Advanced Practice Rheum: Safety of Biologics and Novel Agents Save
Transcription
Hello everyone. In this advanced practice RheumNow video, we'll be covering the safety of biologics and targeted synthetics. You know, when we talk about safety, we usually talk in terms of the drugs. But the fact is that most safety issues really start and are perpetuated by the disease. So in all discussions on safety, the 800 lb gorilla in the room is the disease, the inflammatory load, the disability, the deformity — the disease itself imparts many of the things that we often ascribe to the drugs.
So for instance, RA — it's RA severity, RA inflammation — but we worry about the drugs that we use and risk of, for instance, serious infection, TB, opportunistic infections, heart attacks, shingles. And again, you need to know the data.
Here's a few important safety rules that you may not have heard. Number one, the longer you're on a drug the safer it becomes, which — the converse is — most of the really bad and important safety events occur very early, in the first 3 to 6 months of a drug. There are exceptions to that rule, but that generally applies to methotrexate, to TNF inhibitors, etc.
Second, the lowest dose of a drug isn't always safer. If you use a subtherapeutic dose to avoid safety, you may not be controlling the disease and then the disease takes over as far as safety risk. Meaning RA gets worse. Inflammation gets worse. Inflammation drives infection risk, as an example.
So the third rule, the riskiest thing that you may do is play it safe. Number four, never ask someone who knows less about how to manage a safety issue. Go to the expert, go to someone who really knows. Fifth, again, the patients and their inflammation are way riskier than the drugs that you use. Remember that.
And you need to know the numbers. The patient's got a risk. The drug has got a risk. It's all worsened by comorbidity. And interestingly, people who respond to a drug tend to have less safety issues. That's really interesting, but true.
Let's talk about serious infections. By definition, that's an adverse event — an infectious one — but it leads to hospitalization, morbidity, and mortality. Prior to the introduction of biologics in 1998–1999, the SIE — serious infection event — rate was 3 to 9 per 100 patient years; that's data from the Mayo Clinic. Then with the introduction of all the TNF inhibitors, then IL-6 inhibitors, abatacept, rituximab, and then the JAKs, the risk is roughly 2 to 6 per 100 patient years. When I say 6 per 100 patient years, I mean 100 patients followed for one year — six would get a hospitalizable or a serious infection that may merit IV antibiotics.
The interesting thing about biologics that are out there in the market is that they cause a non-significant doubling. They don't significantly increase serious infectious event rates, but they tend to double it. So there is a box warning for most biologics that says serious infections leading to hospitalization and/or death, including tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections, have occurred or been described. If a serious infection develops, interrupt the therapy until the infection is controlled, and then in some instances test and monitor for TB.
So there is this non-significant doubling in the trials — for instance, etanercept. People on etanercept had a 1% risk. People on placebo had a 1% risk. It didn't double. On the other hand, infliximab — people on placebo had a 3.4% risk and people on infliximab had a 5.3%. Golimumab was really no change. Certolizumab was 1% placebo, 3% on certolizumab. Those are not significant increases, but they could be in someone who's very sick.
So if you want to calculate someone's serious infectious event risk, go to the RABBIT risk calculator. It's RABBIT, from the German biologics registry. And they've got a risk calculator where you can calculate any person's risk based on their age, prednisone dose, number of prior DMARDs, prior SIE event, and current biologic, and it'll spit it out for you.
But the most common infections we see are non-serious infections — URIs and UTIs. They're the most common adverse event in all the clinical trials. And people not on these drugs, about half of them are going to get one in the next year. The problem is most of you wrongly stop a biologic for a cold, a sniffle, a temp of 100.8. And that's silly because the half-life for the drug is often more than two weeks and you're stopping it until they get over that. That makes no sense. I never stop. So these are common and don't stop them for trivial events. We'll talk about the rules for stopping a biologic in a few minutes.
But the risk of getting a serious infection as pertains to rheumatoid arthritis — rheumatoid arthritis is a really great model. It's very inflammatory. It's well studied. Again, the odds of getting an SIE in the next year are highest in people who have really bad RA, and that's RA disease activity, inflammatory disease activity, and also RA severity and
dability and deformity. Number one risk factor. Number two, steroids almost in any dose. But in mild patients, well controlled RA, you know, 5 milligrams not so bad. But in really badly controlled patients, 5 milligrams is not good. In people who are stable, well controlled, they shouldn't be on 10 or 15.
All right. The third greatest risk are comorbidities. And the number one comorbidity is lung disease, COPD, ILD. But then other comorbidities also — heart disease, renal disease, diabetes. Number four, cutaneous breakdown. Which is why number five, major joint surgery. When you cut the person open, you're opening up the skin. The number one barrier against infection. This also applies to wounds that won't heal. So there is very little or no risk imposed by conventional DMARDs, and then biologics pose that very small risk but it is significant in some people.
Okay. So rules that you can live by. Number one, infection is related to activity and inflammation more so than the drug. We said that. Number two, NSAIDs, URIs, UTIs are way too common to freak out about and stop the drug. Number three, steroids are the most dangerous drug you use. Number four, biologic adds an infectious risk primarily in people who are very poorly controlled, most inflammatory, highest risk otherwise. Number five, only hold a biologic when the patient is hospitalized or they have a fever greater than 102. Again, never ask someone who knows less than you or less than me about what to do about infection. Most of those people, including infectious disease experts, are getting their education from television. If you want to reduce risk, reduce steroids, control inflammation, and control or manage comorbidity. And then the way you really manage infection risk is by screening tests like hepatitis B, hepatitis C testing, vaccination, and then having a high index of suspicion.
