Treatment of Axial Spondyloarthritis (including Ankylosing Spondylitis)

Hey guys, thanks so much for joining me today. In this episode, we are going to be talking all about the treatment of axial spondylarythritis. I've got a lot of information for you, but before we proceed, two requests. 1. It is a huge help for me when you hit that like or subscribe button, so if you are enjoying the content and haven't done so yet, please hit one or both of those buttons. 2. For a while now, I've been wanting to pilot a new type of episode called Meet the Professor. Just like what you see at conferences, and in these episodes, we can ask an expert different questions whether basic or advanced. Questions like, "In my patient with psoriatic arthritis who wants to get pregnant, what drug should I use?" Or, "Does plackenal work in psoriatic arthritis?" Now, I'm really excited about this concept. The first episode is going to be about psoriatic arthritis. I've already come up with a few questions, but I would love to hear your questions as well, so I've included a link in the show notes where you can share your clinical scenarios or questions with me, so we can create a practical and useful Meet the Professor episode. Anyway, that's enough about that, let's get into the treatment of axial spondylarythritis. Welcome to Roomatology for the Royal College, where we aim to bring you reviews that will strengthen your knowledge going into exams and clinical encounters. We hope you'll find it useful and enjoyable, whether you're running, lifting, cooking, grocery shopping, driving, you get the idea. I'm your host, Dr. Karim Ladak, an American-trained Canadian Roomatologist. Before we start, my lawyer advised that I should say that the information here only reflects what I have in my personal notes and should not be used in isolation in the management of patients, nor for your boards. I'd like to thank Pfizer and J&J for supporting this podcast through their educational grants. However, it should be noted that they have absolutely no editorial say in its production. Alright, guys, I have three helpful tips that are going to get us through this topic. Firstly, when we say axial spondylarythritis, we are referring both to non-radiographic axial spaw and radiographic axial spaw, aka, ankylosing spondylitis. Now for all intents and purposes, when it comes to treatment, I want you to think of them as the same. For example, if you look at the recent trial of Bemicizumab, a newer IL-17 inhibitor, whether looking at the non-radiographic patients or the radiographic patients, you can overlay the results one on top of the other, and therefore, once again, think about the treatment of radiographic and non-radiographic axial spaw as the same. Number two, there are two large bodies that have recently published guidelines on the treatment of axial spondylarythritis. The first is the 2022 ASAS ULAR combined recommendations, and more recently, the British Society for Rheumatology released their 2025 guidelines. These two sets of guidelines are largely in agreement with each other, and we're going to be citing them a few times today to justify some of the treatment strategies I'm discussing with you. And finally, number three, there are different disease activity scores out there for axial spondylarythritis. You might have heard of the BASDI, but it's older, we don't really use it anymore. Instead, you're going to hear me say ASAS ASDAS a lot today. This is the preferred disease activity score for axial spondylarythritis. And pharmacologic management. Now I know you're here primarily for the drugs, and I can hear some of you groaning already about non-pharmacologic management, but it's important. And for axial spondylarythritis, I want you to remember two strategies you can recommend to your patients. Number one, no brainer here, smoking cessation. Smoking makes your inflammation more severe. It's a risk factor for disease progression in axial spondylarythritis. We all know it's bad. And so if you can, encourage your patient to quit smoking. This second non-pharmacologic strategy is exercise. It is extremely important in axial spondylarythritis. I'm going to say that again. Exercise is extremely important in axial spondylarythritis. In fact, in a recent nature reviews roomatology paper by some heavyweight axial spondylarythritis authors. They stated that physical therapy and regular exercise can be as important as the pharmacotherapy in axial spondylarythritis. Again, physiotherapy and regular exercise can be as important as the pharmacotherapy in axial spondylarythritis. And we know that exercise is beneficial, independent of drug interventions. A large systematic review found that regular exercise improves disease activity. It improves pain. It improves stiffness. And it improves spinal mobility in axial spondylarythritis. And so it should be a core component in your treatment of patients with axial spa. Now, your patients may ask you, well, Doc, which exercises should I do? 2022 ASAS and ULAR guidelines admit we don't know exactly which exercises are best. There's a lot of heterogeneity in the trials. But you can tell them that anything focusing on mobility and postural training are probably good for you. So things like yoga, aquatic exercises, Tai Chi, even Pilates, which seems to be all the rage right now. I've heard. I've never done it. It looks really hard. But I've heard also improves spinal mobility and postural training. Now, these are all relatively low impact activities. For a while now, there's been concern that high-intensity exercises may cause too much mechanical strain and therefore even increase the degree of damage in axial spondylarythritis patients. The rationale behind this theory was that you can see osteitis in the SI joints of healthy athletes. And in the axial spondylarythritis world, maybe that osteitis would translate to a higher risk of permanent structural damage. Well, to answer this question, a Norwegian study was published in the BMJ's British Journal of Sports Medicine, where they took 100 patients with axial spondylarythritis and randomized them to high-intensity exercise, which was three cardio-respiratory and strength training sessions per week or standard care, meaning no program. In this lasted for three months, after which they found that the group with the high-intensity exercise regimen actually had a lower ass dase. And we know in axial spondylarythritis that a lower ass dase score corresponds with the lower risk of syndesmified formation. And so the study provides some reassurance that high-intensity exercise may not be harmful as previously thought in axial spondylarythritis. Now I'm not supporting CrossFit or anything like that for our patients with axial spa, but I am saying that if your patient enjoys high-intensity exercise, it's possibly not as harmful as previously thought. Pharmacologic management. In the last 20 years, there has been major progress in the management of axial spa. And we now have four major categories that treat axial spondylarythritis. Four of them. Number one, N-sets, number two, TNF