®, “Practical Approaches to the Management of Plaque Psoriasis.”

I am Dr Mark Lebwohl, from the Icahn School of Medicine at Mount Sinai in New York.

Joining me today in this discussion are my colleagues Dr Erin Boh of Tulane University School of Medicine in New Orleans; Dr Leon Kircik, also from the Icahn School of Medicine at Mount Sinai in New York; and Dr James Song, North Sound Dermatology in Mill Creek, Washington.

Our discussion today will focus on the currently available biologic options to treat plaque psoriasis. In addition, we will discuss some real-world cases and the practical considerations to help manage plaque psoriasis in these patients.

Dr Kircik, I’m going to ask you to start for us and briefly review the pathogenesis of plaque psoriasis. Discuss the role of genetics. What are the other triggering factors for psoriasis. Leon?

 Mark, thank you for inviting me to this panel. Our understanding of pathogenesis of psoriasis has been ever evolving. The more we are learning, the more we find out that we know less. In the old days we thought the Th1 pathway was involved in pathogenesis of psoriasis. Now we know that IL-17 is the major cytokine that plays an important role in pathogenesis of psoriasis. Then we thought that IL-17, coming from Th17 cells, and the Th17 cells are propagated by IL-23.

Now we know that IL-17 is actually coming not only from Th17 cells but from many other cells including mast cells, microphages, lymphoid cells, and you name it. There’s a huge different resource of IL-17 that comes in.

Then we found out that now it’s not only IL-78 but also IL-17F and IL-17C play a major role, because when we do a biopsy from a psoriatic plaque, we found out that those cytokines are also increased in those lesions.

What do you think, Erin? Do you want to add something else to that? James?

 I do think that pathogenesis circles around this, these inflammatory cytokines. But we have to also keep in mind that other things can trigger that immune response. Looking at the whole picture, each individual is a prototype of which cytokines are in higher levels than in others. That’s why we see our clinical response variances in patients with the same phenotype psoriasis. It’s going to unfold and be quite interesting as we start looking at the individual and which pathogenic cytokine they make. Our targeted therapy will become very exquisite in the future if we can figure that 1 out.

 I would just mention that what’s interesting about psoriasis now is that we understand there’s this chronic feedback loop. Once it gets started, it’s really hard to shut that off. Even for patients who are well controlled on their biologic, when you stop therapy, those plaques seem to come back in the same areas. I think that speaks to the sense that there’s something more that’s going on. We’re understanding these resident memory T cells just lie resident in the skin. Even though they’re clearly invisible, you still may have those inflammatory cells there at the skin level. That will be really interesting, to see if we could get rid of some of those cells as well.

 That’s a really great point, James, that you brought up. That’s a hard issue: the scar of psoriasis, what’s going on underneath that we don’t see. The lesion is gone, but really it’s not. That brings up the issue of those several hundred dysregulated genes that we have in psoriasis patients, either up or down.

Now we’re getting some data with new biologics that actually these dysregulated genes are being regulated, and that’s why we’re seeing these longer clinical results that we see with the geobiologics that we have.

Pathogenesis of Plaque Psoriasis and Triggering Factors

 Let’s go further. Erin, I’ll ask you this question. What are the clinical manifestations of plaque psoriasis? Can you discuss the progressive nature of the disease and the risk for developing other diseases, other comorbidities?

 Psoriasis is a chronic inflammatory immune-mediated process. What we would expect are red scaling plaques. Classically we see them in the elbows and knees. You’ll see scalp involvement in some patients. You’ll see genital. But the classic distribution all of us are familiar with is elbows and knees. Lower back is another common area. And we want to keep in mind that they have a characteristic look, barely sharply demarcated. Actually, as James suggested, they do tend to come back in the same location. We’ll have patients who classically get the same areas of involvement over and over.

What I like to do is look to see what areas are affected, and then I like to then describe in terms of, is it a very little amount? We separate them into mild, moderate, and severe. But I do like to include severe categories: genital, scalp, nail psoriasis. Those are very difficult to treat, and it puts us in a different category.

 And palms and soles, absolutely. Usually psoriasis is a disease that starts in adolescents, but we have a lot of children who do have severe psoriasis. But I do think it starts at a young age. I like to tell people it’s 2 modes of appearance. One around adolescence, 17, 20 years old; then it pops back up in the early 60s. Again, the progression is you start sometimes with mild disease and over time—as our external triggers come into play, other comorbidities are forming—we see a more severe progression or more extensive progression of disease.