Let's talk about TB because most of the biologics say you should test for TB before using the drug. You need to know the risk in the United States. The risk of getting TB is 4 per 100,000. It's very low. It's the same in other developed countries like Australia, UK, Western Europe. But the RA, rheumatoid arthritis TB risk is about 6 to 7. So it's not much higher. RA poses a very small risk in itself. On the other hand, we're talking about RA risk in mainly developed countries. What you need to know is in developed countries, the risk is really low. But in endemic countries where TB is very common — I call that TB land — the risk is not 4 or 6 per 100,000. It's 250 to 12,000 per 100,000. So a 50 to 2,000-fold higher risk if your patient was born in Southeast Asia, in Russia, in South America, in South Africa. A number of countries have a high endemic risk. They're the ones who really need testing and you need to worry about and have a lower threshold to treat.
So TB and opportunistic risk is primarily an issue of TNF inhibition. Why? Patients who have TB, non-tuberculous mycobacterial infections, invasive fungal infections — those infections are controlled by the body because the body builds granulomas around them and sequesters them, and the granulomas are very protective unless someone gets immunosuppressed or gets very old. But what do you need to make granulomas and to maintain them over time? You need TNF, more TNF, and a little bit of gamma interferon. So it's only the drugs that inhibit TNF that really cause breakdown of granuloma and spread of TB. Right? So that's what you need to worry about. So in a TB issue and you don't know what drug to use, or a past issue of candidiasis and you don't know what to use, don't use a TNF — use another MOA.
The number needed to harm to get TB with a TNF inhibitor is somewhere around 500 to 600 patients. All the TNF inhibitors have a box warning that says tuberculosis screening is required. For most biologics, for TNF inhibitors, it's also required — by the way, for all JAK inhibitors, all IL-17 inhibitors, for all IL-6 inhibitors, and interestingly only for canakinumab, the IL-1 inhibitor. The other two IL-1 inhibitors you don't have to require it, because that's the way the trials were done. And requiring TB testing really means that that was done in the development studies of the trial more so than there's a risk imposed by that MOA. So we know the MOA at risk is TB and TNF. Right? All the other ones, not so much.
But you don't have to do TB testing for methotrexate, azathioprine, mycophenolate, apremilast, anakinra, rilonacept, rituximab, belimumab, ublituximab, and peglocase. Now you want to do it, go right ahead. The patient's from a high-risk area and having other issues, go ahead and you can do it. But here are the rules that I published before with Kevin Winthrop and Catherine Dao and Richard Chaisson from Hopkins. Number one, everyone should be screened for a latent tuberculosis infection, LTBI, prior to using a TNF inhibitor. You screen with either skin testing, TST testing, or a PPD test, or a blood test, an IGRA, an interferon gamma releasing assay. When do
you use an IGRA test? When it's available and when there's a history of BCG vaccine, because patients who have BCG vaccine have the same antigens as does tuberculin skin test and you can have a prolonged positive tuberculin skin test PPD related to BCG. You want to uh get rid of that problem, then use IGRAs that don't have the same antigens.
Number three, a BCG vaccinated person should be tested for LTBI because if they come from TB land where they got BCG and they now have positive results 20 years later, it's more more more likely to indicate LTBI or current infection than you know positivity incurred with BCG, because you do get TST positive after BCG but it wanes over time, especially in adulthood, especially 20 or 30 years later. So a positive result is worrisome.
Four, either PPD or IGRA positivity is evidence of infection. You now have to figure out whether it's latent or active. The way you actually do that is number six, with a chest X-ray, which is helpful in diagnosing active TB. No symptoms, negative chest X-ray, and a positive TB test of any kind is the definition of latent tuberculosis infection.
Um, number seven says PPD testing should only be repeated upon reexposure or new increased risk, which largely means reexposure. Annual testing is not recommended, although it is done by the National Psoriasis Foundation guidelines, and they're wrong. Ask the TB experts, they'll tell you.
Um, number eight, patients with a documented history of adequate treatment of either latent TB or active TB can safely be treated again with a TNF inhibitor. Let me say that again. If they've been adequately treated, then they can get a TNF inhibitor in the future.
LTBI. Uh, again, um, what that means is that if you've proved that, you need to initiate TB therapy before giving back the TNF inhibitor. So unlike active TB where it's really not known how long you wait, generally people say 4 months — with LTBI, no symptoms, negative chest X-ray, positive test, you give one month of INH and then you can start the TNF inhibitor. And yes, that is per FDA and in consultation with all the TB experts in the United States.
And lastly, guidelines do not recommend screening for conventional DMARDs including methotrexate.
Who should not restart their TNF inhibitor? The people who have had invasive fungal infections, atypical mycobacterial infections, active hepatitis with hep B surface antigen positivity, um, and patients who had intravesicular BCG treatment for bladder cancer. Now in a few of these — the first three: hepatitis, NTM infections, and invasive fungal infections — if you have to give back because you have no other options, you can prophylax them with uh antiviral therapy for hepatitis, antifungal therapy for um you know uh invasive candidiasis, or um prophylactic therapy for NTM. BCG you really can't prophylax uh safely.
Hepatitis B testing. Everyone should be tested for hep B surface antibodies, but also hepatitis B surface antigen, core antibody, and surface antibody as well. Okay. Uh, and by having those, if they're all negative, you're free and clear and don't need to worry about that.