inhibitors, number three, IL-17 inhibitors, and number four, targeted synthetic demards, or jack inhibitors. So again, that's N-sets, TNF inhibitors, IL-17 inhibitors, and jack inhibitors, or targeted synthetic demards. You may have noticed that I did not include conventional synthetic demards, namely self-assalizing, because they are ineffective in axial disease, and you will also notice that I did not include glucocorticoids, because they only have at best modest effect in axial disease. Okay, so what is the algorithm then? How do we implement these four different drug categories? Let's do a quick bird's eye view of the algorithm. Please turn your brain on for one minute, stay lucid with me for just 60 seconds, while we discuss the treatment algorithm. And it's as follows. Here we go. Number one, you're going to start with an N-sets and titrate up to the maximum tolerated dose. You should see a response in N-sets treatment after two to four weeks if there is a sufficient response at the two to four week mark with N-sets, then continue the drug. If not, then cycle to another N-sets. One total at least two different N-sets should be tried. And if those two N-sets fail, and the patient has ongoing axial symptoms, then you can start a fancy drug, and by fancy drug, I mean either a biologic or targeted synthetic demard. While N-sets only need two to four weeks to kick in, we need to give our fancy drugs at least 12 weeks to work, after which we can assess response. So again, quick bird's eye view. You start with an N-sets. You titrate up to the maximum tolerated dose and you give it two to four weeks. If you see an adequate response, you stay on it. If you don't, then you switch to a second N-sets, give that two to four weeks to kick in. If it works great, continue. If not, then you switch after two N-sets have failed to a fancy drug. So if you see drugs meaning biologic or targeted synthetic demards, and we give those up to 12 weeks to kick in, and officially, the way that the guidelines recommend you judge disease response is based on the ASTAS. So if your ASTAS drops by at least 1.1, then the British society would call those a quote unquote "clinically important improvement." Such that, if your ASTAS drops by at least 1.1, then with your clinically important improvement, you continue that drug. If it does not improve by at least 1.1, then you cycle or switch to a different drug until you've had that ASTAS response of 1.1 or better. Okay, that's the algorithm. N-sets, number one, N-sets, number two, fancy drugs. Keep going until your ASTAS drops by at least 1.1. Now let's get into the individual therapies. Okay, guys. Question one, what are two non-pharmacologic interventions you should be recommending to all your patients with axial spa? Smoking cessation and exercise. Smoking cessation to reduce inflammation and disease progression and exercise. Again, exercise is focusing on postural stability and spinal mobility. Question two, please name the four drug classes we use in axial spa. Okay, N-sets, TNF inhibitors, IL-17 inhibitors, and Jack inhibitors are the four categories. N-sets, TNF, IL-17, and Jack inhibitors. In lastly, question three, let's take a bird's-eye view of the treatment algorithm in axial spa. Remember, you want to see an improvement in the ASTAS of at least 1.1. But if you don't get that, you have to switch drugs until you do. So I would like you to please walk me through your treatment algorithm. What are your first, second, and third drugs? Okay, drug one, N-sets, you're going to try that for two to four weeks. And if you don't see an adequate improvement, you're going to cycle to a second N-sets. Again, you're going to give that two to four weeks to kick in. And if you still don't see an adequate response, now you swap into a fancy drug category, meaning a TNF inhibitor, IL-17 inhibitor, or Jack inhibitor. Usually we're talking about a TNF inhibitor, or IL-17 inhibitor, probably more so a TNF, while Jack inhibitors are typically reserved as a later line choice because of safety concerns. Okay, N-sets are the initial drug of choice for the treatment of axial spondyloarthritis, and this is what the guidelines say. And you can either pick a traditional N-sets that inhibits both COX-1 and COX-2, or you can pick a COX-2 specific inhibitor like cello-coxib. According to a 2015 COCERN review, all of these N-sets work equally. And in terms of your dosing, use the full dose whenever there is active inflammation. Now how good are they? Well, they work for spinal pain, they work for peripheral arthritis, they work for antisidus and UVitis in axial spondyloarthritis, so they're quite effective overall. And we give them two to four weeks to kick in. If the first N-sets doesn't adequately control your symptoms, you move to a second N-sets. And in terms of the timing of N-sets, you can either take them on-demand or PRN, in other words just when your patient has symptoms, to keep their symptoms at bay, or you can take them continuously. So whether or not the patient is going to have symptoms, you take them every day routinely scheduled. And the treatment paradigm nowadays is just to use on-demand N-sets, meaning you do not continuously use them unless needed to control symptoms. This is because of A, the long-term risks of N-sets, and B, because we don't know whether continuous is even more beneficial than on-demand and we're going to discuss this in a second. Now you may be asking yourself, how effective really are N-sets even? They're just over-the-counter medications. And the answer is that they can work quite well in a German cross-sectional study of over 1,000 patients, 20% 1 in 5, had a complete response with a 100% pain relief on N-sets alone. But let's take one step further, let's ask an even more advanced question. Can these simple anti-inflammatories do more than just symptom control? Can they halt or slow radiographic progression of axiospongal arthritis? You know the old paradigm was we used to say yes, especially in patients who had elevated CRPs or in patients with sendesma fights. But nowadays we're less sure and as of now the answer is maybe, maybe N-sets can halt or slow radiographic progression in axiospongal arthritis. And I say maybe because the data is now conflicting. You see a Dutch RCT in 2005 randomized over 200 patients to either continuous N-sets or on-demand N-sets to control symptoms just PRN. And that study found after two years that the continuous group, the ones who took overall more N-sets, had less radiographic progression than the on-demand group. Obviously suggesting therefore that N-sets are disease modifying. However, a newer German study in 2015 that was quite similar looked once again at continuous versus on-demand N-sets this time with declofenach over two years. It though showed no improvement in radiographic progression in the continuous over the on-demand group. And a subsequent meta-analysis in 2020 also found no difference in radiographic progression after two years in patients with axiospongal arthritis based on continuous versus on-demand dosing. So as of now most experts