I do think we see this march from mild to moderate psoriasis in younger people. As you get older— again, those comorbidities are in part responsible from the pathogenesis of psoriasis—we’ll see other comorbidities tending to make the psoriasis become more and more severe. Especially in regard to psoriasis; most of us see that, in terms of arthritis. Most of us see that arthritis tends to be more problematic with people who had severe disease, recalcitrant disease, or disease presenting in childhood or young adulthood.

I watch for that—patients with severe disease. I’m going to be on the lookout for arthritis developing a little later, maybe 5, 10 years after psoriasis. I like to prepare for that with whatever we choose for treating the disease. And it does tend to get a little more progressive and extend over time, and we start to see comorbidities come into play, which contribute to severity of the disease.

 One thing Erin brought up about the arthritis, they did a study and about 87% of the patients who did not have a psoriatic arthritis diagnosis actually had aches and pains and discomfort. It’s very interesting. As we mentioned, those patients will develop—well, we don’t know how many of them, but eventually some of them will develop psoriatic arthritis. In Europe they are doing studies now looking at those joints with the sonogram and ultrasound, trying to find out, which is very interesting. We don’t have it here yet at this clinic, and they’re able to see the joint damage. Because as you know, the disease progression in psoriatic arthritis is crucial. It can be prevented early on with the appropriate treatment so we can prevent disability.

 Leon, you mentioned that, and it’s a good point. Patients don’t out-and-out say, “I have joint pains. I have arthritis.” They have aches in their skin, or they have fatigue, and then they don’t realize how many arthritic complaints they had until they get on therapy and it goes away. We think of it as arthritis, but patients with psoriasis routinely don’t say, “Oh, this is arthritis.”

 Actually, most of them don’t even know that 1 relates to another, right?

 When I ask them about their joints they say, “Doc, I’m here for my skin. What’s wrong with you? Why are you asking me about the joints?”

 Yeah. What’s interesting is, we’re taught that the more severe your skin psoriasis is, the higher the risk of a psoriatic arthritis. That’s certainly true. But just in the real world, when we talk to our rheumatology colleagues, the majority of their arthritis patients who have pretty limited skin psoriasis. When you look at the data, you know up to 50% of arthritis patients will have mild to moderate psoriasis. We just need to remember that even though their plaques might be limited, they’re still at a higher risk for psoriatic arthritis.

And the other thing—I just wanted to switch gears really quick—is pediatric psoriasis. I’m not a pediatric dermatologist, but I have recognized that sometimes the plaque in pediatric patients could look different. They may not be as dark. They may be much lighter pink, much finer scale. Sometimes it’s like, is this psoriasis or is it eczema? I didn’t think they could coexist. But yes, they can coexist. In our pediatric patients that seems to be more common. I just wanted to point that out.

 Fortunately—getting back to arthritis—we don’t have blood tests to tell us if the patient has psoriatic arthritis. The joints, especially early on, will look normal. And the patient goes to a rheumatologist and gets an x-ray and they say, “The x-ray is normal.” So they say, “I don’t have it.”

But in fact, if they have morning stiffness that lasts 30 minutes after they wake up and they’ve got psoriasis, they’re already headed to that diagnosis. They’ve got several of the criteria for that diagnosis. When we have a serologic marker, a blood test, it will expand the population of patients we use. Things like bone marrow edema on MRI, when that’s been looked at, is dramatically increased in psoriasis patients compared with the general public. We hear a number of 10% to 30%. When we have sensitive methods of diagnosing, it will likely do more.

Clinical Manifestations and Progressive Nature of Psoriasis

 Good question, thanks. We have our more recent guidelines for how to approach a patient with psoriasis, so the AAD [American Academy of Dermatologists] and the NPF [National Psoriasis Foundation] have updated their guidelines. That’s a good source for people to look at.

In general, what I like to do is separate mild, moderate, and severe. When patients have limited disease and no other systemic complaints, topical therapies are still going to be the mainstay of therapy. What we’re addressing today though gets you past that. Again, the chronicity of the disease warrants in general a different approach from just topicals, unless the disease is quite limited.

Because mild disease is less than 3%, topicals are fine. When you’re in that middle range of moderate, to moderate to severe, so 5% to 10%, with no comorbidities, phototherapy is a very useful therapy to look at topicals. Sometimes we even rely on systemic therapies for that.

If you get to severe psoriasis, which is greater than 10%, that’s when the door opens for all these choices. The way I approach it is limited disease. I use topicals and phototherapy unless the patients tell me they are quite bothered by their disease, or they complain of fatigue, tiredness, frustration. They get depressed having to do topicals for years. I do move on to systemics and to biologics probably earlier than many, but I think it’s warranted, especially in patients with comorbidities, because I want to stop progression of the comorbidities if I can.