Um, but what if the patient has an occult infection? That means that they have um B surface antigen, which is the most worrisome. Anybody with B surface antigen positivity um is really at um risk — okay, really at risk — and shouldn't receive TNF inhibitors, probably not abatacept, probably not a B cell depleter, okay, um, and probably should be referred to a hepatologist.
But let's say the patient is hepatitis B surface antigen negative but core antibody positive, meaning they had a past infection. If they happen to be surface antibody positive, that means they were probably previously vaccinated. Those people are at very low risk and I use TNF inhibitors in them all the time, all the time in those people. They have a 1% chance of reactivating.
Beyond that, you know, e-antigen positivity and other combinations, you probably should get a consult with a hepatologist to know how to proceed and figure out whether the patient needs prophylaxis.
Again, vaccination is the way to go. Our patients should be vaccinated against pneumococcus because we use a lot of steroids, because they get older, because they're immunosuppressed from the therapies. The best way to avoid — best way to explain which pneumococcal vaccine you can use — you can look at the slide uh that's attached to this, and just if they've never been vaccinated, give them the PCV20. That's the newer Prevnar 20 that was approved I think in 2021, and you give it one time and you're done for life. If people previously received Pneumovax, they have to get a repeat after five years and then you also use PCV20. But look at the ACIP guidelines on how to vaccinate.
What we do know about our drugs in vaccination is that rituximab and B cell depleting therapies really markedly reduce humoral responses and should not be given in people who are on um rituximab and the like. Right. Uh, the other drug that
markedly reduces vaccine responses is methotrexate but we have a fix for that and what I'm not saying is that all the other drugs you can safely use vaccines — influenza, Pneumovax, the shingles — Shingrix, it doesn't matter if you're on azathioprine, antimalarials, low doses of steroids, leflunomide, sulfasalazine, most biologics safe to give vaccination on but if you're on methotrexate. The rule from a good study done by Park and colleagues shows that you can — you're going to give influenza, you're going to give any vaccine, Pneumovax. Basically, what you do is you stop methotrexate for one week, give the vaccine and resume methotrexate a week later. The patient doesn't flare and they have exactly the same immunogenicity from the vaccine as if they weren't on methotrexate.
You need to worry about using live vaccines. You can look at the slide that accompanies this talk that says that live vaccines that should not be received on biologics include nasal influenza. Injectable influenza is good, right? The usual one that's given to everyone except for the high dose. Oral typhoid, yellow fever, varicella, Zostavax, which we don't use anymore. MMR, these are all live virus vaccines. BCG, oral polio, smallpox, rotavirus, and a few others. Again, you don't use live virus. The rule is if they're on a biologic and they need to get a live virus vaccine — you're going to do international travel, whatever — you need to give it before they get their biologic, or be off the biologic for at least four weeks, give the vaccine, wait two weeks, and then restart. That's a rule the CDC came up with.
A little bit about Shingrix. This is the herpes subunit vaccine which has an adjuvant, approved in 2017 based on the ZOE-50 and ZOE-70 studies, which basically says people over the age of — normal people over the age of 50, over the age of 70 — this drug works great at preventing shingles. It's 90% effective in preventing it. It's 90% effective at preventing post-herpetic neuralgia. Why would you not use this? The bottom line here is it's two shots. You get one and then you get the second one two to six months later. Up to a third of people get constitutional manifestations. Very, very low risk of flare and this is highly effective. I use this in everybody that goes on a JAK inhibitor because compared to a TNF inhibitor, JAK inhibitors cause a 5 to 10-fold higher risk of shingles. So I vaccinate everybody with Shingrix if you're going to go on a JAK inhibitor.
Some — let's talk about cancer. I want you to know that most of you are very afraid of cancer. That's fine. But you need to know the data is much more reassuring than you know. Guidelines say that people with a solid cancer can receive any drug that you want to give them. And by solid cancer I mean lung cancer, skin cancer, pancreatic cancer, tongue cancer, you know, any solid tumor, any non-hematologic — you know, lymphoma is another story. There's good evidence that biologics do not cause cancer and do not worsen cancer outcomes, meaning it does not alter mortality. It does not increase the risk of cancer recurrence. And TNF inhibitors don't cause melanoma, right? And biologics can be given in people with melanoma. There's a little bit of evidence out there that you maybe should worry. It's from one study and there are other studies that have refuted it. So again, you should treat the arthritis. Let the oncologist manage the cancer is my guideline.
In rheumatoid arthritis, the prototypic inflammatory disorder, the risk of cancer is not increased — an SIR of one, standardized incidence ratio. But that's not really true because there are certain cancers in RA that are increased. Lung, lymphoma, melanoma, and skin cancer — non-melanoma skin cancer. They're increased in all RA studies with all drugs or no drugs. That's the pattern you see in RA. Interestingly, RA has a lower risk of breast and colon. So when that all kind of evens out to a no risk, an SIR of one.
Now, does the rheumatoid cause the cancer risk or is it the TNF inhibitor? Turns out overall cancer risk is the same between both categories. Risk of lung, skin, and lymphoma is increased in both TNF inhibitors and in RA with no difference. Melanoma and leukemia possibly increased with TNF, possibly increased in RA, but no great data. Colon and breast decrease in RA, decreased with TNF inhibitors. Isn't it really the RA that causes the cancer risk — and by RA I mean inflammation — that applies to other diseases and not the drug.
I want you to know there's very good data out there that the more inflammatory the patient, the higher the risk. A study by Baecklund from Sweden showed that in high inflammation, stage four functional classes, the odds ratio goes from one to over 70-fold higher with the highest degree of inflammation. Another cohort study looked at the risk of lymphoma. Prior to the onset of RA, patients had no increased risk of lymphoma. After RA
they got an increased risk of lymphoma but it took beyond 3 years to get that lymphoma risk. All other cancers were not increased after the onset of RA. Solid tumors — no increased risk. They got a solid tumor, give them whatever you want, TNF inhibitor or whatever. And then melanoma — there's studies that refute that.
