Rheumatoid Arthritis Management: Part 1

Hey everyone, I'm thrilled to report that we are back with season two of room mythology for the Royal College. Firstly, thank you to McMaster University's Division of Education and Innovation for their support, as well as Organon and Pfizer for the educational grants needed to run this program. And most of all thanks to you for tuning in and joining me today. The first topic we're covering here is the management of rheumatoid arthritis, which is a doozy. Therefore I've split it into two episodes each of which, because of the sheer amount of content we have to go through, is a little over the usual one-hour duration. In this episode, I've decided to start us off with the basic management pathways using demards for rheumatoid arthritis as per the guidelines and what you should know about the most commonly prescribed drugs. The second episode, part two on the management of rheumatoid arthritis, will delve into a ton of what I'm hoping will be useful clinical pearls for you and how to approach different situations. This includes optimizing metatrexate, the safety profile of jack inhibitors, and when you can consider using them, how we should look at biosimilars, rheumatoid arthritis management during pregnancy, malignancy risk with our drugs, perioperative management, and much more. That's all I have to say about that. I'm excited to get into the content with you, so let's get at it. Welcome to rheumatology 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 rheumatologist. Before we start, my lawyer advised that I should say the information here only reflects what I have in my personal notes and should not be used in isolation in management to patients, nor for your boards. I'd like to thank Organon and Pfizer for supporting this podcast through their educational grants. However, it should be noted that they have absolutely no editorial say in its production. Guidelines. Both the ACR and ULAR put out recommendations in the last couple years on the management of rheumatoid arthritis. The ACR in 2021 and ULAR in 2019. Today we're going to be modeling our treatment approach primarily on the ACR 2021 recommendations. That's just because they're newer. However, I will be highlighting, comparing, and contrasting the ULAR guidelines here and there as well. The first group of patients we're going to discuss from these recommendations are DMR naive patients. These are patients who are coming to you fresh with the blank canvas of rheumatoid arthritis that requires treatment. Now, ULAR in 2019 said that DMR therapy should be started as soon as a diagnosis of rheumatoid arthritis is made, and I completely agree. So that's commandment number one. Commandment number two is that metatrexate is the main gun in the treatment of moderate to severe rheumatoid arthritis. I'm going to quote them quote, "metatrexate should be part of the first treatment strategy." This means you're going to use metatrexate before hydroxychloroquine, before sulfosalazine, before laflunamide, before biologic demards, and before targeted synthetic demards. ULAR says it very nicely. Methatrexate is the quote unquote anchor drug. It's efficacious as monotherapy or as part of combination therapy. Whether that combination therapy is metatrexate and steroid, metatrexate and conventional synthetic demard, metatrexate and targeted synthetic demard, or metatrexate and biologic demard. And there's good reason for this we have more data that metatrexate is both disease modifying and more tolerable than other conventional synthetic demards like sulfosalazine or hydroxychloroquine. Now some of you are wondering about laflunamide. A lot of people think of this conventional synthetic demard as a metatrexate equivalent, something that's equally efficacious to metatrexate. But here I would caution you. In the ACR 2021 recommendations, the authors state that there's comparable efficacy. But I disagree with them. Because if you look at the original studies comparing metatrexate and laflunamide, they used a dose back then of laflunamide 20 milligrams per daily, which is our standard dose today. However, their metatrexate dosing was much lower than we normally use nowadays in the Western world. Oftentimes they were just using 10 or 15 milligrams a week as opposed to our 20 to 25 milligrams a week. And yet despite that difference, metatrexate still looked really good. And sometimes even superior. For example, in a British study at the University of Leeds in 2000, 999 patients were randomized to laflunamide 20 versus metatrexate 10 to 15 milligrams per week. And the efficacy was comparable. But even with the low dose, metatrexate was better at preventing radiographic progression. So we have to wonder therefore that at the modern day, standard doses of 20 to 25 milligrams per week would metatrexate be superior to laflunamide? Regardless, metatrexate should be the anchor drug, the cornerstone of therapy in your approach to patients with rheumatoid arthritis. And if you need two more justifications for metatrexate over laflunamide, the first is that it offers greater dosing flexibility. And the second is that it's cheaper. So that's the justification for metatrexate over other medications as the cornerstone or anchor drug of therapy. Now you can use metatrexate as monotherapy or you can use it as part of a combination. Whether that combination is with other conventional synthetic demards like laflunamide, sulfosalazine, hydroxychloroquine, or with a fancy drug. And what I mean by a fancy drug is either a biological demard or a targeted synthetic demard aka a jack inhibitor. And the ACR suggests when considering metatrexate monotherapy versus combination therapy, you stick with monotherapy to start. Let's explore why. So the most classic combination therapy with conventional synthetic demards is what we refer to as triple therapy, usually meaning metatrexate plus hydroxychloroquine plus sulfosalazine. Now this is a great combination it tends to outperform monotherapy in at least three ways. Treatment goals are reached faster, they're maintained better, and patients require escalation to biologic therapy less often. However, the reason the ACR conditionally suggests monotherapy over triple therapy is because of the cost and the burden of taking multiple medications. As I imagine the notorious BIG would say mopedos, moproms, in all seriousness though. In the long run, a patient's disease activity should not be different as long as you're adhering to a treat to target strategy, which we're going to talk about later. And there's real world data to back this up. A Dutch study by Dr. De Jong and colleagues showed that while treatment goals are obtained faster, maintain better, and patients require escalation to biologics less often in the triple therapy group as compared to the metatrexate monotherapy group. They ultimately had more adjustments due to adverse effects. And the long-term outcomes were no different in disease activity, functional ability, nor radiographic progression at 12 months, when using the treat to target paradigm, meaning you intensify until the target is reached. Accounting for all of this though, the ACR does qualify that metatrexate monotherapy over triple therapy is just a conditional recommendation. And that some patients may choose combination conventional synthetic demart therapy up front for the increased probability of a better response despite the added burden of multiple medications. Now, when it comes to fancy drugs, a.k.a. biologic demarts or targeted synthetic demarts, the ACR suggests not including fancy drug in your initial therapy for rheumatoid arthritis, whether that's fancy drug monotherapy or fancy drug combination therapy with metatrexate. The reason is because A, the cost is very high. We're talking thousands and thousands of dollars a year. And B, because metatrexate monotherapy has a very established safety profile. However, if despite this recommendation, you and your patient decide to pursue a biologic as an initial therapy for rheumatoid arthritis. The ACR suggests using TNF plus metatrexate combination over metatrexate plus other fancy drug categories. Now, just a quick last word on metatrexate as the anchor drug. If you cannot use metatrexate as a first line, because of contraindications or because of drug intolerance, then what do you do? You are suggests using self-assalzing or laflunamide as part of your initial treatment strategy. So quickly to recap, metatrexate is your anchor drug that you should consider as monotherapy for initial treatment of moderate to severe rheumatoid arthritis. You are says that in the absence of contraindications, everybody should get metatrexate regardless of disease activity. The American guidelines are a little bit different. They suggest that if you have a patient with low disease activity, your patient should instead