will tell you that based on observational data, we cannot say with certainty that N-sets halt or slow radiographic progression in axiospongal arthritis. And for that reason, it is recommended that you dose N-sets in an on-demand fashion as opposed to a continuous fashion. Neutral synthetic demarts and glucocorticoids. Alright guys, two quick honorable mentions for medications that we really do not use in axial disease. The first one is conventional synthetic demarts. These are the preferred agent for peripheral arthritis after N-sets fail and particularly here I'm referring to self-isolazine, not metatrexate. They do not, however, work in axial arthritis. So again, conventional synthetic demarts, specifically self-isolazine, are used in peripheral arthritis for patients with axiospongal arthritis, but we do not use them for axial disease because they do not work there. Once again, I'm not talking about metatrexate because ASAS U-LAR is very clear that metatrexate has not demonstrated efficacy in axial spongal arthritis patients. And the second drug that I'm highlighting is glucocorticoids, specifically systemic glucocorticoids. Now, you'll often hear rheumatologists say that systemic steroids are not indicated in axial spa and the reason is because they are at best, at best, only modestly effective in axial disease. Fancy drugs. Remember the guidelines say that once you've tried two N-sets each for two to four weeks and you've had inadequate response, it is now time to try a fancy drug. And by that, I mean either a TNF inhibitor, an IL-17 inhibitor, or a JAK inhibitor. Again, these targeted therapies are second-line for axial disease after the failure of two N-sets. And just how good are these targeted therapies in axial spongal arthritis? How they are great, that's how good they are, about 65% of patients are going to respond after their first targeted therapy. And the patients who are most likely to respond are those who have elevated CRPs, those who have inflammation on the MRI of their SI joints, male patients, patients who've had short disease duration, so less than two years, and non-smokers. So get those patients off their cigarettes. Okay, let's talk specific fancy drug classes and examples. There are three families we need to remember in axial spongal arthritis. Number one, TNF inhibitors. Number two, IL-17 inhibitors, and number three, JAK inhibitors. Again, that's TNF, IL-17, and JAK inhibitors. As of now, the most commonly reached for initial fancy drug is going to be a TNF inhibitor probably, or an IL-17 inhibitor. Let's name a few from each of these classes to really hammer at home. And we'll start with TNF inhibitors. So the antibodies to TNF are Adalimumab, influximab, Golimumab, Certelizimab, and the fusion protein etanircep that kind of functions as a decoy receptor. In terms of IL-17 inhibitors, Ixachizimab, also known as taltz, sacachinimab, also known as chocentix, and bimachizimab, which is unique, it's a newer IL-17 inhibitor that neutralizes both IL-17A and 17F, and the other name for bimachizimab is BIMZELX. And lastly, JAK inhibitors. We are mainly referring here to tofacetnib, or zeljans, and upotacetnib, or renvoke. So again, that's TNF inhibitors like Adalimumab, or etanircep, IL-17 inhibitors like Ixachizimab, or bimachizimab, and JAK inhibitors like tofacetnib, or upotacetnib. Let's take a deep dive into each of these fancy drugs, and we're going to start with TNF inhibitors first. And we can consider that TNF inhibitors are the mainstay of treatment for patients with axial spondylorethritis, who have failed, or can't tolerate those two NSAIDS at the start of our algorithm. In terms of efficacy, they work quite well. Ultimately, two-thirds of patients are going to have a good response to their first TNF, and all of them, all of the ones that we mentioned, have been shown to improve MSK symptoms and signs of both axial and peripheral arthritis. They'll also reduce CRP levels. They've been proven to improve MRI findings at the SI joints, and again, these are all of them. So I'm talking about Adalimumab, etanircep, infliximab, surtilizimab, and Golimumab. My only caution to you is that when we are talking about patients who have uviitis or IBD, you'll want to avoid etanircep, because this decoy receptor, this soluble TNF receptor, does not work for uviitis, nor for IBD. Okay. Now we kind of explored whether NSAIDS modified disease, and we said as of now, maybe. How about TNF inhibitors, though, today modify disease? And the answer is that the newest data is pointing to yes, based on observational data. It seems like once a patient has been on a TNF inhibitor for two years, and especially once they've been on treatment for four years, there is an improvement in structural progression thanks to the TNF inhibitor. Whether you're looking at North American or any of the European cohorts, they all point to less radiographic progression in patients who are on TNF inhibitors, and this is tied to better disease control. All right. So that's efficacy of the TNF inhibitors. What about their safety? Well, according to a systematic literature review that was informing the 2022 ASAS Ular guidelines, it seems like there's a relatively low frequency of serious adverse effects with TNF inhibitors. And based on anecdotal experience, I have to completely agree. Now that said, there are still some things you want to counsel your patients on. The main side effect with TNF inhibitors is injection site reactions with the subcutaneous formulations of these drugs. So what is an injection site reaction? Well, it's a minor reaction causing redness, swelling, pain, maybe itching at the site of injections. These are usually mild, and they only last a few days. They can be managed with ice, analgesia, and with time, the body acquires a tolerance to the medication. And generally, we see a reduced severity or frequency of injection site reactions with subsequent doses. And additionally, many of the biologic subcutaneous injections now come with citrate, free formulations, and smaller volumes, which both seem to help the degree of injection site reactions. The next adverse effect to tell your patients about is infections. Now, we know that TNF inhibitors can increase the risk of infection, though again, generally the risk of serious infection remains low. And clinic will often quote to patients that TNF inhibitors can lead to a two-fold increase in the risk of infection, and that approximately matches up with what the systematic review showed. Now, if you are a rheumatologist or rheumatology fellow, the chances are you are already aware that TNF inhibitors can reactivate hepatitis B and tuberculosis. And that's why we screen for both hep B and tuberculosis, and usually hep C while we're at it, before starting a TNF inhibitor. Another side effect that has been talked about quite a bit with TNF inhibitors is malignancy, and fair enough because who isn't scared of cancer? And these drugs literally inhibit something called tumor necrosis factor. Like excuse me, you're inhibiting the tumor killer? But as we've had more and more