Let's go on and talk about another cancer risk issue and that's JAK inhibitors. You know the Oral Surveillance study came out in 2022 that said that patients who were treated with a TNF inhibitor or a JAK inhibitor had a greater risk of major adverse cardiovascular events, malignancies mainly lung and lymphoma, and also serious infectious events and also venous thrombotic events. So this is a big issue because JAK inhibitors are approved and used for psoriasis, psoriatic arthritis, ankylosing spondylitis, radiographic, non-radiographic, atopic dermatitis, alopecia areata, psoriasis, polyarticular JIA, juvenile PsA, and now GCA. There's a lot of off-label use.
So the box warning says there's a higher rate of all-cause mortality, including cardiovascular mortality and sudden cardiovascular death on a JAK inhibitor. And that's a label for all the JAK inhibitors even though that data was only proven for tofacitinib. There's a higher risk of malignancies, especially lymphomas and lung cancers. There's a higher rate of major adverse cardiovascular events — that means myocardial infarction, cardiovascular death — and a higher risk of thrombosis, both venous VTEs and arterial, and those warnings are out there for all the drugs.
The issues for you that you need to know: one of the things very important in the analyses of that Oral Surveillance study, also called the 1133 study — it was proven that the people who are at higher risk of CV events and malignancy were not just the patients included in the trial, which are over the age of 50 with a risk factor. It was over the age of 65 who were smokers and had a history of MI. Those are the ones that got all the bad outcomes. So an RA or PsA patient who's 55, doesn't smoke, never had an MI — I'm not going to bat an eyelash about using a JAK inhibitor. But the package insert for all JAK inhibitors says that you should use a TNF inhibitor before using a JAK inhibitor. That's what the package insert says. But I'm giving you data that says that the package insert isn't always right.
On VTE risks: risk goes up with age, obesity, inflammation, disease activity, and most importantly, having had a prior VTE or arterial thrombotic event. You don't want to use a JAK inhibitor in those people. There are many other options. Overall, with JAK inhibitors, risks are low. But when you have a patient who's on those drugs, you have to have that discussion — discuss with them and let them decide, and you tell them what you think based on the data.
I'm going to end up here with a sort of fast lightning round on other newer drugs. Drugs that are incredibly safe that are out there right now include bimekizumab and abatacept. Their safety profiles look really quite good — almost no discontinuations due to safety events, no unique safety issues related to bimekizumab, although the package insert does say there were more mortalities on bimekizumab than on placebo, but that was very very low.
Abatacept — all of the package inserts with biologics say you can't combine biologics because it was studied a long long time ago with IL-1 inhibitors and TNF inhibitors and that wasn't good. So they now extrapolate that to all biologics. You should screen for TB with abatacept but not with bimekizumab. Abatacept has some modest risk of hepatic enzymes. There's a maybe higher risk of respiratory adverse events in COPD patients on abatacept, but generally it's a very safe drug.
IL-6 inhibitors — there are two out there. IL-6 inhibitors and JAK inhibitors all cause an increase in lipids, a pan-lipid increase seen in 20%, not thought to be an increase in MACE. And there's a study called the ENTRACTE study showing that when you compare people treated with tocilizumab versus etanercept — 3,000 patients, 3 years — there were numerically more lipid elevations with tocilizumab but no increase in cardiovascular death or MACE. But patients who have increased lipids, if they have any risk factor, should be put on a statin or lipid-lowering agent. Turns out a lot of patients are already on statins and that seems to be very protective.
With IL-6 inhibitors, there is a very low or non-existent risk of TB or hepatitis B reactivation. And with IL-6 inhibitors, there is a warning about colon and GI perforations — it's 2.6 per 100 patient-years, or 0.1 per 100 patient-years, with the two IL-6 inhibitors. Similar numbers are seen with the JAK inhibitors, but in the real-world studies it's shown that they're not increased. The bottom line is you don't want to use either JAK
inhibitor and IL-6 inhibitor in someone who's had a GI perforation in the past or someone who has problematic diverticulitis because diverticulitis plus steroids equals impending future GI perforations. If they have diverticulosis, you don't worry about that. It's not the same as diverticulitis.
Two more. One, IL-17 inhibitors — they do get a higher rate of candidiasis but it's single digit, it's very low, it tends to be just mucosal and almost never invasive candidiasis. That's good. Maybe the more worrisome issue is the recurrence of colitis in people on ixekizumab or secukinumab — very infrequent event, about one in a thousand, two in a thousand in Crohn's will develop Crohn's or also colitis. It's a little bit higher in the ankylosing spondylitis trials where there was a higher incidence, 3 to 7, 3 to 8 per 1,000 patient years. It rarely occurs, which is to say that patients with a history of colitis you may not want to use an IL-17 inhibitor as your starting drug. There are other options.
And then lastly, not a biologic but it came out during the biologic year — apremilast looks really, really safe. You can increase safety by using a starter pack where patients escalate from 10 milligrams once a day in the morning over a 6-day period to ultimately get to 30 milligrams twice a day. That lowers the overall discontinuation rate due to GI side effects. Most common side effects are diarrhea, nausea, headache. Less than 10% will get a 10% weight loss. Depression is a warning but it's not particularly increased in my experience. Diarrhea seen in 7 to 17% in multiple clinical trials and a few of these people have to stop the drug — it's too uncontrollable. In a few you can manage it either by reducing the dose, stopping temporarily, using probiotics, yogurt, whatever. It's a game you may want to play. That's it for this advanced practice program. There'll be more.