receive hydroxychloroquine. And if they cannot get hydroxychloroquine, then self-assalzing. The reason is because hydroxychloroquine is a gentle drug. Historically, it's been shown to exert weak clinical effect and have no structural benefit. But it's got a great safety profile. And if you can't use that, then they suggest self-assalzing, because it's a less immunosuppressive medication than metatrexate. Now we're just going to spend a hot second longer on metatrexate here because it's truly such an important drug. The ACR lays some groundwork for metatrexate in their 2021 guidelines. Patients can take metatrexate orally or subcutaneously, but the ACR recommends using oral before subcutaneous dosing while starting out. There's data that subcutaneous injections have superior efficacy, but the ACR's rationale is that P.O. dosing is easier than subcutaneous dosing, and that bioavailability is similar at the usual starting doses of metatrexate. Speaking of those starting doses, lots of people will titrate the metatrexate dose from a lower dose to a higher dose. And the ACR says that if you're going to do that, get to at least 15 1/5 milligrams by the 4 to 6 week mark. Though this is not your ceiling, it's just the minimum dose you should be at by the 4 to 6 week mark. They also suggest that you should consider switching to subcutaneous dosing if your patient isn't at target. The idea once again is to maximize metatrexate before switching or adding other demards. Again, this is a conditional recommendation because it's based on patient preferences and their individual disease situation. Lastly, they encourage that if your patient does not tolerate metatrexate, you can try different strategies to improve how well they tolerate it, like increasing full agh acid or changing to felinic acid or splitting the dose or subcutaneous injections. All things we're going to be talking about later. Okay, so that's metatrexate. I'm sorry we beat it into the ground. I realize we did, but it's such an important medication and I never want you to forget it. Let's switch gears now and talk about steroids. The ACR recommends against, I'm going to repeat that. The ACR recommends against systematically prescribing short-term steroids to everyone starting a conventional synthetic demard to bridge them. This is a conditional recommendation because they realize short-term steroids are often needed to alleviate symptoms until the conventional synthetic demard kicks in. If you do use steroids though, they rightfully point out that they should be used at the lowest dose for the shortest duration. There is an incredible rheumatologist named Dr. Stephen Paget and I would often hear him say steroids are a deal with the devil. Stereoids are a double-edged sword and he's right. The ACR for that reason feels that toxicity outweighs the benefits in prescribing steroids systematically on a short-term basis to everyone who comes in. They are strongly opposed to long-term steroids, although obviously there are some patients who need it long-term. If you've been unstable demard therapy for a few months, you should really try to taper down those steroids. And if you can't, then the ACR suggests you try to escalate your demard dose or switch your demards around so you can get the patient off steroids rather than depending on a long-term low-dose steroid strategy. This not only applies to systemic steroids, it also applies to intraticular steroids. Now FYI, this is a little different from the ULA recommendations in 2019. They suggest that steroids should be considered when initiating or changing conventional synthetic demards. They suggest that steroids be used as a bridge until the conventional synthetics can kick in, but that you taper them as quickly as possible within three months. And that brings us to the next commandment in rheumatoid arthritis therapy according to these guidelines. Both the ACR and ULA are strongly recommend a treat-to-target strategy. This is where you define a treatment target, for example, remission or low disease activity, and you consistently measure your patient based on a disease activity score, like CDI or DAS-28. These are composite scores which provide an easy way to calculate disease activity and therefore categorize your patient as being in remission, low disease activity, moderate disease activity, or high disease activity. This is a strong recommendation because it's well-known, understood, and accepted that tight control of disease to get to low disease activity or remission results in a variety of improved outcomes, including improved function, less radiographic damage, and not only that, but you can also reduce extra-articular damage like coronary artery disease and osteoporosis. I'm going to tell you what the guidelines actually recommend and then what you should do in my honest opinion. ULA are recommends that either remission or low disease activity should be your target. The ACR, however, conditionally recommends that you adopt an initial goal of low disease activity over remission, and the reason is because they felt it would be too disheartening and stressful for patients not to reach target. But I think that's kind of soft. Why not strive for perfection? The man who wrote the power of positive thinking, Norman PL1, said, "Shoot for the moon even if you miss your land among the stars, and I think that's a great approach here too." And for that reason, I tell my patients, I want their joints to feel so good. They don't even believe they have RA anymore. And I make it clear that there's a good chance we can get there or at least close to it. I absolutely am not implying that you pursue remission at all costs because many patients with RA cannot get there, so they have to accept low disease activity. But if their treatment burden isn't too much, remission should be pursued because let's not forget that even a small amount of chronic, steady inflammation for years has consequences such as malignancy and cardiovascular disease down the road. The guidelines suggest that you monitor patients frequently, approximately every three months, and therapy should be adjusted if there's no change by three months, or if the patient's not at target by six months, according to you are. Because they point out that if you have not hit at least a 50% improvement by three months, the chances of reaching your goal is low. However, they rightfully qualify that you should consider patient factors like homervidities when deciding how much to escalate therapy. And so when it comes to treating to target, what are the guidelines tell you to do if you cannot get to your pre-specified target of remission or low disease activity by six months? Well, in real life, we usually escalate therapy by adding something to Methatrexate. So the two most common options would be adding hydroxychloroquine and self-assalazine, that combination is called triple therapy, or adding a fancy drug to Methatrexate. The ACR recommends that when you're escalating from Methatrexate monotherapy, you use Methatrexate plus fancy drug combination over the triple therapy option. And this is a key departure from the older 2015 guidelines, which recommended triple therapy before adding a fancy drug. You see, the long-term outcomes between triple therapy and fancy drug plus Methatrexate combination therapy are equivalent. If you follow the treat to target philosophy, and it's obviously cheaper for whoever's paying for the drugs if you go with triple therapy. But the reason that the most recent iteration of the ACR recommendations support Methatrexate plus fancy drug over Methatrexate as part of triple therapy is because of the strong preference of the patient panel on the ACR guidelines, who prioritize getting better fast. Overall, that's fair. But please understand this was a conditional recommendation, and you should incorporate patient preference, cost, and obviously whatever your funding rules are. ULAR 2019 was a little different. They suggested that if treatment target was not met by six months, whether that's remission or low disease activity, that you then stratify by prognostic markers. So if the patient has a highly positive rheumatoid factor or CCP, if they have a high swollen joint count, if they have high inflammatory markers, if they have early erosions, persistently moderate to high disease activity, despite conventional synthetic demarks, or if they failed to or more conventional synthetic demarks, then you consider them to have poor prognostic markers, and therefore you go with fancy therapy. However, if they lack these features, if they don't have highly positive antibodies, if they don't have a high swollen joint count, if they don't have high inflammatory markers, early erosions, persistently moderate to high disease activity, despite conventional synthetics, and they haven't used to or more conventional synthetics that