and um and then we bring that to our patients and we say here's the pros and cons of this, here's the pros and cons of this. What do you think is gonna work best for your family? So someone might be completely terrified of injections, like absolutely not off the table. Um Someone else, you know, might maybe have a relative who had really severe rheumatoid arthritis and they want to treat aggressively so that their child never has the kind of joint damage that that relative had. Um And so it's I really try to come to every family um to understand their values and help use that to inform our decisions. Um And it's important also to frame this for the family in terms of goals of care. So you may remember that this patient we've presented is having some functional difficulties but not really complaining about a lot of pain. And that can be a challenge for us sometimes that, you know, patients may have arthritis, but they're not always wildly symptomatic, sometimes they are and sometimes they're not. Um And so again, framing this in terms of goal of care. So you wanna make sure that their function is good. So they can continue to develop. Normally, you want to prevent that long term joint damage and then prevent growth, delay due to chronic inflammation. So, for kids who have severe enough disease that their um systemic inflammatory markers are high that can start to impact growth. All right. So what do we need to do before we start immunosuppression? Um There's tuberculosis testing PPD or quantum that needs to be done. You do want to check AC MP um especially if the child has never had a reason to have one before uh to make sure their renal and hepatic function is normal before you put them on medications. Um And you wanna assess vaccination status. So let's talk a little more about vaccinating um immunosuppressed Children. The Red book is an awesome resource for this and everything I'm gonna talk about comes straight out of there. Um So live vaccines you probably know are contraindicated while you're immunosuppressed and among the routine um vaccines that are recommended today. Uh The ones that are live that we think about are MMRB CV, rotavirus and then a nasal influenza. The injected influenza is killed and that is not a live vaccine. Um Other live vaccines out there that may be relevant if a child is traveling or um coming from another country could include oral typhoid yellow fever, BC G, cholera, oral polio or smallpox vaccines. So live vaccines should be given at least four weeks before starting immunosuppression or if that is not possible, they should be deferred killed. Vaccines can be given on schedule. It's preferable if you can to give them a couple of weeks before um you start immuno just because the response may be better, but it's safe to give them. Um pneumococcal vaccine is also important especially for our lupus patients who can be particularly due to their hypo uh hypocomplementemia, particularly susceptible to pneumococcal sepsis. Um And so they should get some additional vaccination there. All right. So, coming back to our patient, we're gonna start treatment. So we assess there are no features to suggest poor prognosis. At this time. Together with the family, you decide to start subcutaneous methotrexate once a week with folic acid supplementation. And because he is actually due for his for immune for your immunizations and he's not in significant pain, you make the decision with the family to delay the start of therapy by four weeks. So you can administer those live vaccines and have him on track. Um And then you plan to follow up three months after the start of the drug to assess response. All right. So four months later, he got his vaccines after a month, started his methotrexate, you see him back, he's tolerating the injections. Well, he's not having side effects. He was seen by ophthalmology to screen for UBI Iis and they did not find any which is great. Um However, with regard to his joints, he's not really doing better. He's now starting to complain of neck pain in the morning. And um on exam, you know that he still has swollen joints, but now has a new limited neck rotation that he did not have before. In terms of his labs, things are also not really better. So C MP is normal which tells us he's tolerating methotrexate. He doesn't have any transaminitis, however, he still has anemia thrombocytosis, his side rate and CRP are up. So, what do we do now? So we already tried a conventional D and didn't get the results that we wanted. So where should we go from here. Um And the option that you land on with the family is combination therapy with methotrexate and a biologic dmard because he's tolerating the methotrexate. Well, and he's progressed on methotrexate. So that makes us feel like this arthritis actually is gonna be difficult to treat is what he's showing us. And so we want to be aggressive. Um So we discuss this with the parents. They're in agreement and we decide that we're gonna start at a Lima, which is a TNF inhibitor in addition to me. So let's talk more about TNF inhibitors. This is the most commonly used biologic class for nonsystemic ji A. Um And the drugs include a Tanner, Adalimumab and Flix and Golimumab. Um TNF is a really important mediator of inflammation including especially leucocyte migration. So, bringing all those inflammatory cells to your joints. Um and the indications that we use it for include G I AC RMOUV, IIS and inflammatory bowel disease um side effects. So this is these drugs for the most part are really well tolerated. Um