years with these drugs, the large majority of registry and other large data sets have not shown an increased risk of cancer, excluding non-melonomous skin cancer compared to non-users. So more and more, the cancer data is looking actually reassuring. The last two adverse effects to talk about with TNF inhibitors are a potential increase in the risk of CHF exacerbations in patients on TNF inhibitors. So you want to avoid your TNFs in patients who have a history of CHF particularly if they have a reduced ejection fraction. And lastly, there is an extremely small increase in the risk of demyelinating disease such as multiple sclerosis in patients who are taking TNF inhibitors. So to illustrate just how small I'm talking about in a Scandinavian registry study with many thousands of patients on a TNF, the rate of neuroinflammatory disease such as MS or optic neuritis was slightly higher than non-TNF users, but still very rare. We're talking less than one for every thousand person years. So here's another important question. In room into arthritis, we try to co-treat TNF inhibitors with methotrexate. Do we need to co-treat in axial spondylorethritis in the same way? In other words, can you use TNF monotherapy or do you have to use methotrexate just like an RA to improve survival of the TNF inhibitor and provide a synergistic effect? We'll studies that have examined this question in axial spondylorethritis have shown inconsistent results. And so as of now, the 2019 ACR Spartan recommendations suggest against co-administration of methotrexate and TNF inhibitor in axial spondylorethritis, in other words, unlike an RA where I will suggest that you use methotrexate with your TNF inhibitors. In axial spondylorethritis, this is not recommended. You do not need to co-treat with methotrexate at this time. What do you do if your TNF inhibitor fails? Well, according to 2022 ASAS ULAR, following the failure of a fancy drug, again, this means biologic or targeted synthetic demard, you should consider switching to another fancy drug, including another TNF inhibitor, or IL-17, or a jack inhibitor. Again, they want you to strive for a drop in the ASAS by 1.1 or greater. The British Society guidelines for their part in 2025 said specifically that there is currently inadequate evidence to recommend a specific sequence of targeted therapies. From a practical perspective, if your patient has had a secondary failure of that TNF inhibitor, meaning it worked for a period of time, whether that was 1 or 2 or 3 years, and then the effect waned and your patient became a secondary non-responder. In that case, there's probably enough structural difference between the different TNF inhibitors that it's reasonable to cycle within class to a different TNF inhibitor. However, if your patient's a primary non-responder, in other words, they took the TNF inhibitor to start with, it didn't do enough, then you might want to switch to a different mechanism of action. But truthfully, we need more data on this. IL-17 inhibitors, let's discuss IL-17 inhibitors. These are great drugs. They've got favorable efficacy and safety. And if your patient has concomitant and cutaneous disease, they work really well on the skin. The IL-17 pathway plays a key role in axial spa, so it's nice to see such good effect from drugs that target it. Let's name three example drugs in this category. The first is exochysumab or tals. The second is secokinimab or cosentics. And both exochysumab and secokinimab are monoclonal antibodies to IL-17a. There's a newer agent on the market called Bimicysumab that is a dual inhibitor of both cytokines IL-17a and IL-17f. Now, there are others that are coming out that have been presented, for example, at ULAR this year with good results, but I don't want to overwhelm you. Let's say practical. The three most common IL-17 inhibitors you're going to encounter today in clinic will be exochysumab, again, that's tals, secokinimab, that's cosentics, and now Bimicysumab. Bimselks. Regarding their efficacy, they're generally thought to be as efficacious as tnf inhibitors when you're looking at ASAS-40 results in clinical trials. Now, a question we asked of NSAIDs and tnf inhibitors in the last few minutes was do they modify disease or do they just help symptoms? With NSAIDs, we said maybe with tnf inhibitors, we said yes, probably, and with IL-17 inhibitors, we're going to respond a resounding yes, probably, as well. Walter Maximovich's group recently published that there was less structural damage in patients with radiographic axial spa, who were treated with exochysumab or adalimamab compared to placebo in a post-hoc analysis of the COST-VRCT cohort. In the surpassed study, secokinimab, another IL-17 inhibitor, also showed positive effect when it came to structural progression. In that study, almost 900 patients with a high risk for radiographic progression, meaning they had an elevated CRP or sendesma fights on spinal x-rays, were randomized to either IL-17 inhibition or tnf inhibition. And after two years, there was no difference in radiographic progression between the IL-17 and the tnf groups. And something important to highlight here is that the majority of patients in both groups had no radiographic progression, and that is a very helpful thing to know. Based on the surpassed results, we could be encouraged that once your patient gets on an effective biologic treatment IL-17 or tnf, we blunt radiographic progression, such that after two years, the majority of patients have no radiographic progression, even if they're high risk for it. In terms of safety, IL-17 inhibitors are relatively safe, according to that 2022 systematic literature review that informed the ASAS ULAR guidelines, IL-17 inhibitors have a low frequency of serious infections. And this fits with the general gut feeling within the rheumatology community that these are relatively safe class of drugs when it comes to infections and other things like malignancies, etc. The reason we feel that way is not only because of anecdotal experience, but also based on the mechanism. While tnf alpha is plyotropic and has a variety of immunoregulatory and pro-inflammatory effects, IL-17 is more targeted. Therefore knocking out IL-17 should have less side effects one would think than tnf alpha. And unlike tnf inhibitors that can reactivate TB or reactivate hepatitis B, IL-17s don't show that same increased risk of a specific pathogen with the exception of candidysis. And that should be kept in mind if your patient has a history of skin, oral, or vaginal candidate. The only other two safety issues I would mention when it comes to IL-17 inhibitors, or at least things to keep in mind, are that IL-17 inhibitors should be avoided in inflammatory bowel disease, because IL-17 is important in maintaining the integrity of the GI tract. Therefore, they do not protect against IBD, and they've been associated with new incident IBD, or at least unmasking of subclinical inflammatory bowel disease. Therefore, we do not use IL-17 inhibitors in IBD. The second caveat is that traditionally we have not thought of IL-17 