have failed, then you don't consider them to have poor prognostic markers, and instead of escalating to fancy therapy, you stick with conventional synthetic demarks. I'm just going to point out two more recommendations from the guidelines. The first is that the recommendations from the ACR suggest that if your patient is already on a biologic, or already on a targeted synthetic demark, and they're not a target, then you switch them into a different class of therapy. This means if you are already on one TNF inhibitor as a biologic, you do not switch into a different TNF inhibitor, but you switch into a different category. For example, you might consider a jack inhibitor, and lastly from the guidelines. The ACR discusses something called demark tapering and demark discontinuation. They conditionally recommend that you do not reduce a patient's therapy. However, if you do want to reduce the therapy, you taper it as opposed to discontinuing it. This means that you space out their dosing interval, or you reduce their dose as opposed to stopping their medications. However, if you're adamant that you still want to discontinue as opposed to taper, that you do so gradually as opposed to abruptly, because if you stop it too quickly, the data shows that you are likely to flare. They also offer a little bit more guidance. They say that once your patient is in remission, or low disease activity for six months, this is key for six months, then and only then should you start thinking about it. You are, by the way, stipulates, and I agree with them, that persistent remission is associated with the lowest risk of flaring while tapering, whereas low disease activity is associated with the higher risk of flaring, and therefore tapering would not be recommended in that case. The ACR also offers guidance on a couple specific situations. This includes if your patient is on triple therapy. They say that if you want to taper or discontinue one drug from triple therapy, you should taper or discontinue the self-assousing because it tends to have less persistence than the hydroxychloroquine or the methotrexate given adverse effects. They also discussed if a patient is on methotrexate plus fancy drug combination, i.e. a biologic or targeted synthetic, and you want to taper or discontinue one of their drugs, that you taper or discontinue the methotrexate. Their rationale was that the fancy therapy was likely added because methotrexate monotherapy had failed, and therefore if you discontinue the biologic or the targeted synthetic, you'll once again likely be left with inadequate disease control. However, they also acknowledge something very important, which is that methotrexate blocks the production of anti-drug antibodies against biologic demards. And this is why you'll often hear rheumatologists say that patients should still be on the minimum of 7.5 to 10 milligrams a week of methotrexate if they're also on a biologic demard to increase that drug serum concentration and also improve the longevity of the biologic. Okay, that's it for the 2021 ACR and 2019 recommendations on the treatment of rheumatoid arthritis. I realize I was quite a marathon and genuinely I'm sorry. Let's quickly reiterate six of their key points, some of which are important commandments in the treatment of rheumatoid arthritis. Number one, initiate a patient on demard therapy as soon as the diagnosis of rheumatoid arthritis is made. Number two, methotrexate is the cornerstone of therapy. Consider monotherapy before combination therapy. Although, according to the ACR, if your patient has low disease activity, you should use hydroxychloroquine instead of methotrexate. Number three, the ACR recommends against using steroids and everybody. U-lar suggests use them as a bridge, but for no more than three months. And personally, I follow the U-lar strategy because it's not fair to ask a patient to wait in pain and be functionally disabled for three to six months. As that's how long it takes a lot of our demards to kick in. Four, treat to target. Per ACR escalate to methotrexate and fancy therapy if they fail their methotrexate monotherapy. And as per U-lar, check prognostic markers. If they have poor prognostic markers, then fancy therapy. If not, then stay with conventional synthetic demards. Largely though, your payer will make these decisions for you. For example, here in Ontario, we still need to do triple therapy or something similar to that until we get funding for fancy drugs. Number five, if your patient is already on fancy therapy, that's not getting to target, then change to a different class of biologic or targeted synthetic demards. And number six, avoid tapering or discontinuing. But if you do, taper instead of discontinuing. If you are on triple therapy, let the self-assality go first. And if you're on methotrexate plus fancy drug combination, then let the methotrexate go first. Although I would say try to maintain at least 7.5 to 10 milligrams a week of methotrexate to improve the longevity and effectiveness of your biologic therapy. The reason is because you prevent development of anti-drug antibodies. Question one, we know that methotrexate is the anchor drug in rheumatoid arthritis. The ACR suggests that if you want to initiate and then titrate up your methotrexate, you need to get to a minimum of what dose by the four to six week mark. The answer is 15 milligrams, one five milligrams. But please remember, this is not your ceiling. It's just the minimum by the four to six week mark and you can continue to titrate upward from here. Question two, if you cannot use methotrexate as your anchor drug due to intolerance or contraindication, which two conventional synthetics could you consider instead? Laflutamide and self-assalizing. Question three, when you establish a new demard regimen, the ACR suggests against systematically prescribing steroids to everyone. You, on the other hand, says that you can use low-dose steroids as a bridge for up to how many months, three months, and question four, if your patient is on methotrexate 25 milligrams a week plus a TNF inhibitor and they want to taper, which drug does the ACR recommend tapering? First, methotrexate, and a quick bonus question, what's the lowest dose of methotrexate you might consider going to while still being able to inhibit the development of anti-drug antibodies towards your TNF inhibitor? 7.5 to 10 milligrams per week. The drugs. Let's talk about the disease modifying anti-romatic drugs or demards. In rheumatoid arthritis, so far, you've heard me talk about conventional synthetic demards or CSD mards and the fancy drugs, aka the biologic demards and the targeted synthetic demards. Now, the beauty with rheumatoid arthritis is that we have so many medication choices and apart from some important rules like methotrexate should be your anchor drug, you get to tailor your patient's treatment from a ton of different options without algorithms dictating to you on how to do so. The less beautiful thing, unfortunately, is that you have to memorize them and their major features. Let's try to keep it as beautiful as possible, though. And we are going to start off with the conventional synthetic demards. The classic ones I suggest you know something about are methotrexate, sulfosalazine, hydroxychloroquine, and laflunamide. Drug one of four, methotrexate. This is the cornerstone of rheumatoid arthritis therapy. It revolutionized treatment for the disease back in the 20th century prior to which we were using gold salts and deep penicillamine. The mechanism of action of methotrexate is that it's a die hydropholate reductase inhibitor. It inhibits the folate pathways in terms of efficacy. It's relatively efficacious while still being cheap and safe. Up front, methotrexate monotherapy has a good clinical response with 30% of patients going into remission or low disease activity. And you might say, well, that's the minority of patients, so why wouldn't we just start with combination therapy? Well, one third of patients is still a decent chunk. And if you follow the treat target paradigm and quickly augment their therapy is needed, the long-term outcomes are similar to those who start methotrexate plus fancy drug combination off the hop. In terms of dosing, in the Western world methotrexate is available in 2.5 milligram tablets or in syringes if it's being dosed subcutaneously. You are clarified that the optimal dose target is 20 to 25 milligrams a week. You can either start your patient on that dose or you can start at a lower dose and titrate up. If you do decide to start low and go slowly upward, the ACR recommends that you must be at at least 15 milligrams by the 4 to 6 week mark, though this is not your ceiling. Again, our target is 20 to 25 milligrams per week in most patients. In East Asia, where the body weight is lower and potentially there are some different pharmacogenetics, the