We do certainly think about infections and TB reactivation as a particular concern. So that's why we checked our chronopin before we started any immunosuppression. Um you can get certainly allergic reactions and rarely cytopenias. So these are our most commonly used TNF inhibitors. This is a Tanner Sa or Embry over here and you can see this has a human portion of the FC um section of a human IgG, but then you have an extracellular portion of the TNF receptor. So it's not a full antibody unlike these two. So, Infliximab is a chimeric monoclonal antibody. You'll remember that X I uh that, that speaks to chimeric. Um it's given via IV infusions and this drug can be useful because it's the one TNF inhibitor where you can really push the dose a lot for patients to our refractory. But we tend, it tends to not be our first line in part because it needs to be given IV versus um a medication you can give SUBQ at home. And then finally, we have our two humanized TNF inhibitors and these are Adalimumab um A K A Humira and Golimumab A K A Symphony. Um And both of these are given as home injections. Um Glia is given a little less frequently, but we actually do tend to use Adalimumab more because we have more experience with it. It's been around longer. All right. So you let the parents know that Adalimumab will take up to three months for full effect. Um But the parents are worried now they're their little guys starting to have pain, they don't want it to keep getting worse. So they're asking you, is there anything we can do to help him faster? All right. And so we then think about our adjunctive therapies which could include appropriate options for him and AIDS or a short course of prenazone. You're not able to do interarticular corticosteroids into the neck. And so that wouldn't be a great option for him at that time at this time because his neck is what's really bothering him. So let's talk some more about different nsaids. You may remember that nsaids inhibit cox enzymes to provide immediate analgesic effect. Um However, if they're given at a steady state, so um to maintain a steady state in the blood over a period of about four weeks, they will also achieve an anti-inflammatory effect. These drugs are not disease modifying, but they can have a positive impact on the amount of inflammation present. Um precautions need to be taken in patients with renal disease or any kind of bleeding risk. Um And the side effects people complain about most commonly are. Um I would say stomach uh issues are the biggest, the biggest complaint that I see and I always recommend that patients take them with food. Um if they are taken at higher doses and they should be renal toxicity and hepatotoxic can definitely be a problem less of a concern if they're taking them at the correct dose. Um I have seen cases of aseptic meningitis. Um and then finally, Pseudo poya which um some folks may not be familiar with. So this is a photosensitive rash on the face tends to happen particularly in light skinned Children and it looks like these little cat scratches here. And the reason we care about this is because it's scarring. So if you have a patient on and said, who's developing this rash, you need to stop them. All right. So further, you may remember that there are two types of cox um enzymes that are important in the body. So you have your cox one enzymes that create prostaglandins that are important for housekeeping functions, things like gastric acid, uh or gastric acid and you get secretion and then you have your cox two enzymes. And these are the ones that are really important in inflammation. So these create um prostaglandins that participate in inflammation. So most of our nsaids inhibit both of these cox enzymes. So you get the anti-inflammatory effect, but you also get this negative effect on these housekeeping enzymes that can lead to side effects. Cello Cox is a NSA that is a selective coc two inhibitor. So it only inhibits the cox enzyme that's important in inflammation. Um And the reason that's helpful is it can cause it can have less G I side effects. So to talk a little bit about the drugs that we use most commonly here. So Ibuprofen, um the bad thing about Ibuprofen is to have a steady state, you have to dose it three times per day and people for the most part are terrible at taking medications that often it's just really hard to do. But the upside of Ibuprofen is it is available in a delicious over the counter liquid. That's super easy to get uh Naproxin is only dosed two times a day. So that's better. Um In pills, it's easily available. But the liquid formulation can be a little harder to obtain, not impossible, but often needs to come from a compounding pharmacy and frequently needs insurance authorization. So that's a little more of a pain meloxicam is a really nice option for once daily dosing. Um but only comes in tablet form. And so basically it's dosed for bigger people. But it's a good option in older kids. And then for patients who have abdominal pain with these other nsaids, cello Coca can be um a nice option too. Um again, often needs insurance approval. But if the patient has a history of intolerance to these other um nsaids, I don't usually have too much trouble getting it. Ok. And next to talk about corticosteroids, again, our favorite and least favorite drug is rheumatologist and we use it in lots of different forms, topical steroids for cutaneous inflammation, um intraarticular oral steroids for arthritis. And then for really serious systemic organ muscle vascular inflammation, we