inhibitors as being effective in UVitis. So I'm hesitating a little bit, and I wish you could see the like, mmm, ah, type of look on my face, because there's more recent data on Bemicismab, that dual IL-17-A, IL-17 F inhibitor, which we mentioned a few minutes ago, showing that Bemicismab may actually be pretty useful for UVitis in axial spa. However, for simplicity and to not overwhelm you, let's just say for the time being that if your patient with axial spondylorethritis has UVitis, the first fancy drug you should be pulling off the shelf is probably a TNF inhibitor, excluding a tannercept. And maybe in the future it'll be Bemicismab, but for the time being, we would like to preferably avoid IL-17 inhibitors in the face of UVitis. Jack inhibitors. Jack inhibitors are a beautiful drug class. These oral, targeted synthetic demards were a boon when they first came out, and in my opinion have remained so. They are a small molecule, and they tend to kick in quickly. Examples in axial spa, most commonly include tophicit nibb, which is a Jack-13 inhibitor, and upoticit nibb, which is a Jack-1 selective inhibitor. But it's unclear how much this Jack-1 selectivity confers, any kind of clinically meaningful benefit. When it comes to efficacy, it looks like they are pretty much on par with TNF inhibitors and IL-17 inhibitors, based on the ASAS 40 outcomes in the primary trials. In terms of safety or side effects, Jack inhibitors do increase the risk of infection. Just like TNF inhibitors have a predilection for reactivating tuberculosis or hepatitis B. Like IL-17 inhibitors increase the risk of Candidal infections, Jack inhibitors have their own specific infection, and that is Zoster or Shingles. Such that we see about a two to fourfold increase in the risk of Shingles in patients who are on a Jack inhibitor. And so it's important to vaccinate your patients for Shingles when starting a Jack. Shingrics is the main vaccine you will see in most of the developed world, and many expert bodies recommend vaccinating ideally prior to starting the Jack inhibitor. This includes the CDC last time I checked, though obviously with the current state of affairs, this could be a state of flux. But as of today, that remains the case. Now, if you don't have the chance to vaccinate until after your patient is already on a Jack inhibitor, it's not the end of the world. Kevin Winthrop's group found that in patients who are already on established Jack inhibition and other demards, most patients will still achieve a humoral and some mediated immune response to Shingrics. It's not necessarily as good as if you had vaccinated pre-drug, but still pretty solid. In terms of other side effects we counsel patients on, there is an increased risk of infection, usually mild infections such as upper respiratory tract infections. Students can have elevated LFTs, rarely patients can also get GI perforations at the same rates as IL-6 inhibitors, and that makes sense because Jack inhibitors also work on the IL-6 pathway upstream. So please avoid Jack inhibitors in those with prior diverticulitis, and lastly, extrapolating from data on patients with rheumatoid arthritis who are treated with Jack inhibitors, there may be an increased risk of malignancy, cardiovascular disease, and venous thromboembolism in patients on Jack inhibitors. This data comes from a trial called the oral surveillance study. I'm going to talk about it at the end of this episode if we still have time, but I'm not going to elaborate on it right now just for flow's sake. All right, so we've got three really solid choices for drug categories when treating axial spondyloarthritis after your enzymes have failed. To reiterate, these fancy drugs are number one, TNF inhibitors, including Adelimumab and a Tenercept. Number two, IL-17 inhibitors, including Ixochismab and Sekokinimab, and number three, Jack inhibitors like Tofacidinib and Uphataidinib. So how do you choose between them? There are no head-to-head trials, so it's hard to differentiate based on efficacy, but it seems like all of them have similar efficacy when it comes to treating both radiographic and non-radiographic axial spa. ASUS, you are offers a little bit here. It says that the current practice is to start with a TNF inhibitor or IL-17 inhibitor and probably even a TNF more than an IL-17. Whereas the Brits in their 2025 guidelines advocate for a TNF inhibitor first, as mandated by the NICE or National Institute for Health and Care Excellence, unless there are contraindications. Jack inhibitors, on the other hand, are probably going to be a later-line drug to use unless the patient really wants oral therapy, and this is primarily driven by safety concerns that we are extrapolating from the RA population in the oral surveillance trial. Again, if we have time at the end, I'll elaborate on this study. All right, guys, I got some rapid-fire questions for you. Number one, true or false? We prefer on-demand NSED administration over continuous administration. True. Question two. Again, true or false? We are certain that NSEDs will halt or at least slow structural progression in axial spa. False. We used to feel that way much more, but it's definitely less clear now. Question three. True or false? TNF inhibitors and IL-17 inhibitors modify structural disease progression. True. Most of the data we have available, it seems like both TNF and IL-17 inhibitors will halt or at least slow structural disease progression in axial spa. Question four. Self-isalazine and systemic glucocorticoids, systemic, not injections, but oral or IV. So self-isalazine and systemic glucocorticoids are useful in axial disease, true or false. False. Self-isalazine is not and systemic glucocorticoids are only modestly effective at best. And this is why you'll hear rheumatoid just say that systemic steroids and self-isalazine are not useful in axial disease. Question five. True or false? We think of TNF inhibitors, IL-17 inhibitors and Jack inhibitors as all being similarly efficacious for axial disease, true. Question six. Which infections do you always screen for prior to starting a TNF inhibitor? TB, hepatitis B and usually you'll throw in a hepatitis C as well. And lastly, question seven. IL-17s are thought of as being relatively safe with regards to serious infections. But there is a specific infectious pathogen that we see more commonly in patients on IL-17 inhibitors. Which bug am I referring to? Candida. Okay, so these drugs are all probably equally efficacious. And according to current guidelines and practices, we're reaching first for a TNF or IL-17 inhibitor and more accurately, we're probably reaching first for the TNF inhibitor than the IL-17 inhibitor. And then because of safety concerns, the Jack inhibitor comes a little bit later. But can we tailor or individualize therapy a little better for each of our patients? And the answer is of course, we can do that not only with shared decision making, but really by considering their extraarticular manifestations and their comorbidities. So let's hone in on a few examples of how your treatment paradigm might be