When I get to patients who have 10% or greater, or they have psoriasis in the genital, the scalp, palms and soles, areas very difficult and not amenable to topical therapy or phototherapy, I will try to go straight away to the biologics, especially if my insurance companies allow it; they often don’t. I set the stage very early and start people on systemic therapy. Even if I start them on methotrexate and I give it to them and tell them, “Don’t take it; take it; whatever.” I get them on biologic as soon as I can, and I use as my index of choices what their other comorbidities are, or what they have been treated with in the past and their response.

I like to move early on to systemic therapies because this disease is 1 of chronicity; it’s 1 of foreverness. If we can intervene and make people more comfortable and possibly mitigate some of the effects of comorbidities, we really should do that. And the biologics are the way to go with doing that.

 We’ve spoken a lot about psoriatic arthritis and other comorbidities. What factors will tell you to use 1 biologic over another? Start with psoriatic arthritis, for example. We can talk about obesity, diabetes, cardiovascular disease, history of malignancy. There are many things that influence our prescribing patterns. What would play a role here? I’ll ask each of you to pick a comorbidity and show how it would influence your pattern of prescription of a biologic.

 Mark, that’s your lecture at the Mount Sinai [Winter Symposium].

 I’ll tell you a story. I was once invited to give this lecture to a group of patients at the [National] Psoriasis Foundation [Residents] Meeting. I came in the room and there were over 100 patients in the room. I said to everyone, “I want you to stand up.” And I said, “I’m going to read a list of signs and symptoms and conditions. I don’t want to embarrass anyone, so don’t sit down until the end. But if you have any of these conditions, at the end I want you to sit down.”

We started with, “Do you have joint pains or psoriatic arthritis? Are you obese? Do you have cardiovascular risk factors? Smoking, hypertension, diabetes, family history of heart disease? Have you had a malignancy? Do you have or has someone in your family had multiple sclerosis, Crohn disease, lupus?” I went through a long list of different comorbidities. Then I said, “Anyone who had any of those diseases, sit down, because they all influence the prescription, we’ll give you.”

At the end, of more than 100 people in the room, 1 person was left standing. [Laughter.] Clearly, when insurance companies say to us, “Here’s our order. You’ve got to give this drug first and that drug second,” they don’t care. They don’t care about the patient. They’re getting more money from Company A to give that drug, even though the patient might have a history of squamous cell carcinoma, which is caused by that drug. They just don’t care. For example, you mentioned, Erin, palms. Some of the drugs are fairly well; some don’t work at all. Take the comorbidity and tell me how it would influence your prescribing pattern. Leon, why don’t we start with you?

 The simplest 1 is psoriatic arthritis. If the patient has a psoriatic arthritis, I’ll shy away from IL-23; I will not do an IL-23. If I can, I will start them on an IL-17 drug. If I can’t, usually we have to use a TNF [tumor necrosis factor]–alpha inhibitor first, which is fine. I can use a TNF alpha inhibitor first, and actually American College of Rheumatology recommends first-line drugs for psoriatic arthritis with a TNF-alpha inhibitor. The problem is, they may not work as well on the skin. If the patient is obese, which most of them are, as we know, TNF-alpha inhibitors lose their efficacy in obese patients.

 It’s a catch-22.But that’s what I would be doing.

If a patient has IBD [inflammatory bowel disease], I would certainly avoid IL-17. I will not use an IL-17. I would pick a drug such as IL-12/23, which is approved both for IBD as well as psoriasis.

 I agree with you, Leon. It’s interesting: The American College of Dermatology [Clinical] Guidelines, almost came out too early in the course of the data we now have on IL-17 inhibition. The IL-17 blockers are safer and as effective as TNF blockades. Also, new data are that most of the drugs, even ustekinumab, which is not the best drug for psoriatic arthritis, is approved for psoriatic arthritis. But recently guselkumab released data. It’s interesting: If you give that drug every 4 weeks—and you know it’s only approved for every 8 weeks, but if you give that drug every 4 weeks—not only does it give comparable reduction in ACR [American College of Rheumatology] scores to the every-8-week administration, but interestingly it was statistically significant in preventing the radiographic progression of joint disease. That is something the TNF blockers and IL-17 blockers certainly do. If they get approval for every 4 weeks, they may also enter that competition there.

 You know it’s ironic because it always requires more drug than all other drugs. But in this case, the joint is requiring more.