use both oral and ID forms. There are multiple mechanisms of action for corticosteroids. Um they work by binding, you may remember to the Glucocorticoid receptor in the CY is which then translocated to the nucleus and changes gene expression and also binds directly to MRN A and proteins. So the thing to take away from that is that steroids have a super broad effect. These are like extremely non targeted drugs. They are super potent anti inflammatories but have lots, um lots of side effects particularly if they're taking them for a long time. So short term steroids and side effects can be minimal to none but long term steroids and moderate or high doses have very significant steroids or very significant side effects. Um I'm sure you all have seen this Cushing Syndrome picture before but to remind you, um some of the cutaneous and musculoskeletal um uh changes that you can get with chronic steroid use in terms of the most important things that we see um in our patients, they can include growth delay. Um hydro steroids are profoundly immunosuppressive. These are probably the most immunosuppressive drugs that we actually give. Um And so these are the patients that are actually among those at highest risk for infections. Um adrenal insufficiency over time um can become an issue and then you really can't overstate the importance of the cosmetic changes for our young people. They develop acne, they gain weight, their face gets huge and it can be totally devastating for them. So that's just a really important thing for us to keep in mind. You know, I try to ask myself every time I'm prescribing a hy Doster, I do, I need to do this and for how long? And I ask myself that question on a very regular basis and really try to taper as quickly as possible to avoid some of these long term complications. Um and it's been really nice to see over, you know, the course of my career in the last 10, 12 years as our other drugs are getting better, we don't have to use as much steroids as we used to. Um, and the field in general is moving towards um, fewer and fewer steroids. So we're getting fewer patients who, um, are really having to suffer with these difficult side effects. All right. So chronic steroids are never recommended for polyarticular ji A because we have too many other drugs that work better. But short courses of steroid can be very helpful while that longer term ami suppression is taking effect. And we typically use prenazone for liquid or prenazone for tablets. And so coming back to our patient with poly ji A, we talk um with the parents about the pros and cons of nsaids versus doing a steroid taper. They're a little worried about effects on growth. And so they decide um given that his symptoms aren't that bad that we're gonna go ahead and just start liquid. And approximately 10 mg per kilogram twice a day. All right. So moving on to our next case, this is a seven year old boy who presents with three weeks of daily spiking fevers up to 104, mostly in the evening and sometimes early in the morning. Um they, he has a rash that is characterized by flat erotic spots on his trunk and arms that come and go, especially with fever. He has chest pain with deep inspiration. He's not complaining about any joint pain and past medical history and family history are totally unremarkable. So on exam, he has a febrile, he has normal vital signs, but he just doesn't look great. He's tired. Um, he has differ, diffused, cervical axillary and ay heart sounds are normal and lungs are clear. He has some hepatosplenomegaly. And you notice when you're doing your joint exam that when you flex his right wrist, he kind of pulls back a little bit. He has a faint pink macular rash um on his trunk that looks kind of like these pictures here. So you go on to get some labs um and he has a leucocytosis. He has a normal cytic anemia. Um His rate is a little elevated or sorry, a lot elevated as his, his er P his um A ft and LT are up just a little bit and his L DH normal uric acid, normal BN and creatine eggs are normal. His fin is quite elevated at 5670 fibrinogen is a little bit high. The dimer is normal um as are triglycerides and you've done some infectious studies too. So, blood cultures are negative EBVC allies are negative and you check his chest x-ray and he has of note a small right sided plural effusion. So this is systemic ji A, it's defined as arthritis in one or more joints with a daily. Um what's called quotidian fever for at least two weeks. So, these fevers, typically, the patient will often be a fibri all day long and then usually in the evening, occasionally, early in the morning, they will have a very high spike up to like 104. Um And then they need to have one or more of the following which is a um evanescence erythematous rash. Um I showed you guys a picture of the rash already. The rash will often come and go with the fever. And what's really remarkable about it is it can be super diffuse bright pink and then you come back two hours later, the patient is deer vs and the rash is completely gone. So when you see this, it's an incredibly helpful finding. It's really very specific for systemic ji A, um, generalized lymph node enlargement HEPA mali or, and SEIS, um, are other findings that are, um, important but a little less specific for systemic ji A. Ok. So I'm gonna take us into a little conversation here about innate versus adaptive immunity to try to understand a little bit about the path of physiology of systemic j and how that translates into the way that we treat it. Um So you guys probably