swayed if a patient has different extraarticular manifestations. And we're going to start with UVitis because remember that acute anterior UVitis is the most common non-MSK manifestation of axial spa, occurring in up to a quarter of patients with this condition. In these individuals, the first fancy drug you want to pull off the shelf is probably going to be a TNF inhibitor, excluding a tannercept, but drugs like Adelima Mab and influximab are still very fair game that should address both disease processes. You want to avoid the IL-17 inhibitor class based on pretty lackluster data on secukinimab showing that it was not very effective in UVitis. Though remember a few minutes ago, we also said that a newer study came out showing Bimicismab, the dual IL-17A-17F inhibitor could actually be quite effective in UVitis. And lastly, you may want to consider a Jack inhibitor in these patients as well since there is data suggesting it improves UVitis, though not enough yet to say with certainty. What about your patients with inflammatory bowel disease? Remember that 7% of your axial Sponeloarthritis patients are going to have IBD. In these individuals you can use either a monoclonal antibody against TNF, so all the TNF inhibitors other than a tannercept or a Jack inhibitor. Flushing out the TNF inhibitor perspective a little more, we are primarily referring to influximab and adalimumab. You can also make the argument for acetylizmab and Crohn's and glymumab and ulceric colitis, though approval varies by country. Again, we are not using a tannercept with IBD. On the other hand, Jack inhibitors like Uppodacidnib and Tofacidnib are helpful in individuals with inflammatory bowel disease. Tofacidnib can be used in patients with ulcerative colitis, whereas Uppodacidnib can be used both in ulcerative colitis and Crohn's disease. We don't have any head-to-head trials comparing Jack's and TNF's, but the general sense is that they are roughly comparable. And lastly, IL-17 inhibitors are contraindicated in patients with active inflammatory bowel disease according to ASAS ULAR, due to a paradoxical worsening of inflammatory bowel disease with second kinemab. Now, if your patient has a history of IBD that's now inactive, IL-17 inhibitors are not absolutely contraindicated, but we try to avoid them if an alternative exists. And the last core morbidity to consider is psoriasis, because there's about a 10% prevalence of psoriasis among patients with axial spinal or arthritis. In these individuals with both psoriasis and axial spinal or arthritis, you can reach for any of your fancy drugs, meaning TNF inhibitors, IL-17 inhibitors, or Jack inhibitors. However, you should note that IL-17 inhibition is superior to TNF inhibitors for skin disease. And so, in a patient who has severe or extensive skin disease, you might want to reach for an IL-17 first. And this is based both on RCT data, showing that IL-17 inhibitors outperform TNF inhibitors in the treatment of skin disease, as well as observational data, showing that IL-17 inhibitors have better treatment retention than TNF inhibitors in these patients. Again, Jack inhibitors work well, they are effective, but usually are going to be a second or third-line option given safety concerns. There are some good predictors of positive response to fancy drugs in radiographic axial spa and non-radiographic axial spa. I'm going to give you five of them in no particular order. Here we go. Number one, elevated CRP. Number two, inflammation of the SI joints on MRI. Number three, male sex. Now, I don't know why, but men are almost twice as likely to respond successfully to target a therapy than women. Number four, short symptom duration. And number five, not smoking. So please convince them to quit. Monitoring. We used to use something called the BASDI, B-A-S-D-A-I, BASDI, but we don't anymore. Currently, the recommended instrument is called the ASTAS, A-S-D-A-S, which stands for Axial Spondyloarthritis Disease Activity Score, ASTAS. It takes into account four questions, plus the patient's CRP. So, axial pain level, peripheral pain level, morning stiffness duration, global disease activity, and the CRP. Again, axial pain, peripheral pain, morning stiffness duration, global disease activity, and the CRP. And based on these five factors, the ASTAS gives you a score that actually correlates with syndesma fights and structural damage over time. So to reinforce this one more time, ASS ULAR says the appropriate instrument for monitoring disease activity in Axial Spondyloarthritis is the ASTAS, not the BASDI. You can test as well by doing things like inflammatory markers, though remember that only 40% of Axial Spawn patients are going to have an elevated CRP, or you can do serial X-rays to assess for structural damage, looking for things like syndesma fights, for example. But you should be waiting at least two years between X-rays according to ASS ULAR, since radiographic damage progresses quite slowly. And doing X-rays more frequently than this might just be wasteful. Instead, when it comes to imaging, I find that MRI can be more useful, because it can be used to see whether inflammation is still present, and therefore, guide treatment. For example, if your patient has ongoing symptoms, but it's unclear whether they're inflammatory or non-inflammatory, MRI can offer one more data point to help you decide. So what do you do with this monitoring? What do you do with the serial ASTAS scores? Well, we frequently hear about treat to target in inflammatory arthritis nowadays. We hear about it in RA, we hear about it in GOUT, and we know that a high ASTAS score corresponds with structural damage, such as syndesma fights. So you think it only makes sense to push treat to target in Axial Spawn to lower arthritis too. However, we don't push as hard as we do in rheumatoid arthritis, for example, for different reasons. You see, for starters, we don't have a ton of drugs unlike in RA where you not only have TNF inhibitors and jack inhibitors, but you also have IL-6 inhibitors, B cell inhibitors, selective co-stimulation modulators, and all the different conventional synthetic demards. Whereas in Axial Spawn, once you're done NSAIDs and three different fancy drug categories, you're out of options. Secondly, the truth of the matter is that once your patient is on a biologic demard or a targeted synthetic demard, you're probably starting to dramatically flatten the curve of radiographic damage. If you look at the SERPAS study, for example, most patients at high risk of radiographic progression don't progress, even though they're high risk, after two years of treatment with either a TNF inhibitor or IL-17 inhibitor. And the third point is that there was actually a trial called the Tacospa trial in 2021 that looked at the merit of treat to target in Axial Spawn to lower arthritis. They took patients who had a high disease activity and split them into either treat to target or usual care. And at the one-year mark, using treat to target with ASTAS was not shown to be superior in Axial Spawn compared to usual care. Now, there are fair