maximum dose might be lower. For example, in Japan, a maximum dose of 16 milligrams could be considered. Now you must must must give folic acid with methotrexate. If you run into common symptoms such as cytopenia or GI symptoms or stomatitis, these can often be alleviated by increasing the folic acid dosing. Speaking of adverse effects, there is a misconception that methotrexate is poorly tolerated, but in actuality it's a safe and well tolerated medication in most individuals. About two-thirds of patients will remain on methotrexate after five years. People also get scared because they hear that methotrexate is a chemotherapy drug and they're not wrong, but methotrexate is a chemo drug at higher doses and its side effects are also largely dose-dependent. Therefore, we don't see the same degree of side effects at the considerably lower doses that we are using in rheumatology. The side effects that we are most likely to see are fatigue, malaise, GI intolerance, stomatitis, and cytopenias. Less common ones include hepatotoxicity or elevated LFTs and pulmonary fibrosis. Interestingly, methotrexate can also cause the development of subcutaneous nodules, but these are not rheumatoid nodules. And so if your patient has rheumatoid nodules, these are not a contraindication to methotrexate according to the ACR. Only if the nodulosis is accelerated, should you consider switching out of methotrexate for something else. And lastly, methotrexate is also teratogenic, and therefore in your women of child bearing age, they should be using effective contraception. For these reasons, patients need monitoring. Your patient should get SCBC, ALT, and creatinine, not because of nephrotoxicity, but because it's a renaly-cleared medication, and so toxicity can increase if renal function decreases. Consider blood work monthly for the first three months, and then every three months after that. You should also obtain a baseline chest X-ray prior to starting methotrexate because of the risk of pulmonary toxicity. And lastly, there are some contraindications you should know about. These include alcohol use disorder and chronic liver disease, as you might expect, based on the risk of hepatotoxicity, as well as pregnancy, because of the significant teradogenicity of methotrexate. Drug number two of four is self-assality. This is a safe, effective drug that's compatible with pregnancy and breastfeeding in most cases. The mechanism of action is that it's a pro-drug of five ASA and self-apyridine, which is cleaved by digestive tract flora. In terms of efficacy, self-assalazine is not usually used as monotherapy, but as part of triple therapy. Self-assalazine is dosed BID using 500 milligram tablets, and your target dose is 1 gram POPID to a maximum of 1.5 grams POPID. It's prudent to start self-assalazine at 500 milligrams POD, and then increase by one tablet per week until you're at the target dose. In terms of adverse effects, generally self-assalazine is a pretty safe medication. GI intolerance is the most common issue with it, though, nausea, dyspepsia, diarrhea. These occur in about 20% of patients. Rashes are also common, and headaches. Cytopenia's and abnormal LFTs can occur, but are less common, and there are some rare side effects, too, like pancreatitis or interstitial nephritis. And lastly, men can get a reversible oligospermia. Again, for all the men listening out there, this is a reversible issue, and it's probably worth mentioning as well that dose-related hemolysis can also occur in patients with G6 PD. So use it with caution there. Monitoring is required for self-assalazine, just like Methatrexate, get a CBC, ALT, and creatinine monthly for the first three months, and then every three months after that. The truth about self-assalazine is that while it is a good medication, the long-term adherence unfortunately is poor, primarily because of GI intolerance. Conventional synthetic demard number three of four. Hydroxychloroquine aka Plaquenil. This is an anti-malarial, just like chloroquine. It's one of our safest demards with a low toxicity profile. It's a gentle drug with gentle effects on the disease and gentle side effects. The mechanism of action is unclear, potentially lysosomal disruption, but who really knows. In terms of efficacy, in rheumatoid arthritis, Plaquenil is effective, but it's a gentle medication, and therefore it's either used in mild disease as monotherapy for the ACR 2021, or as part of combination therapy, either triple or dual therapy. Something to note about hydroxychloroquine is that it takes a particularly long time to kick in. Because of the terminal half-life, steady state is not reached for many months. And so as a word of caution, number one, warn your patients that they'll need to be patient. And number two, remind yourself to also be patient and not just discontinue hydroxychloroquine prematurely. In terms of dosing, hydroxychloroquine comes as a 200 milligram tablet in this part of the world. Importantly, you want to max out the dose at no more than 5 milligrams per kg of actual body weight. Not ideal body weight, actual body weight. And this can either be done as a single dose, like 400 milligrams a day, or divided, for example, 200 milligrams POBID, or by splitting the tablets like 300 milligrams PO daily. In terms of adverse effects, I tell my patients that hydroxychloroquine is a gentle medication with gentle side effects. It's immunomodulatory as opposed to immunosuppressive, and therefore it modifies as opposed to suppresses the immune system. So it's relatively safe for patients with a higher risk of infection. Common side effects would include headache and GI complaints like nausea and diarrhea. Hyperpigmentation of the skin can also occur in up to 7% of patients. It's a macular, patchy, gray tan that prefers the shins for some reason, but it can also affect the arms, the face, the nails, and the mucus membranes. If you stop the drug, it can partially improve over months, but total clearance of this tan is pretty rare. And then comes retinal toxicity. This is the feared dose and duration dependent adverse effect of hydroxychloroquine. And it is not reversible. It occurs because hydroxychloroquine pigment deposits directly into the retina. And usually this happens when the doses are more than 5 milligrams per kg per day of actual, not ideal, body weight. Usually this happens after more than five years of therapy. And for this reason, the American Academy of Ophthalmology recommends not exceeding 5 milligrams per kg per day in your plack-winnel patients. And to prevent the development of clinically significant retinopathy, it's recommended that you screen your patients annually. In the olden days, this screening would entail an ophthalmologist looking for bullseye maculopathy. But nowadays in resource-rich settings, the modern techniques are much more sensitive whereby we use OCT or optical coherence tomography OCT to detect pigment deposition in the early or pre-syptomatic phase before the fundus is affected. If you stop, once you see these pre-syptomatic changes, you can usually prevent any vision changes that the patient will ever notice. Of note, both ophthalmologists and optometrists can perform the screening. And while we're on the topic of vision changes with hydroxychloroquine, I'm going to mention that it can also cause a reversible, a reversible dose-dependent disturbance of accommodation that can occur much earlier than retinopathy, but this is not the same as retinal toxicity. And the last group of adverse effects to discuss is cardiac adverse effects with plack-winnel toxicity. More of these came to light during the COVID-19 pandemic because some of our world leaders and celebrities were using it for COVID-19. I see you, Aaron Rodgers. There is a lengthening of the QTC which can occur in five percent of patients, according to the American College of Cardiology, soon after starting the medication. But it is not associated with an increased mortality and therefore at this time it's not recommended to get a baseline EKG in your patient's starting hydroxychloroquine. Additionally, there are case reports of restrictive cardiomyopathy and conduction blocks happening in patients who've taken higher doses of plack-winnel for prolonged periods of time. And lastly, conventional synthetic D-Mart number four of four, Laflunamide aka Arrava. Now oftentimes, classically, we would think of Laflunamide as a methatrexate alternative when methatrexate cannot be used. The mechanism of action, though, is distinct. It inhibits pyrimidine synthesis. Its efficacy, according to the 2021 ACR recommendations, is that it's comparable in efficacy to methatrexate. But as we discussed earlier, those are based on older trials where they compare lower doses of methatrexate with today's standard doses of Laflunamide. And therefore, it's conceivable that maybe methatrexate