So for instance, RA — it's RA severity, RA inflammation — but we worry about the drugs that we use and risk of, for instance, serious infection, TB, opportunistic infections, heart attacks, shingles. And again, you need to know the data.
Here's a few important safety rules that you may not have heard. Number one, the longer you're on a drug the safer it becomes, which — the converse is — most of the really bad and important safety events occur very early, in the first 3 to 6 months of a drug. There are exceptions to that rule, but that generally applies to methotrexate, to TNF inhibitors, etc.
Second, the lowest dose of a drug isn't always safer. If you use a subtherapeutic dose to avoid safety, you may not be controlling the disease and then the disease takes over as far as safety risk. Meaning RA gets worse. Inflammation gets worse. Inflammation drives infection risk, as an example.
So the third rule, the riskiest thing that you may do is play it safe. Number four, never ask someone who knows less about how to manage a safety issue. Go to the expert, go to someone who really knows. Fifth, again, the patients and their inflammation are way riskier than the drugs that you use. Remember that.
And you need to know the numbers. The patient's got a risk. The drug has got a risk. It's all worsened by comorbidity. And interestingly, people who respond to a drug tend to have less safety issues. That's really interesting, but true.
Let's talk about serious infections. By definition, that's an adverse event — an infectious one — but it leads to hospitalization, morbidity, and mortality. Prior to the introduction of biologics in 1998–1999, the SIE — serious infection event — rate was 3 to 9 per 100 patient years; that's data from the Mayo Clinic. Then with the introduction of all the TNF inhibitors, then IL-6 inhibitors, abatacept, rituximab, and then the JAKs, the risk is roughly 2 to 6 per 100 patient years. When I say 6 per 100 patient years, I mean 100 patients followed for one year — six would get a hospitalizable or a serious infection that may merit IV antibiotics.
The interesting thing about biologics that are out there in the market is that they cause a non-significant doubling. They don't significantly increase serious infectious event rates, but they tend to double it. So there is a box warning for most biologics that says serious infections leading to hospitalization and/or death, including tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections, have occurred or been described. If a serious infection develops, interrupt the therapy until the infection is controlled, and then in some instances test and monitor for TB.
So there is this non-significant doubling in the trials — for instance, etanercept. People on etanercept had a 1% risk. People on placebo had a 1% risk. It didn't double. On the other hand, infliximab — people on placebo had a 3.4% risk and people on infliximab had a 5.3%. Golimumab was really no change. Certolizumab was 1% placebo, 3% on certolizumab. Those are not significant increases, but they could be in someone who's very sick.
So if you want to calculate someone's serious infectious event risk, go to the RABBIT risk calculator. It's RABBIT, from the German biologics registry. And they've got a risk calculator where you can calculate any person's risk based on their age, prednisone dose, number of prior DMARDs, prior SIE event, and current biologic, and it'll spit it out for you.
But the most common infections we see are non-serious infections — URIs and UTIs. They're the most common adverse event in all the clinical trials. And people not on these drugs, about half of them are going to get one in the next year. The problem is most of you wrongly stop a biologic for a cold, a sniffle, a temp of 100.8. And that's silly because the half-life for the drug is often more than two weeks and you're stopping it until they get over that. That makes no sense. I never stop. So these are common and don't stop them for trivial events. We'll talk about the rules for stopping a biologic in a few minutes.
But the risk of getting a serious infection as pertains to rheumatoid arthritis — rheumatoid arthritis is a really great model. It's very inflammatory. It's well studied. Again, the odds of getting an SIE in the next year are highest in people who have really bad RA, and that's RA disease activity, inflammatory disease activity, and also RA severity and
dability and deformity. Number one risk factor. Number two, steroids almost in any dose. But in mild patients, well controlled RA, you know, 5 milligrams not so bad. But in really badly controlled patients, 5 milligrams is not good. In people who are stable, well controlled, they shouldn't be on 10 or 15.
All right. The third greatest risk are comorbidities. And the number one comorbidity is lung disease, COPD, ILD. But then other comorbidities also — heart disease, renal disease, diabetes. Number four, cutaneous breakdown. Which is why number five, major joint surgery. When you cut the person open, you're opening up the skin. The number one barrier against infection. This also applies to wounds that won't heal. So there is very little or no risk imposed by conventional DMARDs, and then biologics pose that very small risk but it is significant in some people.
Okay. So rules that you can live by. Number one, infection is related to activity and inflammation more so than the drug. We said that. Number two, NSAIDs, URIs, UTIs are way too common to freak out about and stop the drug. Number three, steroids are the most dangerous drug you use. Number four, biologic adds an infectious risk primarily in people who are very poorly controlled, most inflammatory, highest risk otherwise. Number five, only hold a biologic when the patient is hospitalized or they have a fever greater than 102. Again, never ask someone who knows less than you or less than me about what to do about infection. Most of those people, including infectious disease experts, are getting their education from television. If you want to reduce risk, reduce steroids, control inflammation, and control or manage comorbidity. And then the way you really manage infection risk is by screening tests like hepatitis B, hepatitis C testing, vaccination, and then having a high index of suspicion.