remember the innate immune system is your rapid response system. So this is your dendritic cells, macrophages, neutrophils, um, natural killer cells, um, as opposed to your adaptive immune system. So this is your B cells and T cells that are trained to distinguish between self and nonself and produce antibodies. Um And these two parts of the immune system work together uh along sort of a continuum. Um So, auto inflammatory conditions are those that are involving the innate immune system with over activation of macrophages, et cetera. And examples of those conditions are systemic ji a familial mediterranean fever and bichette's disease. Autoimmune conditions involve the adaptive immune system. And these are really focused on that loss of tolerance to self antigens. And the quintessential autoimmune disease is lupus. Um but other examples include type one diabetes and celiac disease. Um This is a diagram I found that I like that sort of displays how this is really a continuum here um as opposed to a totally binary system. But over here, on the left side, on the auto inflammatory side, we have mono genetic um systemic auto inflammatory diseases like familial mediterranean fever. And then on the far right, we have um purely autoimmune uh conditions like systemic lupus and anti foid antibody syndrome. And then we have some that fall in the middle. So il one is really important in recruiting those inflammatory cells that are a part of the innate immune system. Anti lil one drugs include anti and canb and these are used to treat systemic JI A. On the other hand, we know the B cells for are super important rate for autoimmune processes. They um produce antibodies that identify and attack self antigens. You have that loss of self tolerance. And therefore we have anti B cell drugs to treat conditions where this is the pathologic process, including riTUXimab and open Azuma. And inca associated vasculitis is an example of a condition that is treated with these drugs. All right. So, coming back to our patient, um while you're waiting for test results, the patient develops a high fever that actually persists all through the day. Um He becomes confused and then has a generalized tonoclonic seizure um and is noted to have a new rash on his legs that looks quite different from the rash he had before. And this is a fixed rash. So the team orders stat labs and the patients um findings have changed quite a bit. So now there's um the white count is dropping, the hemoglobin is dropping and the platelets are also dropping. So there's um thrombocytopenia. Now, the fin has gone up further now, greater than 14,000 and the D dier is very elevated as well. LFTs are going up. Um triglycerides are going up, the set rate is now normal. Interestingly. So has fallen, but the CRP is over 100. Um there's coagulopathy and fibrinogen is low at 2 45. So this is macrophage activation syndrome, which is a very serious complication of systemic ji A it's caused by an overwhelming inflammatory reaction due to immune dysfunction So basically, you get this positive feedback loop between activated T cells that are secreting cytokines to activate macrophages that are secreting cytokines to activate T cells. So it goes in a circle and you get this massive oversecretion of pro inflammatory cytokines. Common findings can include non remitting fever, cns, dysfunction, and hemorrhagic manifestation. Um and you tend to see pancytopenia, which is a really helpful finding to distinguish from active systemic gi a where you may have anemia, but you don't expect um thrombocytopenia or Leuke Penia and a very, very high Perin. Another helpful finding is when your set rate drops. So you can have a normal set rate with a very high CRP is suggested of, of ma s fibrinogen often drops. And then if you do a biopsy, um these patients will often end up with bone marrow biopsies if there's concern for malignancy, um you will see hemogo cytosis and what is that? So, hemogo cytosis is when activated macrophages are eating um hematic cells and eating um um other cells in the blood. So, these are examples here of activated macrophages in a bone marrow aspirate. Um And you can see, so here's a big macrophage right here with a couple of neutrophils hanging out inside of it and a basophil. So um you can see these macrophages are just going around, they're over activated and eating all these cells around them. Um So this is a really nice diagram by my um a colleague of ours, Alexi Gram um that I think does a nice job of explaining how um MA S works in systemic ji A. So patients often have a genetic predisposition. Um And when genetic testing is done, they will sometimes have some of the genetic abnormalities seen in um HLH, which is a um another version of, of the same side of kind of storm process. Um And then there's a background of inflammatory activity with high levels of inflammatory cytokines and a um transient defect uh in the site of like pathway here. Um that then leads to this increased T cell activation. Um And this process of um this kind of positive feedback loop between macrophages and T cells that I talked about before infection. Whoops, sorry, infection can also trigger the same process. Um again, activating macrophages, activating T cells and leading to this positive feedback loop with cytokine storm. Um And if you want to learn more about system at JAA I or sorry about macro activation syndrome. Um I'd like to refer you to a grand rounds given in January by my colleague, Doctor SOLs. Um for a lot more about this. All right. So let's