at standard doses would be even better than Laflunamide at standard doses. Either way, the dosing is 20 milligrams P.O. daily for Laflunamide. We used to do loading doses but don't typically do it nowadays because of increased rates of adverse effects. Now, if your patient cannot tolerate 20 milligrams P.O. daily or your patient's doing really well with 20 and you want to taper them down, you could prescribe the lower dose of 10 milligrams P.O. daily. In terms of adverse effects, patients can experience GI upset, but they can also get hepatotoxicity, just like with methatrexate, hypertension interestingly, peripheral neuropathy, and pulmonary toxicity, particularly in patients with preexisting ILD. Furthermore, Laflunamide is a geratogen and therefore it must be avoided in patients with pregnancy. If you run into minor toxicity, like maybe GI upset, consider lowering the dose from 20 to 10 milligrams P.O. daily. If however you run into more serious toxicity, say, for example, peripheral neuropathy from Laflunamide, then you should immediately stop the medication and perform a washout of the drug using colostyramine. Now, that's it for the conventional synthetic demards of methatrexate, self-assalazine, hydroxychloroquine, and Laflunamide. Before we move on to fancy therapies, we're just going to quickly discuss glucocorticoids and NSADS. Let's start with glucocorticoids. The classic glucocorticoid we usually refer to in rheumatoid arthritis is prednisome. This is a synthetic glucocorticoid with potent efficacy about four to five times the potency of endogenous cortisone because of its configuration, and it kicks in fast. The mechanism of action is that it's absorbed through the small intestine and metabolized to its active drug prednisolone, which induces its anti-inflammatory and immunosuppressant effects. And in fact, in terms of efficacy, it does prevent joint destruction, and increases clinical and radiologic response when combined with standard demards. In terms of dosing, there's a huge range. For a flare, depending on the severity, patients will frequently get anywhere between 10 and 50 milligrams per daily, though usually on the lower end, for example, 10 to 20 milligrams per daily, and it should be tapered off as quickly as possible, as much as they symptomatically will tolerate. However, many of your patients will be on long-term low-dose prednisone, and here I'm referring to less than or equal to 10 milligrams per daily. In terms of adverse effects, prednisone or steroids are a deal with the devil. They're a double-ledged sword. They can cause hypertension, hyperglycemia, cataracts, peptic ulcer disease, mood changes, insomnia, myopathy, osteoporosis, a vascular necrosis of the bone, and the list just goes on and on. Most of these are dose-dependent side effects, and so frequently we'll tell patients that doses of 5 milligrams or less daily are safe. That's not entirely true, but definitely less common than the higher doses. And lastly, just a quick honorable mention to end-seds. These are medications that will reduce the symptoms of rheumatoid arthritis, but please do not be fooled. They are not demards. They do not modify disease activity. Question one, you have a patient with rheumatoid arthritis in whom you want to add hydroxychloroquine as part of triple therapy. That patient weighs 60 kilograms. What is the maximum dose of Methatrexate you're going to use to prevent retinopathy? According to the American Academy of Ophthalmology, the maximum dose is 5 milligrams per kg per day of actual body weight, and in this case, 5 times 60 kilograms is 300 milligrams per daily. Just in case your exam asks for three risk factors of Plaquenol retinal toxicity, you could list doses over 5 milligrams per kg per day, duration of drug over 5 years, and an age over 60. Question number two, what are the mechanisms of action of Methatrexate and Leflonomide? Methatrexate is a die-hydrofolate reductase inhibitor, meaning it's going to inhibit the formation of reduced folates and therefore interfere with DNA synthesis. Leflonomide, on the other hand, is going to inhibit pyrimidine synthesis. And finally, question number three, which conventional synthetic demards are associated with pneumotoxicity or lung toxicity? Methatrexate and Leflonomide. Biologic demards. The biologic demards, or biologics, are monoclonal antibodies. These are large molecules that are produced in living cells. They are targeted therapies honing in on specific inflammatory targets such as TNF or interleukin-6, and they have truly revolutionized the treatment of rheumatoid arthritis. We are going to discuss four different categories of biologics today, anti-TNF inhibitors, interleukin-6 inhibitors, co-stimulation receptor inhibitors, CTLA-4, and those that target B cells. But before we do, I just want to remind you, as I said earlier, that when you're able to, you should be combining your biologic therapy with metatrexate. The reason is in regards to efficacy and immunogenicity of these demards. You see, firstly, the demards have synergistic effect when combined. And secondly, biologic demards are large monoclonal antibodies, which are immunogenic, meaning that the body can develop antibodies to the drug. This will lower the serum drug concentration, the medication will lose the therapeutic effect, and therefore the medication must be discontinued. This is, in fact, quite common. And if we use metatrexate, we can lengthen the longevity of these important medications. And metatrexate does not even need to be that high. 10 milligrams is probably adequate to get the protective immunotolerance and increase efficacy based on a German RCT, which showed no difference in drug longevity between 10 milligrams, and higher doses. Some practitioners will even drop down as low as 7.5 milligrams weekly. Biologic demard #1, TNF inhibitors. These are the OG biologic in rheumatoid arthritis. And they're the most widely prescribed biologic demard in the disease. So we're going to spend some time on them. When it comes to biologic demards and targeted synthetic demards, you have a lot of options. Which one you choose will come down to comorbidities, patient and physician preference, etc. But if all things are equal, the vast majority of rheumatologists will prescribe a TNF inhibitor as the first fancy drug therapy. There are five TNF inhibitors you'll hear about. Etanersept, Adolimumab, Infliximab, Golimumab, and Certelizimab. Again, that's Etanersept, Adolimumab, Infliximab, Golimumab, and Certelizimab. In terms of the mechanism of action, TNF alpha is made by macrophages, and it's a central inflammatory cytokine in the pathogenesis of rheumatoid arthritis. Therefore, it makes sense that we try to block it. These medications are primarily monoclonal antibodies that block the activity of soluble and cell-bound TNF alpha. Etanersept, on the other hand, is a little bit different in that it's a decoy receptor that sucks up the freely floating TNF, and therefore also stops TNF alpha from activating cell surface receptors. Regarding efficacy, the different anti-TNFs are all about equally effective. Generally, they're a pretty potent drug class. When it comes to dosing, the TNF inhibitors are primarily administered subcutaneously, but in Fliximab is given IV, and the dosing frequency is very from drug to drug. For example, Etanersept is given every week, Adolimumab is every two weeks, and so on. When it comes to adverse effects, these medications are usually well tolerated. Most side effects from TNF inhibitors are minor and do not require drug discontinuation. This includes headaches, increased minor infections like upper respiratory tract infections, and something called injection site reactions, which are redness, pain, itching, and swelling at the side of the injection, and they last a couple of days, and generally over time, they get less and less severe. There are, however, some serious side effects we should talk about, and the first is serious infections. This includes bacterial infections, fungal infections, and viral infections. They're more common if the patient is also on other immunosuppressives, such as steroids, but overall, based on a meta-analysis of about 42,000 patients, we know that there's an approximately 30% increase in the risk of infections with standard dosing of TNF inhibitors compared with conventional synthetic demards alone. If your patient does develop an infection, a safe recommendation is to just hold the TNF inhibitor if they need antibiotics, or if they develop a fever, and to continue to hold it until one week after the infection has resolved. Two specific serious infections that it's worth mentioning are number one, tuberculosis reactivation, and number two, hepatitis B reactivation. The risk of reactivating tuberculosis is 18 times the risk in those individuals not on a TNF inhibitor, and