Factors That Influence Choice of Treatment for Plaque Psoriasis

 Mark, you mentioned multiple sclerosis, your current typical inflammatory central nervous system disorder. Certainly, we have seen new cases as well as exacerbation of preexisting cases of multiple sclerosis—optic neuritis demyelinating disease, etc—with a TNF [tumor necrosis factor]–alpha inhibitor class. That would be 1 that I would certainly avoid. We actually have data that maybe the IL-17 inhibitors could potentially help multiple sclerosis. I think I’d lean more toward that. Ustekinumab was actually looked at in multiple sclerosis too. Maybe more of a neutral effect doesn’t hurt it but maybe doesn’t really benefit as much.

For anyone with a history of that, I probably would maybe favor an IL-17 or an IL-23 inhibitor, although we’d probably need more data on that class.

 Obesity is 1 that that’s tough for many of us, especially for those patients who have some arthritis as well as obesity of metabolic syndrome. One of the things I like to go to when people have both is obviously something like infliximab, which not a lot of people use, and it’s got a lot of baggage. But it is useful sometimes for people who are very, very obese because it is weight based.

We have some other quasi-weight-based therapies, but I think infliximab is probably the best of them. Having said that, the newer drugs—the IL-23s—seem not to be as influenced by weight as the earlier drugs. I tend to now move a little more to the IL-23s because they do work well. It’s just that they’re, at least in my hands, not as effective for arthritis early on. If we stay the course and you get people on it for 4 or 5 months, then I see much more improvement with those, and they’re not as much in the weight-based category. But obesity is a tough one.

One thing I wanted to throw out and ask this group: The group I have most trouble with deciding—not deciding but getting a drug for, especially biologics—are our patients in the Medicare range. At least in our area, they are cutoff from everything except infliximab. It’s not that the insurances don’t approve them. Medicare approves them, but there is no way patients can pay for them. I would like to hear what you all do for patients who are in the Medicare range and their insurances don’t really pay for it. They approve it, and by approving it, the drug companies can’t give them drugs. In my area those are the patients I just scratch my head over, and I don’t know what to do with them if they can’t do infliximab.

 Put in perspective, the drug companies are not allowed to give coupons, discounts to the patients. The patients who have, for example, Medicare Part D, have a large doughnut hole, and then they’ve got to pay 5% of the cost of the drugs. If you have commercial insurance and you’re not a Medicare patient, that can be dealt with by the pharmaceutical company; they give you a discount. They can give you even a credit card that pays for that balance. But if you’re a Medicare patient, that’s against the law. I have my solutions. Leon, what would you do?

 A drug that has medical benefit rather than a pharmacy benefit—infliximab is 1 of them because of IV [intravenous] infusion, but the easiest 1 is still tildrakizumab. So tildrakizumab, because it’s given in the doctor’s office, is the only drug. Ustekinumab used to be like that but not anymore. With tildrakizumab you can get a medical benefit directly, but you have to buy and then charge Medicare directly. And you actually get about 4% or so revenue back, because you have the right to be able to charge 104% of AWP [average wholesale price]. It’s really a good deal for the patients, a good deal for us in all honesty.

Speaking of the metabolic syndrome, they have a recent poster. Mark, it was you or April Armstrong who was able to show that in the efficacy, there is no difference between patients with metabolic syndrome and no metabolic syndrome. That was a great eye-opener. It’s the first one I have seen in biologics; they did a really nice study. You can kill 2 birds with 1 stone because most of those Medicare patients are old, have high blood pressure, have diabetes, are obese, so it’s a great combination of getting 2 things together.

Effect of Multiple Sclerosis and Obesity on Treatment of Psoriasis

 What we have done, we’re not buying and billing at this point. It may be something we consider in the future, but if you can find what they call an ASOC, that’s an Alternate Site of Care, so like a local rheumatologist or a hematologist, and they could inject them there, they’re just going to be paying their copays. And I think it’s the matter of having that relationship with an Alternate Site of Care. I go through the same thing, it’s really challenging. I don’t have a great solution.

 I will tell you what we do at Mt. Sinai. Tildrakizumab by the way is the only drug that is only approved for in-office use. It’s not supposed to be given in the patient’s home. The insurance company cannot say to you, “Oh, you have to give it to the patient to give it home.” Because once it’s given in the patient’s home, they can call it a pharmacy benefit and then they’ve got to pay the copay, they’ve got to pay the donut hole, and they can’t do that to tildrakizumab. So tildrakizumab is always a medical benefit. The other biologics that until now have been treated that way are ustekinumab, Risankizumab, and the other.