Let's talk about TB because most of the biologics say you should test for TB before using the drug. You need to know the risk in the United States. The risk of getting TB is 4 per 100,000. It's very low. It's the same in other developed countries like Australia, UK, Western Europe. But the RA, rheumatoid arthritis TB risk is about 6 to 7. So it's not much higher. RA poses a very small risk in itself. On the other hand, we're talking about RA risk in mainly developed countries. What you need to know is in developed countries, the risk is really low. But in endemic countries where TB is very common — I call that TB land — the risk is not 4 or 6 per 100,000. It's 250 to 12,000 per 100,000. So a 50 to 2,000-fold higher risk if your patient was born in Southeast Asia, in Russia, in South America, in South Africa. A number of countries have a high endemic risk. They're the ones who really need testing and you need to worry about and have a lower threshold to treat.
So TB and opportunistic risk is primarily an issue of TNF inhibition. Why? Patients who have TB, non-tuberculous mycobacterial infections, invasive fungal infections — those infections are controlled by the body because the body builds granulomas around them and sequesters them, and the granulomas are very protective unless someone gets immunosuppressed or gets very old. But what do you need to make granulomas and to maintain them over time? You need TNF, more TNF, and a little bit of gamma interferon. So it's only the drugs that inhibit TNF that really cause breakdown of granuloma and spread of TB. Right? So that's what you need to worry about. So in a TB issue and you don't know what drug to use, or a past issue of candidiasis and you don't know what to use, don't use a TNF — use another MOA.
The number needed to harm to get TB with a TNF inhibitor is somewhere around 500 to 600 patients. All the TNF inhibitors have a box warning that says tuberculosis screening is required. For most biologics, for TNF inhibitors, it's also required — by the way, for all JAK inhibitors, all IL-17 inhibitors, for all IL-6 inhibitors, and interestingly only for canakinumab, the IL-1 inhibitor. The other two IL-1 inhibitors you don't have to require it, because that's the way the trials were done. And requiring TB testing really means that that was done in the development studies of the trial more so than there's a risk imposed by that MOA. So we know the MOA at risk is TB and TNF. Right? All the other ones, not so much.
But you don't have to do TB testing for methotrexate, azathioprine, mycophenolate, apremilast, anakinra, rilonacept, rituximab, belimumab, ublituximab, and peglocase. Now you want to do it, go right ahead. The patient's from a high-risk area and having other issues, go ahead and you can do it. But here are the rules that I published before with Kevin Winthrop and Catherine Dao and Richard Chaisson from Hopkins. Number one, everyone should be screened for a latent tuberculosis infection, LTBI, prior to using a TNF inhibitor. You screen with either skin testing, TST testing, or a PPD test, or a blood test, an IGRA, an interferon gamma releasing assay. When do
you use an IGRA test? When it's available and when there's a history of BCG vaccine, because patients who have BCG vaccine have the same antigens as does tuberculin skin test and you can have a prolonged positive tuberculin skin test PPD related to BCG. You want to uh get rid of that problem, then use IGRAs that don't have the same antigens.
Number three, a BCG vaccinated person should be tested for LTBI because if they come from TB land where they got BCG and they now have positive results 20 years later, it's more more more likely to indicate LTBI or current infection than you know positivity incurred with BCG, because you do get TST positive after BCG but it wanes over time, especially in adulthood, especially 20 or 30 years later. So a positive result is worrisome.
Four, either PPD or IGRA positivity is evidence of infection. You now have to figure out whether it's latent or active. The way you actually do that is number six, with a chest X-ray, which is helpful in diagnosing active TB. No symptoms, negative chest X-ray, and a positive TB test of any kind is the definition of latent tuberculosis infection.
Um, number seven says PPD testing should only be repeated upon reexposure or new increased risk, which largely means reexposure. Annual testing is not recommended, although it is done by the National Psoriasis Foundation guidelines, and they're wrong. Ask the TB experts, they'll tell you.
Um, number eight, patients with a documented history of adequate treatment of either latent TB or active TB can safely be treated again with a TNF inhibitor. Let me say that again. If they've been adequately treated, then they can get a TNF inhibitor in the future.
LTBI. Uh, again, um, what that means is that if you've proved that, you need to initiate TB therapy before giving back the TNF inhibitor. So unlike active TB where it's really not known how long you wait, generally people say 4 months — with LTBI, no symptoms, negative chest X-ray, positive test, you give one month of INH and then you can start the TNF inhibitor. And yes, that is per FDA and in consultation with all the TB experts in the United States.
And lastly, guidelines do not recommend screening for conventional DMARDs including methotrexate.
Who should not restart their TNF inhibitor? The people who have had invasive fungal infections, atypical mycobacterial infections, active hepatitis with hep B surface antigen positivity, um, and patients who had intravesicular BCG treatment for bladder cancer. Now in a few of these — the first three: hepatitis, NTM infections, and invasive fungal infections — if you have to give back because you have no other options, you can prophylax them with uh antiviral therapy for hepatitis, antifungal therapy for um you know uh invasive candidiasis, or um prophylactic therapy for NTM. BCG you really can't prophylax uh safely.
Hepatitis B testing. Everyone should be tested for hep B surface antibodies, but also hepatitis B surface antigen, core antibody, and surface antibody as well. Okay. Uh, and by having those, if they're all negative, you're free and clear and don't need to worry about that.
Um, but what if the patient has an occult infection? That means that they have um B surface antigen, which is the most worrisome. Anybody with B surface antigen positivity um is really at um risk — okay, really at risk — and shouldn't receive TNF inhibitors, probably not abatacept, probably not a B cell depleter, okay, um, and probably should be referred to a hepatologist.