therefore you must screen your patients who are about to start the TNF inhibitor for tuberculosis and hepatitis B. Again, you must screen your patients who are initiating TNF inhibitor therapy for both tuberculosis and hepatitis B. It's also good practice to also screen for hepatitis C. The last thing I'll say with TNF inhibitors and serious infection is that if they are a serious concern for your patient, perhaps they're elderly, they're on glucocorticoids, or perhaps they've had sepsis in the past, then you might consider using a tanorcept as your choice of TNF inhibitor because a couple large European registries have shown a lower rate of serious bacterial infection with the tanorcept as compared with other TNF inhibitors. This hasn't been found in all studies, but probably in most of them, and you can quote your patient about a 10% less risk of infection. And that brings us to some of the rare and super rare side effects of TNF inhibitors. The first is drug induced lupus. Anti-nuclear antibodies or ANAs are very common when you treat patients with TNF inhibitors. As our anti-double-stranded DNAs, up to 30% of patients on a TNF will have these antibodies. But true drug induced lupus is rare, only about two out of every thousand patients. Unlike other forms of drug induced lupus, the anti-histone antibody is only rarely seen. Thankfully, the manifestations of this condition are typically mild, like rash, serocytus, but serious manifestations like nephritis and neurologic disease are quite rare. If you stop the TNF inhibitor, the vast majority of cases will resolve within weeks to months. Rare side effect number two is psoriasis, with a very low patient-year incidence rate of 0.5%. It's higher amongst smokers. You can see all kinds of psoriasis from TNF inhibitors, but an unusually high proportion of patients will have pommel planter postulosis, up to 41% of anti-TNF induced psoriasis. If your patient does get it, weigh the effects of TNF discontinuation versus the severity of their psoriasis. If it's really mild, for example, you might just consider some topical treatment, whereas if it's more severe, you would consider switching therapy. If you switch to a different TNF, there's a one in three chance that it won't recur. Again, if you switch to a different TNF, there's only a one in three chance that it won't come back. Rare side effect number three, with TNF inhibitors, is exacerbation of underlying congestive heart failure. This is based on older RCTs where the investigators actually gave in Fliximab and a 10 receptor patients with CHF because these patients tend to have higher TNF levels. And patients who were on TNF inhibitor therapy and those trials got worse rather than better. There was an increased all-cause mortality and CHF-related hospitalizations. This hasn't consistently been reproduced in real-world data registries, but as of now, and likely for a really long time to come, the FDA package insert says that TNF inhibitors are contraindicated in moderate to severe CHF. But another way, you should avoid TNF inhibitors in patients who have an NYHA three to four. The one caveat to this is that as far as I can tell, based on my literature searches, this pertains to patients who have HF-REF, so reduced ejection fraction. Not patients with HF-PEF. I have not been able to find data pertaining to patients who are on TNF inhibitors with underlying HF-PEF, but I would probably shy away from using it in HF-PEF patients too, who have an NYHA three to four. Rare complication number four from TNF inhibitors is super rare, but scary. It's demyelinating disease such as MS or optic neuritis. These are seen at a higher incidence rate in those patients who are on a TNF inhibitor compared to controls, but still exquisitely rare. The American Academy of Neurology's scientific journal published real-world data that identified 35 out of 13,489 patients who developed demyelinating disease on a TNF inhibitor. Rare/super rare side effect number five, interstitial lung disease. Now, there's a lot of controversy over whether TNF inhibitors help or worsen RA associated ILD. There's some data that inflicts a minor attack or a sub could stabilize lung function, but other case reports in case series where patients have had worsening ILD on TNF inhibitors. It's hard to know how much is from the RA and how much is from the methotrexate that's usually co-prescribed in this patient population. In a real-world data study by Jeff Curtis' group in 2015, over 11,000 patients with RA were identified who were on biologic therapy and no differences were seen in the incidence of ILD between the TNF and non-TNFI groups. So I don't really know, but it's been a possible very rare side effect we've quoted for a few years to our patients with RA and something I just wanted to make you aware of. And lastly, super rare side effect number six, the question of malignancy with the TNF inhibitor. You see TNF stands for tumor necrosis factor, i.e. it kills cancer. So the longstanding theoretical concern has been that if you block a TNF inhibitor, you can promote malignancy. And hence the FDA put a black box warning on all TNF inhibitors about the possible association with malignancy, especially lymphoma. However, after more than two decades of this drug class being around and a heck of a lot of observational and real-world data and post-talk analyses on thousands and thousands and thousands of patients with TNF inhibitors, there's no definitively increased risk of malignancy other than non-melanoma skin cancer. This includes no definite evidence of increased risk of lymphoma. The only association, as I said, is with the increased rate of non-melanoma skin cancer. It's a small but real increased risk of about 30% with these two malignancies, basal cell cancer and squamous cell cancer of the skin. We will discuss drug therapy and malignancy a little bit later on. When it comes to contraindications of TNF inhibitors, one is a hypersensitivity to the drug. Another is active infection, as we discussed earlier. Additionally, NYHA class 3-4, latent TB infection. So please, please, please screen your patients for latent TB, latent hepatitis B, and you may as well also screen for hepatitis C. And it's probably also worth mentioning that your patients on TNF inhibitors should not receive live vaccines. So that's it for TNF inhibitors. We spent a lot of time on them because they are the big biologic class in rheumatoid arthritis, but we're going to spend less time on the other biologics. Biologic class number two is the IL-6 antagonists. The two commonly prescribed once-year are tosalismab, aka actemra, and cerulumab, aka kevzara. There's another one that just came out in the New England Journal of Medicine called olocizumab that was superior to placebo and non-infuri to IL-limamab. So you may hear more about it in 2023, but we won't get into it for now. The mechanism of action, obviously with IL-6 inhibitors, is that they target interleukin-6. Their efficacy is quite good, probably similar to the TNF inhibitors when combined with methotrexate. And you hopefully remember that methotrexate is the anchor drug at this point in rheumatoid arthritis. So if you're prescribing biologic, you should be combining it with methotrexate. However, in situations where you cannot prescribe your patient methotrexate or they really don't want it or another conventional synthetic demard. Then when it comes to monotherapy, a trial called the adacta, ADA, CTA, adacta, randomized control trial published in the Lancet in 2013, very clearly showed that tosalismab is superior to TNF inhibitor as monotherapy biologic in patients with rheumatoid arthritis. When it comes to dosing, IL-6 inhibitors can be given subcutaneously or intravenously. And when we talk about adverse effects, there's just a few to note. Just like TNF inhibitors, IL-6 inhibitors can give you injection site reactions. They can increase your risk of infection. But there are some unique changes that they induce as well. They can increase your ALT and AST. They can cause neutropenia and thrombocetepenia. And there have been increased rates of GI perforations seen with IL-6 inhibitors. Particularly, this is driven by an increased risk of diverticulitis. So I would advise you to avoid tosalismab in your patients with a history of diverticulitis. The last side effect of tosalismab in other IL-6 inhibitors is that they significantly increase your cholesterol level more than other biologic demons. But they have comparable cardiovascular safety profiles when compared with other biologic demons. This is probably because inflammation in rheumatoid arthritis normally lowers your cholesterol levels, which you initially would think is a good thing. But it's not because the inflammation also adversely alters important parameters like lipoprotein structures, and the HDL to total cholesterol ratio in