get into the treatment of systemic JI A. So as we've talked about, this is really an autoinflammatory path of physiology. It's different. And therefore we use different medications. These patients do not respond to TNF inhibitors, but they have often an excellent response to anti I one and anti I six drugs, methotrexate can be a useful adjunct for arthritis, but it does not treat the systemic inflammation. Um So it's worth mentioning that systemic JI A has changed wildly just in the time that I have been taking care of these patients. So I had a patient when I was a fellow who looked a lot like this um growth failure in the pre biologic area era was really common. These patients were caught in this total catch 22 between fevers and chronic inflammation and steroid dependence. So we could go up on their steroids to control their symptoms. But then they ended up with all these long time or steroid complications um with osteopro osteoporosis and pathologic fracture fractures. And I'm pleased to say that we virtually never see this anymore in the biologic era. All right. So let's talk a little bit more about the treatment. So we have our patient here with systemic JI A and it um this is an algorithm from the uh American College of Rheumatology Treatment guidelines for systemic JI A. And we ask ourselves is there ma s present no or yes. And for our patient, it is yes. So options for treatment include a aisle one or aisle six inhibitor, no preferred agent. Again, very little head to head data for us in rheumatology um and or systemic steroids. So, coming back to our patient, he's now in the IC U, you start pulse. So UOL um given for three doses um every 24 hours and you also start Anara um given IV every 24 hours mental status normalizes and the labs improve with treatment. Uh you transition once he finishes those three sol pulses to prinos, one mg per cake per dose. Um Given orally twice a day fevers stop. There's a little bit of ongoing mild rash kind of on and off his uh systemic ji A rash, the uh pete rash goes away. Um and he gets discharged home on Anakinra and a prenazone paper. So let's talk a little more about our Aisle one inhibitors. As I mentioned, aisle one is an early mediator of the immune cascade and that's why it's used in our auto inflammatory conditions. Um and systemic J A and MA S side effects can include cytopenias um and especially for Anna kra local injection reactions. So great things about anti camera are that it has rapid onset, which is different right from most of our other biologics. Um and it's available IV for inpatient use. So this is a good drug for sick kids. It can also be given as a daily subcutaneous injection at home, which is much less preferable. So it is painful, it burns and you have to give it every single day. Canakinumab is another option that it um has been out there for the past several years. And this one is actually FDA approved for systemic GI A which Anna camera is not um which makes the whi which what that means for us is that it's easier to get insurance to pay for it. Um And it's been approved for both systemic J and genetic auto inflammatory syndromes. It's given um as a subcutaneous injection every four weeks, so much better than a daily injection and less painful to boot. Um So coming back to our patient, he gets tapered off prenazone over six weeks, transitions from anti to canakinumab rash goes away. There's no more fever. Um But they do know that he's still having some right wrist pain and stiffness in the morning. Mom thinks he's limping sometimes when he gets out of bed and when you examine him, you see that he has some right, greater than left wrist swelling with pain on inflection as well as some right angle swelling. He has a, a mildly elevated Barret and platelets um as well as ESR and CRP, but no labs concerning for MA S at this point. So what do we do now? So what we have here is residual arthritis and therefore we can add a conventional synthetic beard like methotrexate or switch to a different biologic beard. So you discuss the options with the parents, which could be adding methotrexate. We could try some low dose po if they don't want additional injections or could do sub Q for better efficacy and fewer side effects or we could switch Canakinumab to another medication um an ale six inhibitor, Touma. The parents prefer to keep him on only one medicine. So you decide that you're going to switch to Touma. And three months later he comes back. Unfortunately, arthritis is resolved and the labs have normalized. So your patient is doing well on therapy. Tocilizumab um is another really great workhorse drug for us. So this is the only drug that is actually quite effective both in polyarticular ji A and in systemic JI A which speaks to the um sort of between innate and adaptive immune system roles of uh of il six. It's an IgG antibody that blocks um the soluble il six receptors. Um So they are not able to stimulate this jack pathway here. Um They can be given either IV or SUB Q. Um And you do need to keep a lab, an eye on labs with this one. So, in addition to infections, um they can develop a t abnormalities and cyto. All right. So, moving on to our last case, this is a 16 year old young lady with one month of fatigue, fevers, achiness and diffuse hair thinning. She um went to the beach last weekend and came back with this erythematic butterfly rash. Her analysis is significant for blood and protein. She has a high, tighter positive A na A positive antidouble strand of DNA and a positive anticardiolipin IgG. Her set