But let's say the patient is hepatitis B surface antigen negative but core antibody positive, meaning they had a past infection. If they happen to be surface antibody positive, that means they were probably previously vaccinated. Those people are at very low risk and I use TNF inhibitors in them all the time, all the time in those people. They have a 1% chance of reactivating.
Beyond that, you know, e-antigen positivity and other combinations, you probably should get a consult with a hepatologist to know how to proceed and figure out whether the patient needs prophylaxis.
Again, vaccination is the way to go. Our patients should be vaccinated against pneumococcus because we use a lot of steroids, because they get older, because they're immunosuppressed from the therapies. The best way to avoid — best way to explain which pneumococcal vaccine you can use — you can look at the slide uh that's attached to this, and just if they've never been vaccinated, give them the PCV20. That's the newer Prevnar 20 that was approved I think in 2021, and you give it one time and you're done for life. If people previously received Pneumovax, they have to get a repeat after five years and then you also use PCV20. But look at the ACIP guidelines on how to vaccinate.
What we do know about our drugs in vaccination is that rituximab and B cell depleting therapies really markedly reduce humoral responses and should not be given in people who are on um rituximab and the like. Right. Uh, the other drug that
markedly reduces vaccine responses is methotrexate but we have a fix for that and what I'm not saying is that all the other drugs you can safely use vaccines — influenza, Pneumovax, the shingles — Shingrix, it doesn't matter if you're on azathioprine, antimalarials, low doses of steroids, leflunomide, sulfasalazine, most biologics safe to give vaccination on but if you're on methotrexate. The rule from a good study done by Park and colleagues shows that you can — you're going to give influenza, you're going to give any vaccine, Pneumovax. Basically, what you do is you stop methotrexate for one week, give the vaccine and resume methotrexate a week later. The patient doesn't flare and they have exactly the same immunogenicity from the vaccine as if they weren't on methotrexate.
You need to worry about using live vaccines. You can look at the slide that accompanies this talk that says that live vaccines that should not be received on biologics include nasal influenza. Injectable influenza is good, right? The usual one that's given to everyone except for the high dose. Oral typhoid, yellow fever, varicella, Zostavax, which we don't use anymore. MMR, these are all live virus vaccines. BCG, oral polio, smallpox, rotavirus, and a few others. Again, you don't use live virus. The rule is if they're on a biologic and they need to get a live virus vaccine — you're going to do international travel, whatever — you need to give it before they get their biologic, or be off the biologic for at least four weeks, give the vaccine, wait two weeks, and then restart. That's a rule the CDC came up with.
A little bit about Shingrix. This is the herpes subunit vaccine which has an adjuvant, approved in 2017 based on the ZOE-50 and ZOE-70 studies, which basically says people over the age of — normal people over the age of 50, over the age of 70 — this drug works great at preventing shingles. It's 90% effective in preventing it. It's 90% effective at preventing post-herpetic neuralgia. Why would you not use this? The bottom line here is it's two shots. You get one and then you get the second one two to six months later. Up to a third of people get constitutional manifestations. Very, very low risk of flare and this is highly effective. I use this in everybody that goes on a JAK inhibitor because compared to a TNF inhibitor, JAK inhibitors cause a 5 to 10-fold higher risk of shingles. So I vaccinate everybody with Shingrix if you're going to go on a JAK inhibitor.
Some — let's talk about cancer. I want you to know that most of you are very afraid of cancer. That's fine. But you need to know the data is much more reassuring than you know. Guidelines say that people with a solid cancer can receive any drug that you want to give them. And by solid cancer I mean lung cancer, skin cancer, pancreatic cancer, tongue cancer, you know, any solid tumor, any non-hematologic — you know, lymphoma is another story. There's good evidence that biologics do not cause cancer and do not worsen cancer outcomes, meaning it does not alter mortality. It does not increase the risk of cancer recurrence. And TNF inhibitors don't cause melanoma, right? And biologics can be given in people with melanoma. There's a little bit of evidence out there that you maybe should worry. It's from one study and there are other studies that have refuted it. So again, you should treat the arthritis. Let the oncologist manage the cancer is my guideline.
In rheumatoid arthritis, the prototypic inflammatory disorder, the risk of cancer is not increased — an SIR of one, standardized incidence ratio. But that's not really true because there are certain cancers in RA that are increased. Lung, lymphoma, melanoma, and skin cancer — non-melanoma skin cancer. They're increased in all RA studies with all drugs or no drugs. That's the pattern you see in RA. Interestingly, RA has a lower risk of breast and colon. So when that all kind of evens out to a no risk, an SIR of one.
Now, does the rheumatoid cause the cancer risk or is it the TNF inhibitor? Turns out overall cancer risk is the same between both categories. Risk of lung, skin, and lymphoma is increased in both TNF inhibitors and in RA with no difference. Melanoma and leukemia possibly increased with TNF, possibly increased in RA, but no great data. Colon and breast decrease in RA, decreased with TNF inhibitors. Isn't it really the RA that causes the cancer risk — and by RA I mean inflammation — that applies to other diseases and not the drug.
I want you to know there's very good data out there that the more inflammatory the patient, the higher the risk. A study by Baecklund from Sweden showed that in high inflammation, stage four functional classes, the odds ratio goes from one to over 70-fold higher with the highest degree of inflammation. Another cohort study looked at the risk of lymphoma. Prior to the onset of RA, patients had no increased risk of lymphoma. After RA
they got an increased risk of lymphoma but it took beyond 3 years to get that lymphoma risk. All other cancers were not increased after the onset of RA. Solid tumors — no increased risk. They got a solid tumor, give them whatever you want, TNF inhibitor or whatever. And then melanoma — there's studies that refute that.