 And infliximab, of course; and I’m missing one of them. But the 323 blockers are TILDRA, guselkumab – they can be given in the office. The problem is that they’re also approved for at-home administration. And Medicare is threatening to remove that and put them on the self-administered drug list December 5th.

 Actually, that’s going to have January 1st, right with the new year.

 We’re worried that that’s going to happen because until now we are able to give those drugs. I will say, particularly applying to tildrakizumab, but also those other drugs, we actually had a dermatologist in Connecticut who’s having difficulty getting the drug. She does not want to pay the drug and take the risk that he won’t get reimbursed. And I told him at Mt. Sinai, you know the hospitals do great with this. They get 340B dollars they’re called. I told him, “You know we’d be happy to take care of your patients for you.” And he now sends his patients for one visit a year to what is called “The Biologic Therapy Clinic.” And it can even be done by video. And they take every insurance. They will pay for the drug, have the drug administered. And, of course, if it’s going to be tildrakizumab, they’ll have to come in four times a year to have it at Mt. Sinai.

But he continues to be their doctor and give them all their care. They actually never see any of us in the departments. They go to an infusion center where they get the drug administered there. He is the supervising physician. We’ve arranged for him to get an appointment in the department, so he’s joined my voluntary faculty. And it solves the problem for his patients because his patients have no other way of getting the drugs that they need.

It’s complicated, it’s difficult. The rules, by the way, Erin, are different in every State. But it took us a while to fight this at Mt. Sinai and we got it done for the good of our patients, and we were able to get it done so that they; a lot of our Medicare patients, like you said, are unable to afford those drugs because of the copays and donut holes and all of those rules.

Medical Benefit of Office Administration of Tildrakizumab

 What about women and child-bearing potential, or pregnant women? What’s your treatment of choice there?

 I think that’s easy. There is only one indicated biologic, right; TNF alpha inhibitors seems to be the only one.

 I think that’s really easy, it’s no brainer.

 Yeah. It’s the only one that doesn’t cross the placenta.

 I have a lot, not a lot, but I have a number of patients who are currently on biologics and then they get pregnant. And I’ve thrown this question out to the high-risk obese – do we switch them to certolizumab? Do we keep them on? And I can tell you, at least in my area, 9 out of 10 of the time they tell me, “Keep them on what they’re on, and discuss it with the patient.” Because if you look at the risks associated with just having bad psoriasis or psoriatic arthritis in pregnancy, the babies do fine but there is a tendency for low birth weight and a few other things, but not really anomalies. They think it’s more risky to switch to certolizumab as opposed to just staying on what they’re on.

I think when you have a young woman and she comes in and she goes, “I want to get pregnant in the next year, what do I do?”, certolizumab is where I go also. But if they’re already on it and they go, “Oops, I’m pregnant,” I have of late just, I don’t change them, I just keep them on it. But I said everybody – the high-risk OB – and work through it with them, and ultimately the patient and the OB and I make that decision.

 None of the drugs have been shown to be teratogenic. And in fact, I agree with what Erin said. You know there’s probably some risk to bad psoriasis that certainly in some patients outweighs any, even it’s really a theoretical concern about using biologics in these patients. Patients do fine during pregnancies, so far supports that.

 I think there’s a registry, isn’t there? I can’t remember the name.

 There’s several, mostly in the GI, the GIs have a very good history.

 And they keep them on it whether TNF or IL-12/23s, they just stay on their biologics.

 Yeah, certainly the risk of bad Crohn’s Disease is a lot worse for a pregnancy than the risk of any of the TNF blockers; or at this point, the 23 blockers that are coming out for that.

I’m going to ask James to tell us about your experience with the older biologists – TNF alpha inhibitors, ustekinumab, or the IL-17 inhibitors.

 Yeah, Mark. We have several classes of biologics and I’ll start with the first ones, the TNF inhibitors. We have three (3) subcutaneous injections, one’s an infusion. And to me this is a class that has been repurposed for dermatology. And what I mean by that is, all of these drugs are actually approved for a non-dermatologic indication, right? We’re talking Crohn’s Disease, Psoriatic Arthritis, Dermatoid Arthritis. And years later it turns out it works well for the skin too. And one of the advantages of having that is we have the most amount of experience with this plaque. I mean you have literally hundreds and thousands of years, of patient year experience. And for a lot of patients and clinicians, they feel better knowing this has been on the market for a decade and we’ve been using it for a lot of patients.

The other advantage though is you have a lot of indications. Some of these conditions are comorbid in their psoriasis patients, right? If someone has psoriasis and Crohn’s Disease, it’s a no-brainer. Use a TNF [tumor necrosis factor] inhibitor such as infliximab or adalimumab or certolizumab.