an unfavorable manner. We call this the lipid paradox in rheumatoid arthritis, where the total cholesterol number looks better, but the patient's cardiovascular risk increases because of active inflammation. And so tosalismab will largely reverse these changes in the lipid profiles, and therefore cholesterol levels will also increase. Nonetheless, even with similar cardiovascular safety profiles compared to other biologics, the FDA still suggests that you check lipids every one to two months, initially after starting tosalismab. There are some monitoring parameters to be aware of with anti IL-6. For what it's worth, any biologic demard that's about to start should be preceded by screening for TB, hepatitis B, and hepatitis C. So you should do that on all your patients who are starting a biologic. You should additionally be checking a CBC and ALT every month for the first three months, and then every three months after that. It's also worth getting a lipid profile two months after starting therapy, and then kind of routinely checking in accordance with local guidelines. Please also note that when you are monitoring disease activity with your patients on anti IL-6 therapy, the IL-6 antagonist will prevent the production of acute phase reactants like CRP, so you can expect a relatively normal CRP level. However, this normalization of CRP does not reflect inflammatory disease activity. Again, instead a different way. If you have a patient who's on anti IL-6 therapy like tosalismab, their CRP will likely fall, but that does not mean that their disease is necessarily getting better. It's just because the anti IL-6 is preventing the production of the acute phase reactant. Biologic demard number three is co-stimulation inhibitors, specifically here I'm referring to abatacept or orrencia. We're not going to spend too much time on it because I don't think it's a great drug. However, here we go. The mechanism of action of abatacept is that it's a fusion protein comprised in part of CTLA-4, which binds to CD80 and CD86 on antigen presenting cells, therefore preventing them from associating with the co-stimulator receptor, and thereby blocking T-cell co-stimulation and B-cell stimulation. That's a mouthful. If you want to know a little about the mechanism of action, just remember that abatacept is a CTLA-4 fusion protein and blocks co-stimulation. That's it. In terms of efficacy, it's a little less efficacious compared to other biologic demards based on real-world data and based on an RCT that was head-to-head with a jack inhibitor. The dosing of abatacept is IV or subcutaneous, and when it comes to side effects, the common ones include injection site reactions, GI upset, and headaches. A more serious side effect would include infections. Now, we used to think that abatacept had a lower infection risk than other biologic demards, but that had caused more COPD exacerbations than other biologics. However, real-world data has shown us that they have comparable infection risks in rheumatoid arthritis, and that COPD exacerbation risk was probably overestimated. Lastly, there's also potentially a higher risk of malignancy with abatacept that makes sense because it's a CTLA-4 fusion protein that works exactly the opposite of some of our newer cancer therapies, i.e. the checkpoint inhibitors. We're going to discuss more about potentially increased cancer signals with abatacept later on. The bottom line with abatacept is that it's a weaker biologic, and yet it has a similar infection and potentially even a slightly worse malignancy profile compared to other biologic demards, so I need a pretty good excuse to prescribe it. And the last biologic to note is class number four, anti-CD-20s, or retuximab. Now, this is a drug we stole from the hematology oncologists. The mechanism of action is that it's an anti-CD-20 antibody that promotes B cell depletion by binding to CD-20, and its immune effects will last for six to nine months. Therefore, it's only dosed every six months. In terms of efficacy, it works well. Usually much better if your patient with RA is seropositive for either CCP or rheumatoid factor, compared to your seronegative patients in whom it doesn't work as well. To illustrate that for you, if you have a seropositive patient with rheumatoid arthritis who you put on retuximab versus a seronegative patient, the seropositive patient is three and a half times as likely to respond to retuximab as your seronegative patient. When it comes to dosing, there are 500 mg and one gram dosing schedules for rheumatoid arthritis, but with retuximab in rheumatoid arthritis, it's usually given as one gram infusion following a pre-medication of 100 mg of methyl prednisolone. You infuse it on day one, and then you infuse it again two weeks later, and that cycle is repeated every six months. Now, you can play with the interval such that it can be re-dosed as early as every four months, or if the patient's disease can tolerate it, you can stretch that out further as well. When some rheumatologists are deciding on dosing intervals, some of them will monitor something called the CD-19 level, not the CD-20, but the CD-19 level. This is a transmembrane protein expressed by B cells, which can fall when the retuximab causes B cell depletion. If the CD-19 level starts rising, they would give the dose, if not, they wouldn't dose it. However, it's not perfect, and sometimes even with a low CD-19 level, your patient could still have very active disease. So if you want to try to use it, that's fine. Just remember it doesn't work all of the time. Please also remember that just like with other biologic demarcants, you should be trying to combine retuximab with Methatrexate. And lastly, for adverse effects, common side effects include infusion reactions, hepatitis B reactivation, so make sure you do your standard screening of TB hepatitis B hepatitis C before initiating this biologic, infections, more commonly non-serious infections rather than serious infections, and hypogamaglobulinemia. And we know that if your IgG falls with retuximab therapy, it's associated with the doubling of the risk of serious infection. So it's worth while checking it before the next infusion of retuximab and giving them immunoglobulins prior to the next infusion to reduce their infection risk. There are just a couple of rare side effects I'm going to mention. First is arrhythmias, very rare. The second is something very rare called progressive multifocal lucone cephalopathy, PML. This is a very rare condition. It affects only 2.5 patients per 100,000 with rheumatoid arthritis, who receive retuximab. Again, exquisitely rare. The problem with it is that it's an often fatal demyelinating infection caused by the JC virus, which is ubiquitous, and usually lays dormant in various organs, including the brain. It's characterized by clumsiness, aphasia, vision changes, confusion, and memory loss. And kind of along the same lines of infection with retuximab, retuximab is a B cell depleter, and therefore it shuts down humoral immunity. At the start of the COVID-19 pandemic, we were seeing as much as 5.5 times the risk of severe COVID in patients who were on retuximab. However, as the pandemic has progressed, we have better treatment for COVID, more patients are vaccinated, later variants like Omicron seem to be less severe than earlier ones, and now that Evye Sheldt, the dual monoclonal antibody for pre-exposure prophylaxis in COVID-19 has been approved for our patients in retuximab. We've overall seen a pretty nice improvement in the risk of moderate to severe COVID-19 that's dropped to 2.6 per 100 patient years, and that's basically the same rate of severe infection we've always expected with retuximab even before the COVID-19 pandemic. The bottom line, or what I'm trying to say with that last point regarding retuximab and COVID-19 is that while we used to be very scared of retuximab during the pandemic, as long as your patient is vaccinated, it's looking much more favorable, and you should once again strongly consider retuximab as a therapeutic option in your patients with rheumatoid arthritis. The last drug category I want to discuss with you in this episode is targeted synthetic demards, and here we're referring to jack inhibitors. There are four that we use in rheumatoid arthritis commonly. Tofis etnib, aka zaljans, upatis etnib, aka renvoq, berry etnib, and philgodinib. There are others out there too, but let's just focus on a couple of these. In the grand scheme of things, there are relatively new drug class in the treatment of rheumatoid arthritis, and they've been very popular because they're oral, they're potent, and they tend to work quickly. Regarding their mechanism of action, jack inhibitors block the Janus kinase signal transducer and activator of transcription, aka the jack stat pathway. This pathway is involved in cell signaling from