Let's go on and talk about another cancer risk issue and that's JAK inhibitors. You know the Oral Surveillance study came out in 2022 that said that patients who were treated with a TNF inhibitor or a JAK inhibitor had a greater risk of major adverse cardiovascular events, malignancies mainly lung and lymphoma, and also serious infectious events and also venous thrombotic events. So this is a big issue because JAK inhibitors are approved and used for psoriasis, psoriatic arthritis, ankylosing spondylitis, radiographic, non-radiographic, atopic dermatitis, alopecia areata, psoriasis, polyarticular JIA, juvenile PsA, and now GCA. There's a lot of off-label use.
So the box warning says there's a higher rate of all-cause mortality, including cardiovascular mortality and sudden cardiovascular death on a JAK inhibitor. And that's a label for all the JAK inhibitors even though that data was only proven for tofacitinib. There's a higher risk of malignancies, especially lymphomas and lung cancers. There's a higher rate of major adverse cardiovascular events — that means myocardial infarction, cardiovascular death — and a higher risk of thrombosis, both venous VTEs and arterial, and those warnings are out there for all the drugs.
The issues for you that you need to know: one of the things very important in the analyses of that Oral Surveillance study, also called the 1133 study — it was proven that the people who are at higher risk of CV events and malignancy were not just the patients included in the trial, which are over the age of 50 with a risk factor. It was over the age of 65 who were smokers and had a history of MI. Those are the ones that got all the bad outcomes. So an RA or PsA patient who's 55, doesn't smoke, never had an MI — I'm not going to bat an eyelash about using a JAK inhibitor. But the package insert for all JAK inhibitors says that you should use a TNF inhibitor before using a JAK inhibitor. That's what the package insert says. But I'm giving you data that says that the package insert isn't always right.
On VTE risks: risk goes up with age, obesity, inflammation, disease activity, and most importantly, having had a prior VTE or arterial thrombotic event. You don't want to use a JAK inhibitor in those people. There are many other options. Overall, with JAK inhibitors, risks are low. But when you have a patient who's on those drugs, you have to have that discussion — discuss with them and let them decide, and you tell them what you think based on the data.
I'm going to end up here with a sort of fast lightning round on other newer drugs. Drugs that are incredibly safe that are out there right now include bimekizumab and abatacept. Their safety profiles look really quite good — almost no discontinuations due to safety events, no unique safety issues related to bimekizumab, although the package insert does say there were more mortalities on bimekizumab than on placebo, but that was very very low.
Abatacept — all of the package inserts with biologics say you can't combine biologics because it was studied a long long time ago with IL-1 inhibitors and TNF inhibitors and that wasn't good. So they now extrapolate that to all biologics. You should screen for TB with abatacept but not with bimekizumab. Abatacept has some modest risk of hepatic enzymes. There's a maybe higher risk of respiratory adverse events in COPD patients on abatacept, but generally it's a very safe drug.
IL-6 inhibitors — there are two out there. IL-6 inhibitors and JAK inhibitors all cause an increase in lipids, a pan-lipid increase seen in 20%, not thought to be an increase in MACE. And there's a study called the ENTRACTE study showing that when you compare people treated with tocilizumab versus etanercept — 3,000 patients, 3 years — there were numerically more lipid elevations with tocilizumab but no increase in cardiovascular death or MACE. But patients who have increased lipids, if they have any risk factor, should be put on a statin or lipid-lowering agent. Turns out a lot of patients are already on statins and that seems to be very protective.
With IL-6 inhibitors, there is a very low or non-existent risk of TB or hepatitis B reactivation. And with IL-6 inhibitors, there is a warning about colon and GI perforations — it's 2.6 per 100 patient-years, or 0.1 per 100 patient-years, with the two IL-6 inhibitors. Similar numbers are seen with the JAK inhibitors, but in the real-world studies it's shown that they're not increased. The bottom line is you don't want to use either JAK
inhibitor and IL-6 inhibitor in someone who's had a GI perforation in the past or someone who has problematic diverticulitis because diverticulitis plus steroids equals impending future GI perforations. If they have diverticulosis, you don't worry about that. It's not the same as diverticulitis.
Two more. One, IL-17 inhibitors — they do get a higher rate of candidiasis but it's single digit, it's very low, it tends to be just mucosal and almost never invasive candidiasis. That's good. Maybe the more worrisome issue is the recurrence of colitis in people on ixekizumab or secukinumab — very infrequent event, about one in a thousand, two in a thousand in Crohn's will develop Crohn's or also colitis. It's a little bit higher in the ankylosing spondylitis trials where there was a higher incidence, 3 to 7, 3 to 8 per 1,000 patient years. It rarely occurs, which is to say that patients with a history of colitis you may not want to use an IL-17 inhibitor as your starting drug. There are other options.
And then lastly, not a biologic but it came out during the biologic year — apremilast looks really, really safe. You can increase safety by using a starter pack where patients escalate from 10 milligrams once a day in the morning over a 6-day period to ultimately get to 30 milligrams twice a day. That lowers the overall discontinuation rate due to GI side effects. Most common side effects are diarrhea, nausea, headache. Less than 10% will get a 10% weight loss. Depression is a warning but it's not particularly increased in my experience. Diarrhea seen in 7 to 17% in multiple clinical trials and a few of these people have to stop the drug — it's too uncontrollable. In a few you can manage it either by reducing the dose, stopping temporarily, using probiotics, yogurt, whatever. It's a game you may want to play. That's it for this advanced practice program. There'll be more.
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