This is a double-edge sword though, and that is because some of the safety concerns that we have seen with the TNF [tumor necrosis factor] inhibitors, and in particular patient populations, may not apply to our psoriasis patients, right? For example, you look at hepatosplenic T-cell lymphoma, that’s a terrible lymphoma and very rare, but we only saw it in our GI patients that were getting a higher dose of adalimumab, and they were also being on other immunosuppressive agents. But because it’s the same drug and different indications, they get all the same labeling. And I feel like sometimes it’s a hard sell for patients when they see that on the package insert.

When it comes to efficacy, you know we typically use 75 percent improvement from baseline, which I’ll refer to as PASI(?) 75. The class does pretty well, and anywhere from 50 to 80 percent of patients will get PASI(?) 75, depending on the drug and the trial.

What I found made it a little bit more difficult is when our treatment goals get more ambitious and we’re looking at maybe 90 or 100 percent clearance, this class as a whole does struggle a little bit more I would say. Let’s take it down to the next class, the IL-12/23 inhibitor. We really just have one. That’s ustekinumab. And I think to me this is a milestone because this was the first biologic where it was approved for a skin disease first, and then you had the arthritis indication second. And as far as efficacy, just as good, perhaps better than some other TNF inhibitors. And you were able to dose these patients much less often. You’re not doing it every were or every other week, but you’re doing it every 12 weeks. And if you look at a lot of studies looking at kind of drug persistence, right, how long will the patients be on the biologic before they stop their medication, this class does very, very well. And I think some of that may be because of the favorable and dosing regimen, and the fact that a lot of these patients are still coming in for their injection.

Now we mentioned that ustekinumab also had a psoriatic arthritis indication. That’s true but maybe not quite as robust for the joints as it is for skin. I’ve had a number of patients where I made that switch from a TNF inhibitor to ustekinumab, and it did flare, they do flare. And so that’s something that we need to be mindful of.

As far as the next class IL-17 inhibitors, there’s three. There’s two that block the IL-17 a-cytokine, which is the most potent cytokine for psoriasis. And then we have a receptor blocker and about all pretty much where IL-17 will bind to. And then we have one in the pipeline that’s going to be blocking both IL-17A and IL-17F.

As far as efficacy, I would say some of the highest numbers we have seen with PASI 90, PASI 100, you know, somewhere in the 70’s to 80’s or PASI 90. And over half of patients are PASI 100, so I think that has set the high water mark for a lot of drugs. And as far as speed, I would say it’s unprecedented, and we are talking in just four (4) weeks 75 percent improvement with a lot of these patients. I think the skin deal looks really good. Arthritis there looks just as good as well. I mean we have now head-to-head studies with IL-17 inhibitors, and TNF alpha antagonists look just as good, maybe numerically better. We also have studies showing that people who have failed multiple TNF agents also do quite well with an IL-17 inhibitor. And lastly it works well not only for kind of a classic psoriatic arthritis, but we have some data showing it works along the spine too, which is a distinct disease.

I think the big knock against the IL-17 inhibitors is you have to dose these patients more aggressively, and they do require more injections upfront. And then of course you have the inflammatory bowel disease risk. It’s rare but it’s a real thing, something that we have to make sure we’re mindful of when we’re using those agents.

Experience With Using Older Biologics to Treat Psoriasis

 Leon, what about the adverse effects of the older drugs. I’ll concentrate perhaps on the really older drugs, which are the TNF [tumor necrosis factor] blockers—malignancies, infections, allergic reactions.

 It’s interesting. As I was getting ready for this, I looked at the TNF alpha inhibitors’ package insert, vs the IL-17 and IL-23. It’s 101 pages. Just to pick 1, adalimumab, the most commonly used TNF alpha inhibitor; it’s 101 pages. IL-17 is somewhere about 21, 18 pages. The most common one, tildrakizumab, is about 15 pages. The difference is amazing, right?

Given the fact that, as James [Song] mentioned, all the TNF alpha inhibitors tear the package because they came from the factor of the rheumatoid arthritis. They have the IBD [inflammatory bowel disease]. They have so many several other patient populations where they collect all these adverse events in their package insert. Regardless, they are still there, vs all the IL-17s and IL-23s that are directly studied for psoriasis. They have a much cleaner package insert.

But when we talk about adverse events, definitely serious infections, opportunistic infections are there, right, for the TNF [tumor necrosis factor] alpha inhibitors. Tuberculosis is a big 1. With fungal infections, you know we don’t think about it, but I’m in Kentucky, in the Ohio Valley, so histoplasmosis is rapid.