rate is over 100 but her CRP is normal. She has a low C three and C four. Um And an exam is noted to have this hard palette ulcer here. And this is an example of the Mila rash. You can see the skin looks kind of a little thick in here and red. Um So these are the slick classification criteria for systemic lupus erythematosus, don't memorize these, but I point them out because you can look them up if you're thinking about lupus. Um And it is super helpful always to go through these criteria and just figure out how many boxes your patient checks. And that can help you to understand whether you need to be worried about lupus or not. Um Because I know lupus can be a difficult di uh a difficult diagnosis, especially for folks who don't think about it every day. So the class of patient criteria you need to have um at least four criteria and it needs to include at least one from the clinical bucket or um and one from the immunologic bucket or you can also classify with Lupus nephritis on biopsy plus a positive A N A or double strand of DNA antibodies. And I put in red here, all the things that our patient has. So she certainly meets criteria and then some, all right. So the patient um is treated initially with pulse celled because she has significant organ disease with nephritis. And so that's an indication for treating aggressively with hysteroid. Um And then she has a renal biopsy done which demonstrates class four Lubis nephritis with minimal chronicity. So what that means is that she has very active Lubis nephritis but not a lot of scarring. So a lot of kidney there to save um just very briefly to touch on lepus nephritis classification. So the um types of lupus nephritis that are most serious and most likely to lead to renal failure are proliferative le Vitis. So, with active and sclerotic lesions and that is either class three or class four. And the difference between those two really just depends on the percent of glo marli that are involved. So, our patient has greater than 50% of glome involved with these proliferative lesions. And therefore, she is in class four, which is the the subtype we worry about the most. All right. So what's our initial therapy for proliferative le lupus nephritis? Either class three or four options can include cyclophosphamide or mycophenolate for your primary immuno suppression. You will always give steroids um to try to cool off the inflammation as much as possible. And um get the the kidney inflammation to settle down and hydroxychloroquine um is given to virtually all lupus patients unless there's a real contraindication. Um So, cystine to talk a little bit more about this. This is the drug that we use in our sickest rheumatology patient. Um It is used in class four. Lupus nephritis, um CNF lupus severe vasculitis and uh helpful also for lung disease and systemic sclerosis. Um There are two main dosing regimens that we use. Uh There's the NIH regimen which is a higher dose regimen given monthly for six doses. And then the Euro Lupus regimen, which has been very extensively studied in adults. Um is a lower dose regimen given every two weeks for six doses. So in the adult world, it's definitely been shown that the Euro Lupus regimen has fewer side effects um and equal efficacy to the higher dose regimen. But we have not fully answered that question in Children. Um And the mechanism is that it binds to guanine and destroys the purine ring and DNA preventing cell replication. So the side effects um that you would expect then with that prevention of cell replication, you get cytopenias, alopecia, um you also get nausea, um a very tagen drug as well. And then one thing that patients really worry about a lot is the possibility of infertility because it um there's concern that it can affect ovarian reserve. Um However, there's, as I mentioned, been really nice work done on the Euro Lupus Cytoxan regimen in adults. Um And this is a long term study demonstrating that a one course of low dose Uup regimen Cytoxan does not impact ovarian reserves. So that's some reassuring data we can share with our patients. Um The other main option here is mycophenolate and that is given in one of two forms. The one we use most commonly is mycophenolate LAK A. Uh The other option is mycophenolic acid A K A. MYC MMF is what we usually use first, it's cheaper. Um But for kids who get G I toxicity with MMF um mycophenolic acid is often better tolerated. This drug is used in lupus. Um many different manifestations as well as myositis, vasculitis and PMA. There are multiple mechanisms of action but again, um preventing guanine sy synthesis to inhibit TNB cell proliferation um and side effects. So this drug does pretty significantly increase infection risk. Um G I toxicity is a big one and then cytopenias and there is long term risk of malignancy demonstrated in adults. And finally, hydroxychloroquine. I think of this as my lupus vitamin I give it to virtually everyone and the side effect profile is excellent. Um It's an antimalarial and there is very good data demonstrating that if you take your hydroxychloroquine on a daily basis, you will have fewer flares of your lupus. So um it's nice in that it's an easy drug to give and we actually have good data to show that it's helpful. Um The biggest side effect that we worry about is retinal toxicity. So these patients need an annual eye exam. Um Skin and CNS manifestations are also or uh side effects are also things that we see as well sometimes. So you talk about treatment options with your patients and she notes that she actually