criticisms of this trial in terms of external validity of the results, but we don't have a trial that we can stand on and show about treat to target in Axial Spawn to lower arthritis. So with all of this in mind, ASTAS ULAR admits that as of now, the real effectiveness of treat to target in Axial Spawn to lower arthritis is undetermined. We have fundamentally changed the treatment paradigm of Axial Spawn with the three advanced therapy classes that we have and hopefully more to come in the future. It's gotten very good, such that we're now asking if we can taper off treatment. And actually, ASTAS ULAR says if a patient is in sustained remission, tapering of a biologic teamard can be considered. The British society takes it a step further and says tapering of therapy should be considered in individuals who have achieved sustained remission. What does tapering look like? It looks like either spacing out the doses or reducing the doses. So let's take the example of a 10 or 50 milligrams weekly. You might decide to space out the doses to something like every eight or nine or 10 days or you might decide to reduce the dose instead of doing 50 milligrams a week. You might go down to 25 milligrams a week. And really, the main factor predicting success of your taper is the duration in remission prior to reducing that dose. And remission can be defined as an ASTAS of less than 1.3. It's reasonable to aim for six months of remission prior to attempting a taper. Now that's taper or reduction. Your patient's in remission for six months and you decide that it's time to either space out the dose or reduce the dose. But what about discontinuation? Well, ASAS Ular is vague, abstaining from saying which raw can be considered. But the British society has a firmer stance on this. They say that even with sustained remission, withdrawal of targeted therapies is not recommended. And this is probably because of two factors. Number one, that the risk of flare is high when you fully discontinue a treatment. And number two, that you may not recapture the sustained remission you had prior to discontinuation. So we'll study, for example, by Canon Bosch published in the Journal of Rheumatology in 2023 looked at a tannercept withdrawal in patients with non radiographic axial spa who achieved remission. Now 67% of them flared after coming off a tannercept, usually within four months. But that's not the big deal in my opinion. The big deal is that only two thirds of those who are retreated with a tannercept were able to once again achieve inactive disease. This is important. Coming off drug and flaring as one thing, but trying to restart the drug and not being able to get back to your level of sustained remission, to me, that's an even bigger thing. All right, guys, even though we think of all the fancy drugs as being equally efficacious in axial spa, we can still try to individualize therapy for our patients based on comorbidities and extraarticular manifestations. Let's run through some scenarios. So you have Chris right now in your office and Chris is a 40-year-old male who has axial spa and UVitis. He's tried two NSAIDs both of which have failed and now you need to pick a fancy drug. Which drug classes are effective for axial spa and UVitis? I'll give you a few seconds to think about it. So definitely TNF inhibitors with the exception of a tannercept. These are an excellent first line drug to try in patients who have axial spa and a history of UVitis. You have other options too though because there's also good emerging data supporting Jack inhibitors and UVitis. So these could be a reasonable option as well. Generally, we try to avoid IL-17 inhibitors in UVitis because they're not as effective. The caveat here being that bimicismab, the dual IL-17A-17F inhibitor, may turn out to be an exception to that rule. Okay, scenario 2. Sabrina is a 22-year-old female with IBD and axial spa. Her gastroenterologist does not want her on NSAIDs because of her inflammatory bowel disease. She's not sexually active at this time, so fertility is not currently a consideration when you're choosing your therapy. Which drugs can you suggest that are effective for both axial spa and inflammatory bowel disease? So TNF inhibitors are an excellent first choice in patients who have axial spa and inflammatory bowel disease. With the exception of a tannercept, which is not useful in IBD. I'm going to re-emphasize that again, TNFs are a great choice for IBD and axial spa. A tannercept is not a good option in this case. Additionally, Jack inhibitors have become one of the other preferred drugs in inflammatory bowel disease. Tofocytinib is now indicated in ulcerative colitis and upotocytinib is indicated in both ulcerative colitis and Crohn's disease. Unfortunately, just like in our patients with UVitis, we are trying to avoid IL-17 inhibitors. And the last scenario is Manuel is a 32-year-old male with axial spa and psoriasis. Like Chris, he's also failed two NSAIDs. Can you therefore please tell me which drugs are going to treat both his arthritis and his skin disease? The answer is all of them. Jack inhibitors, IL-17 inhibitors, and TNF inhibitors will all treat both axial spa and psoriasis. But IL-17 inhibitors are shown to outperform TNF inhibitors when it comes to psoriasis. So for Manuel, you may first want to reach for an IL-17 inhibitor. Okay, just two more questions in this section. And the first of those is what are five positive prognostic markers that a patient is going to respond to your fancy drug therapy. Five of them. Okay, high CRP, evidence of inflammation on MRI, male sex, short disease duration, and non-smoking status. So please get them off the cigarettes. And last question. The guidelines suggest considering tapering fancy drugs when our patients are in sustained remission, meaning spacing out the dosing or reducing the dosing of TNF inhibitors, IL-17 inhibitors, and jack inhibitors. Tapering. But what does the British Society of Rheumatology say about full-on discontinuation where we stop the drug? It is not recommended. This is because of firstly, the high risk of flare, and secondly, the concern that even if you go right back on the same drug regimen, you may not recapture sustained remission. Some extra stuff. People love jack inhibitors. They're oral. They work well. They work fast. However, there were concerns about cancer and cardiovascular disease in patients taking jack inhibitors. So years ago, the FDA mandated a study called the oral surveillance trial. This was a head-to-head non-inferiority safety trial meant to compare tophysid nib, which is our Jack-13 inhibitor, with TNF inhibitors, Adalimumab and North America, and a tanner-sept internationally. This study found three important safety concerns. Number one, an increased risk of malignancy, number two, an increased risk of cardiovascular disease, and number three, an increased risk of venous thromboembolism, primarily I'm referring to pulmonary embolism here. This trial was done in patients with rheumatoid arthritis, and the population was enriched with patients who would have a higher risk of