the cell surface to the nucleus and mediates signaling for a variety of things, including cytokines, growth factors, chemokines, T cell development. They're also upstream from IL-6, so hopefully it's easy to see that jack stat plays a major role in rheumatoid arthritis. We have four families of jacks in our bodies. Jack one, jack two, jack three, and tick two, TYK tick two, and then a bunch of different stats. The different jack inhibitors inhibit different jacks. For example, tofacytinib will inhibit jack one and three, very sitinib will inhibit jack one and two, upada sitinib will inhibit jack one, and when it comes to efficacy, like the biologic demards, jack inhibitors are clearly superior to methotrexate monotherapy in terms of clinical improvement and structural joint damage. And like biologics, there is a synergistic effect when you add methotrexate to targeted synthetic demards. When we compare the efficacy of targeted synthetic demards against biologic demards, they're at least as efficacious if not more efficacious than TNF inhibitors. For example, when you look at the phase three oral strategy trial in 2017 that compared to opacytinib plus methotrexate with adoleumab plus methotrexate, the results were overall not inferior. And when you look at some other phase three trials comparing very sitinib plus methotrexate or opacytinib plus methotrexate with adoleumab plus methotrexate, these studies were able to show some superiority in their respective primary outcomes. For example, in select compare, which looked at opacytinib plus methotrexate versus adoleumab plus methotrexate versus placebo with methotrexate, the UPA group had higher rates of low disease activity and remission at six months without a particularly higher rate of adverse effects other than herpesoster and CPK elevation. We don't really know what this time if one jack inhibitor is superior over another in terms of efficacy. It's hard to say because all these jack trials are a little unique in terms of patient population, timeline, the outcomes they measured, and other things. I tried to compare their outcomes to each other and even looked in the supplementary materials in the major trials, but fell short. Real-world data also so far has not been able to draw from conclusions yet, probably because these are such a relatively new drug. A systematic review and meta-analysis in the Mayo Clinic Proceedings in 2020 evaluated 20 RCTs on TOFA, Barry, and UPA, and they found a total of 8,982 patients. They also tried to assess the same question as one jack inhibitor superior to another. They felt, based on their findings, that TOFA satinib was superior to the others, but there was a lot of overlap of the confidence intervals, especially for the doses that we use in rheumatoid arthritis. And so for the time being, I think I'd probably just assume that all the jack inhibitors we commonly use, TOFA, UPA, Barry, likely have similar efficacy. There are two more things I want to say about efficacy with jack inhibitors that make them unique. Number one, they work fast. Patients report improvements in as little as two weeks, though the max effect can take beyond three months, like our other biologic demarts. The second unique feature is that they also seem to attenuate central pain processing, because patients can experience pain relief well before their inflammatory markers drop back to normal. In terms of dosing, jack inhibitors are oral, which is awesome for a lot of our patients. It's the only oral "fancy drug" option we really have in rheumatoid arthritis. They're all dosed as one-stayly medications, though if needed TOFA satinib also has BID dosing, which anecdotally has shown some success when patients are having gastrointestinal side effects with one-stayly dosing. Now, you are clearly recommend that if a patient is on a biologic or if a patient is on a targeted synthetic demart, they should be combined with a conventional synthetic demart as well. However, unlike biologic demarts, the targeted synthetic demarts have been shown to be efficacious as monotherapy, even on a long-term basis. And as their smaller molecules and not large monoclonal antibodies, they are not immunogenic. So theoretically, there's less concern about anti-drug antibodies. And lastly, regarding adverse effects with targeted synthetic demarts, usually they're minor, headaches, diarrhea, and minor infections. We can also get some laboratory abnormalities, including dyspidemia, much like tosalismab, cytopenias, elevated LFTs, and interestingly also an elevated CPK. This seems to be idiosyncratic and not related to any clinically significant adverse effects like myopathy, so there's no clear recommendation about monitoring CK levels at this time. Infections are also increased with targeted synthetic demarts. Overall, they confer a similar risk of infection for the most part to TNF inhibitors. You can quote your patient about a 30 percent increased risk of infection. However, there is a three to four times increased risk of shingles compared with other biologic demarts. And therefore, please strongly consider vaccinating your patients for disaster prior to starting therapy with regards to other serious side effects. There are reports of increased rates of GI perforation with targeted synthetic demarts, and it could be because Jack inhibitors block IL-6 signaling upstream. So have a mechanism similar to tosalismabs when it comes to GI perforations. Just to weigh that with regards to risk and benefits in your patients before starting this medication if they have a history of diverticular disease. And then the three notorious adverse effects that were found in the oral surveillance trial in patients on Tophisitinib. Number one, increased risk of venous thrombomellism. Number two, increased rates of malignancy. And number three increased rates of mace or major adverse cardiac events. Now I'm not going to elaborate on those at this time. Episode one was just a quick run through through the guidelines and giving you details on individual drugs. Instead, we're going to discuss the side effects and safety profile of Jack inhibitors in a later episode. And I highly, highly encourage you to have a listen before you make up your mind about the overall safety of Jack inhibitors. When it comes to monitoring, do your standard tuberculosis and hepatitis screening before starting in Jack inhibitor. And just like Tophisitinib, check a CBC and ALT every month for the first three months, then every three months after that. Also get lipids, two months after starting therapy with the Jack inhibitor. And then in practice with your standard local guidelines. My bottom line with Jack inhibitors is that overall they're an appealing class of medication because they're oral. They tend to work fast. Their efficacy is at least as good as other biologics, almost definitely better than habitat sept and possibly even slightly better than the TNF inhibitors. They can be used as monotherapy if really needed. And while they've garnered a lot of unwanted attention recently for side effects based on the oral surveillance trial, i.e., venous thrombomellism, increased rates of malignancy, and major adverse cardiac events, I would encourage you to not just throw out this drug class because it is still a great option for a lot of your patients. You just need to be careful who you prescribe it to. In the words of the FDA, healthcare professionals should consider the benefits and risks for an individual patient prior to initiating or continuing treatment with tovacitinib, berry citinib, or upada citinib, particularly for patients with the history of smoking, those with risk factors for cardiovascular disease, and those with a malignancy. Question 1. Which drugs have an increased risk of GI perforation? Anti-IL-6 therapy and Jack inhibitors. Question 2. Anti-IL-6 therapy does what to your CRP level? It will drop it, not necessarily because it's decreasing inflammation, but because it prevents production of acute phase reactants by the liver. And so you may have a patient in whom you have a pronounced improvement in the CRP, but only a partial improvement in their rheumatoid arthritis, you must go off your clinical suspicion and not the CRP in deciding how effective that medication is. Question 3. It's best to use retoximab in which specific group of patients with rheumatoid arthritis. Seropositive patients. They're three and a half times as likely to respond to retoximab as zero-negative ones. And lastly, what are you screening for prior to starting any biologic demerit therapy or targeted synthetic therapy? Hepatitis B, tuberculosis, and for safe measure, also hepatitis C. Now this is most applicable to your TNF inhibitor patients, but it's good practice to also check in all biologic demerit patients and targeted synthetic patients. 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.