I always check histoplasmosis urine antigen, which is a cheap thing to do. I talked to the infectious disease doctor, she said, “Don’t do an x-ray. Everybody’s lung(?) is do a white(?) count(?) 

 and both. But if you do a urine antigen test, it’s easy, it’s cheap, and it is active when they have active disease.

So those are the more common ones. Now malignancies are really tricky. Most of the malignancies in their package insert comes from different populations. For example, lymphomas were seen mostly in kids and young adult males from IBD [inflammatory bowel disease], who were on mercaptopurine or Imuran, right? That’s where the lymphoma population comes, but it’s still there.

Certainly, CHF [congestive heart failure]. But that’s a problem because the drug was studied for CHF and didn’t show any effect, so it got into the label. Well, MS [multiple sclerosis] demyelinating diseases are there. But 1 thing we need to pay attention with the TNF alpha inhibitors is hepatitis B. We don’t think about it, but if somebody has hepatitis B, you should not be giving them TNF alpha inhibitors. That’s really a problem, and we don’t want to miss that, especially when we have other options. In the old days we didn’t, but now we do.

Having said that, there was a very nice article. About a year and a half ago they looked at meta-analysis of all cumulative biologics that patients were on from Europe. It included Israel, Italy, Spain, Ireland, a couple of other European countries. They have a nationalized health care system; they have great data. They took people and they age mixed, gender matched, and even weight matched with a normal population and compared all the malignancies. Actually, it says that there was no risk of cancers, they were not significantly associated with simulative exposures to biologics. Again, given all those things you will find in the package search for patients with psoriasis, the risk is there, but it’s minimal, just like anything else.

 Your discussion of that is fascinating because malignancies are a box warning. As you mentioned, many of the patients were inflammatory bowel disease, around 6 MP [6-mercaptopurine]. We actually assigned some medical students years ago to do a literature review on all of the malignancies reported in any of the patients on a biologic for psoriasis. And we accumulated it: There are a large number of malignancies. Then we looked at what dugs they were on, and it turned out that about two-thirds of them were on combination therapy, usually with a TNF blocker with 6 MP steroids, methotrexate, or some other combinations that you really could pin the malignancy and you couldn’t pin it on the biologic alone. It’s questionable.

But I will say that the black-box warning about malignancies does get me to go to other drugs. You know, the 17s and 23s have some data, and they’re animal data or cell tissue data, suggesting that they might actually be protectives. Whether that’s true or not, and I don’t know that it’s true, it does get me to prescribe that in the dose instead of TNF blockers in patients who have a history of malignancy.

 Mark, you have thousands of patients. I guess I have a lot as well. From a clinical observational standpoint, patients with psoriasis to me—even on the TNF—do not see an increased incidence of malignancy, even though the black-box warning is there. It doesn’t make me not go to the TNF. What you said is exactly on the mark. We tend not to treat with combination therapy for long term as they do in the GI [gastrointestinal] literature. And that’s the key: long-term immunosuppression. Thinking about efalizumab, we saw that that is not the way to go even with monotherapy. But these patients aren’t severely immunosuppressed with the biologics, even the TNFs that we have.

When I say I don’t worry about malignancy, I don’t make that a stopper for me. If a patient needs a TNF, I go to the TNF. I have actually put people back on anti-TNFs—once their malignancy has cleared—if there’s a reason they really have to have it. Again, in conjunction with the oncologists we have many other choices but sometimes we’re limited in what we can do. Malignancies are something we need to keep in the back of our head as a possibility or as a consequence of these TNFs. But it’s a very low risk in general. We just need to be aware that patients who are of certain populations will get malignancies. Age-related screenings are the way to go, and we just need to be up on that and not be scared to use any of these for fear of malignancy.

 I agree with you. Maybe the exception of squamous cell carcinoma of the skin, and people who got PUVA [psoralen–ultraviolet A radiation] a long time ago.

 The guy who’s getting 12 is getting 12 squamous cells a year. If he’s on a TNF blocker, he gets 20.

Adverse Events of TNF Inhibitors Used to Treat Psoriasis

 Let me turn to you, James. Can you tell us about what contraindications you have for the conventional treatment landscape with biologics? Are there any contraindications you have in your mind?

 Yeah. Leon and Erin did a good job of taking my thunder from me, but I would say the biologic class in general is so darn safe. You look at the contraindication list, and it’s really minimal compared with some of our systemic agents. I would say first and foremost, if you have a known hypersensitivity to that biologic, don’t use it. Right? It makes common sense, and we see that with all the drugs, not just the biologics, but that’s an obvious contraindication.