cardiovascular disease. Namely, patients were at least 50 years of age or older, and they had to have an additional cardiovascular risk factor, so something like cigarette smoking or diabetes. This trial was done in patients with rheumatoid arthritis, not axial spawn to lower arthritis, and that's something important to remember. Nonetheless, those three safety concerns are important, and they might still apply to our patients with axial spawn. Hence, we're going to spend just a couple of minutes trying to summarize as quickly as possible. So back to trial design. Patients were randomized to tophysid nib 5BID, which is the rheumatology dose that we use, tophysid nib 10BID, which is higher than what we usually use, or a TNF inhibitor. At the end of a median of approximately four years of follow-up, the incidences of mace or cardiovascular disease, cancer, and venous thromboembolism were higher in the tophysid nib group than in the TNF group. Cancer were more frequently lung cancer and lymphoma, and non-inferiority was not met. This was published in 2022, and yet to this day, we still don't definitively know the mechanism for why this happened. However, we do know that the risks are highest in patients who are over the age of 65, and those with the significant smoking history. The FDA extrapolated these findings and applied a black box warning for the entire class of Jacque inhibitors, and the European Medicines Agency said that Jacque inhibitors should only be used in patients at high risk if no suitable alternatives exist. These findings have definitely affected prescribing practices. So slam dunk, right? Jacque inhibitors increased the risk of cancer, cardiovascular disease, and venous thromboembolism. Well, actually wrong. You see, despite the oral surveillance findings, real world data from registries have not been able to consistently reproduce the increased risk of cancer and cardiovascular disease. And post-talk analyses have shown that the 5 milligram tophysid nib group, which again is the dose we actually use in rheumatology, is not as harmful as the 10 milligram group. So for example, the patients in the 5 milligram group may not have a higher risk at all of venous thromboembolism. And another post-talk analysis showed that there's no increased risk of cardiovascular disease in the 5 milligram BID tophysid nib group. Again, the dose that we use in rheumatology, unless a patient has preexisting atherosclerotic disease. Another highly cited piece of data published by Dr. Christensen's group from Denmark in 2023 showed that if you look at the oral surveillance population, there's a very clear increase in the risk for cardiovascular disease and cancer in patients over the age of 65 and in those who smoked. But if you remove these patients, those over the age of 65 and those who smoked, and you just maintain those who are under 65 and non-smokers, there is no statistically significant increase in the risk of cardiovascular disease or cancer compared to TNF inhibitors. And lastly, the risk of these three things, cardiovascular disease, cancer, and venous thromboembolism, was higher in the tophysid nib group in oral surveillance, but not by a ton. So if you're looking at the actual numbers, you'll find that they're only about a percent or a percent and a half off from the TNF group. Let me illustrate this a different way, with something called the number needed to harm. So if we say a patient is going to be on a jack inhibitor for five years at the lower dose of five milligrams POB ID, how many more patients would we need to treat with a jack inhibitor as opposed to a TNF inhibitor before we see an additional adverse effect? Well, for a five-year time span, it would take 113 high-risk patients, again, high risk over the age of 65 and smokers, on a jack inhibitor at five milligrams BID for an extra cardiovascular event, it would take 55 high-risk patients, on tophysid nib five milligrams BID for an extra cancer event, and it would take approximately 152 high-risk patients for an extra venous thromboembolism event, usually being a pulmonary embolism. Now unlike so many other things in medicine, with time, this question of how deleterious a jack inhibitor might actually be for cardiovascular disease, or malignancy, or venous thromboembolism, has just become more confusing than straightforward, and that's because of all the real-world data that's conflicting with oral surveillance. Not to mention the fact that Uphatisid nib is touting itself as a jack-1 selective jack inhibitor, raising the question of whether there's reduced risk with that selectivity, but we don't know. And so at the end of the day, here's how I've reconciled it. Patients tend to be more satisfied with their jack inhibitor therapy over their TNF inhibitor therapy for various reasons based on survey data, and this includes because they're oral and they work quickly. I've also appreciated that the number needed to harm is quite high if you look at the dose that we actually use in rheumatology, which is the equivalent to five milligrams BID of tophysid nib, and that we have ways to reduce the risk. We can avoid prescribing jack inhibitors in smokers, we can avoid prescribing jack inhibitors in those with the history of atherosclerotic disease, and we can avoid prescribing jack inhibitors in those over the age of 65. Jack inhibitors are great drugs, and I'd like to continue using them. So I try to mirror my approach off of what the European Medicines Agency says, which is that in four groups of patients, those who are over the age of 65, smokers, those at increased risk of cancer, and those at increased risk of cardiovascular disease, avoid jack inhibitors unless no other suitable treatment option exists, and avoid in patients at a higher risk of venous thromboembolism. Great job, guys. We are pretty much there. Just two questions for you. Question one, what are the three concerning safety signals found in the oral surveillance trial that prompted the FDA to create a black box label across the entire jack inhibitor class? Cardiovascular events, cancer, and venous thromboembolism. However, I still think jack inhibitors are a great drug class that we should be prescribing, but there are ways for us to reduce the risk. So question two is as follows, other than avoiding jack inhibitors in patients with established cardiovascular or cancer history/risk, we avoid their use in patients with two risk factors. What are those two specific risk factors? I'll give you a hint. One of them is an age cut off, and the other one is something I've emphasized a few times during today's episode. Okay, age over 65, and significant smoking history. And that's it for today, guys. Great job on making it through this topic. You deserve a well-earned break. If you enjoyed today's session, please subscribe. I would also tremendously appreciate your feedback in the form of an Apple podcast review or feel free to email me with suggestions for future episodes, content, accuracy, or sound issues. My email is room for the RC. That's R-H-E-U-M-F-O-R-T-H-E-R-C at gmail.com. Have a great one.