has an aunt who died at a very young age from renal failure due to lupus. So she really wants to treat aggressively. She's very worried about this. Um But she's also worried about pre preserving her fertility. So you talk together and decide on a Euro Lupus cyclo Fosalite uh regimen plus hydroxychloroquine and a steroid taper. So let's talk a little bit about contraception in Lubis. Um The patient is sexually active and she is currently on estrogen containing oral contraceptives. Um So if we look, this is a, a really nice diagram um available for patients based on the AC R American College of Rheumatology Reproductive Health Guidelines from 2020. Um This is directed at adults. So I've crossed out this top option here for uh tubal, which we obviously would not do in our young patients. Um But the important takeaways here are that implants like Nexplanon and Iu Ds um like Mirena are always safe, effective options for these patients. So, these are good contraceptive options for your patients with Lupi for depot estrogen containing pills. Um Ring patch and mini pill. It gets more complicated. So you can see patients with high blood clot risk patients who either have a prior blood clot, a positive antifa antibody, which our patient does and Proia greater than 3 g, which our patient also may have um should not be using most of these regimens. The mini pill is safe but it's very difficult to take. You have to take it at the same exact time every day for it to work. Which a lot of our young people, that's, that's pretty challenging for them. If you have a low blood clot risk, then it's broken down by your degree of lupus activity. So, depo may be a fine option um for patients who have either higher load, um lupus activity as uh could be the mini pill um with low lupus activity and no anti antibodies. We can think about options like um estrogen containing pills or the ring. Um The patch is never a good option for our patients with lupus. So our patient decides that she is going to stop her estrogen containing pill, which is contraindicated in the setting of proa and positive anti antibodies and transition to a contraceptive implant. So you follow up with her three months later, she's completed her opus cyclo foam. She's starting to feel better. Her pronoia is improving and pres has been tapered down to 5 mg daily. You switch her to MMF for maintenance immunosuppression. So what do we use for maintenance therapy for proliferative Levis, nephritis? Um MMF is um has been shown to be better relapse prevention option than a a thin, which was another drug that we used to use more commonly for this. Um based on a study in the New England Journal in 2011. Um you continue um you do wanna continue hidra oral steroids as needed ideally, you're able to taper off of them and then for some persistent Proia, once you feel like the inflammation is well controlled and there's no chem material, you can consider an ace inhibitor as well. So our patient comes back six months later. She now has unfortunately new lower extremity edema and is found to have worsening proa. But she's really hesitant to treat with additional CYO. I due to her worries about fertility. And so you decide to add re Touma therapy to mmf So how do we treat refractory or relapsed, proliferative leus nephritis options can include pulse, steroids are often good upfront again, just to try to put the anti-inflammatory fire hose on it and, and get the kidneys to, to settle down. Um, you can increase your oral steroid dose with a taper. Again, don't wanna leave patients on that high to moderate dose for a long period of time and you can switch from MMF to cyclophosphamide or vice versa depending what has been done so far. Another option that we often do is to add a B cell depleting agent like r Touma or open it to the mab. The last drugs I'm gonna talk about today. RiTUXimab um is an anti B cell drug uh used for both induction and maintenance treatment and endo vasculitis as um as well as refractory lupus, um and other autoimmune connective tissue diseases. Um It works by destroying all CD honey positive cells. Pre B and B cells, side effects include um infusion reactions um are particularly an issue with riTUXimab. Um And then it does significantly increase your infection risk. Um and one course will suppress B cells for about six months. So for patients who have an adverse reaction to re Touma, they have, they get an infusion, they have an infusion reaction and we don't want to give them more. We um typically switch them to open Azuma and this um is a fully humanized antibody leading to less immunogenicity and lower frequency of infusion reaction. Um has the same mechanism of action as ret Touma. The reason why we are not giving this upfront to everyone is really about insurance. Um But this drug does tend to have a lower rate of infusion reactions. All right. And then the last thing I wanted to mention just because I know it comes up for you all so often. What do I do when my immunosuppressed patient has a fever? Um So it's important to remember that it, it's important to think about the degree of immunosuppression. Not all of these patients are the same, not all of them need empiric antibiotics. It is good to look at them and lay hands on them whenever you can. So assess vital signs, hydration status. You wanna look for those treatable etiologies just like you would in any patient. So can we do we have a streit otitis media, bacterial pneumonia, things we can treat with antibiotics any time the patient is toxic, appearing or just sounds very concerning on the phone. Definitely send them to the ED for more comprehensive evaluation in terms of thinking about who you need to worry about. Our lowest risk patients are those on methotrexate and TNF inhibitors. The highest ones are those on with active Lubis on hysteroid or cyclo plasm and those who are B cell depleted. But when in doubt, we are here to help. So just call your on call rheumatologist. All right. So to summarize um most dmards and immunosuppressants take effect. Slowly. Adjunctive therapy can be helpful if you need to address the symptoms quickly. Poly J A should always be treated with dear um to prevent disease damage. There's little head to head treatment data for our medication. So this is where shared decision making is really helpful. You wanna make sure to avoid live vaccines and immunosuppress patients, talk about contraception with any adolescent taking a transgenic medication who could become pregnant. Um in-person evaluation is usually indicated for patients with fever and your friendly rheumatologists are here to help. Thank you. Thank you so much. Um That was a great overview, especially for some topics that are a little out of reach um for some of us. So, um if anybody has any questions, um please go ahead and put them in the Q and A I wanna be respectful of people's time. Um But there is one in here right now. Um And the question is what kind of symptoms or history. Do outpatient doctors tend to miss that lead to, um, a delay in diagnosis. Hm. That's a great question. Um, I think that when I think that basically if something isn't acting the way that you feel like it should just think about other possibilities. So what comes to mind for me are patients who are very athletic and got sent to like, three orthopedists before someone figured out they had inflammatory arthritis and it might have been the right thing to send them first to the orthopedist. But when things aren't adding up, take a step back and remember your differential and think about what else you might need to be worrying about. Um Another example I can think of is a patient of mine who had uveitis, um acute anterior UBI IIS and was treated over and over for conjunctivitis. So again, if it's not behaving like conjunctivitis, make that ophthalmology appointment because it might be the zebra. Um you know, and I know it's always a balance most of the time. Of course, it's not gonna be the zebra, but you know, when things are not going the way that you feel like they should take that pause, take that step back and think about what else it could be and then also feel free to call us. We're always helpful happy. You know, any time you're thinking about a rheumatology, rheumatology thing is a possibility. We're totally happy to talk it through with you. Thank you. Um And then we have one more question. And again, if people need to head out, that's fine, we'll just go over a couple of minutes. Um When might you discuss o site prior preservation prior to onset of treatment? Um Like given that the patient in case three will likely be on those meds long term. So, yeah, good question. So as I mentioned, the patient actually, in case three was treated just with Euro Lupus Cytoxan. And that is the regimen that um we have that longitudinal data demonstrating that it really doesn't affect ovarian reserve. So when we're able to use a low dose cyclotomy regimen, and we use it only one time, you don't have to worry about it too much, which is great um with the NIH regimen of Cytoxan. And then we do start to think about um usually um ovarian suppression rather than cryopreservation at this age is what we'll do. So um we will put them, um we will, you know, use hormonal treatments to put them um into ovarian suppression for the period of time that they're being treated with CYCM and that helps to protect um their fertility. Cool. Thank you. Um And then we have one last one. And how often do you see lupus cerebritis in adolescence? Not that often, unfortunately, but when we do, it's, it's, it's really tricky and lupus or can be incredibly difficult to diagnose. So it's really important to look for those other signs of lupus. And then, you know, to think about um it as a possibility, a patient that I will always remember when I was a first year fellow, um came to us 13 year old young lady with a new diagnosis of Lubis. And the family was telling us she was just not acting right. She was not herself and she had a neurologic evaluation. The MRI was normal, the LP was normal, the neuro exam was normal. Everything looked, you know, everything we could looked, ok. And Neo said, we don't think this is the and then very tragically, she developed an acute pulmonary hemorrhage and she died. Um and when they did the autopsy in her frontal lobes, they found all this macrophage infiltrate. So it was really just her frontal lobes, which is what the family was telling us that her behavior was off. Like, you know, her movement was fine like and, and these infiltrates were so small, they were below what we could discern on MRI imaging. So, um I try to remember that our tools have limitations um and that, you know, we just need to think really broadly and uh and do our best, but it can be hard. Yeah, that's a really tragic case. But thank you for sharing with us. Um Well, thank you for joining and thanks to all the attendees for joining as well. Um Remember to fill out that survey um if you're looking for ac me credit. And um again, thank you so much for your wonderful talk. Thanks for having me. Bye. Created by