Active infections are big. Leon hit on this already. Active TB [tuberculosis], active hepatitis, active HIV, COVID-19 [coronavirus disease 2019]. Make sure these are treated first before we start. I think TB is interesting though because TB reactivation has been reported with a TNF [tumor necrosis factor] class. But we have some data with the newer biologics where some patients actually had treatment-emergent TB. They didn’t even treat those patients for TB. They left them in the trial, and we saw this both in ixekizumab and risankizumab. That’s a paradigm shift into thinking maybe we don’t necessarily have to be screening our patients regularly when they’re on some of these newer agents.

As far as hepatitis B, it’s important to know if it is antigen positive or antigen negative, poor-antibody positive? Because I agree that if they’re antigen positive, you probably want to stay away from the TNF alpha inhibitors. But if they’re antigen negative and they’re core-antibody positive, I’ve had a number of hepatologists who just make me order a DNA load, an LFT [liver function test] every couple of months.

As far as advanced congestive heart failure, which we would define as New York Heart Association [Functional Classification] III or IV, you probably want to avoid a TNF. It’s true what Leon was saying about the ATTACH trial, where they’re looking at infliximab for CHF [congestive heart failure]. It really didn’t show a benefit. It actually did worse, which is why it’s labeled that way. At least in theory, etanercept might help with some of the ventricular function. One can say maybe it will help, maybe it doesn’t. The conservative recommendation is don’t use it in someone who has advanced heart failure.

I think the IL-17 class, as great of a class as it is, you have the inflammatory bowel disease risk. What’s interesting is that psoriasis itself will increase the risk of Crohn disease, right? And some cohorts are 2-fold. The question is, is there risk of new cases of Crohn disease? Is that higher than what we are seeing with some of these IL-17 agents? To this point, it doesn’t necessarily look that way. That’s just important to recognize. Still, I would be cautious of that group.

Brodalumab, which is the IL-17 receptor blocker, is the only 1 that has this black-box warning. But anyone who has active suicidal ideation or a history of suicidal behavior may not want to go on that agent. Unfortunately, with the study design, they allowed certain patients to enroll in that trial, which other trials may have not. But because of that, unfortunately, that’s the way the drug is labeled.

I would say those are probably the main ones. We talked about malignancy. Blood tumors make me a little more nervous than solid tumors—leukemia, lymphoma. Most of these trials did allow people to enroll if they were free of disease for 5 years, right? We have data on that as well. Those are probably the main ones that come to mind.

 Sure. Do any of you have comments or examples that fit with James’s description. I’ll tell you about 1 that I saw today, and this is obviously off-label, not approved. TNF blockers are quite effective for sarcoid. A patient was sent to me who has severe skin sarcoid, but he also has sarcoid of the heart, and he has heart failure. We tried everything. We tried antimalarials, minocycline, a number of other treatments—nothing worked. Finally, he’s really desperate. So I dictated a letter to his cardiologist and his pulmonary doctor, who’s sort of the quarterback of the sarcoidosis, saying, “You know, the adalimumab pivotal trial showed fewer cases of heart failure in the active group than in the placebo group.” They all, unfortunately, got that warning from the infliximab study. And I’m trying to persuade them to allow him to be treated with adalimumab despite the heart failure, because I’m convinced it’s not going to make it worse, and it probably will benefit his sarcoid a lot. We’ll see if they let me do it.

Contraindications to the Conventional Treatment for Psoriasis

 I have a question to the panel. What do you guys do with patients infected with HIV?

 I can tell you, most of them, I start with the anti-TNFs [tumor necrosis factor inhibitors], mainly because of the comfort level, it’s in the literature. There have been several peer-reviewed publications looking at not worsening of the disease. In rheumatic disease, the patients with HIV did quite well on the anti-TNFs. So, I do not use that as a contraindication, period. As long as they’re on appropriate heart therapy and they’re being followed, I use that. I also will go to the IL-12/23s [interleukin-12 and 23 inhibitors]. For me, HIV is not a game stopper for anything. I don’t say it’s not an infection, but it is not one that I put into the exclusion category for any of these drugs, truthfully. We just follow along with ID [an infectious disease specialist] and get counts.

There was a published paper a few years ago looking at all of the anti-TNFs. They saw that the viral loads really didn’t change that much, with the exception of infliximab, where it was a little bit higher, but it didn’t change the course. I usually will start with etanercept because of its short half-life; if they get in trouble, I can take them off. But I will quickly, if they don’t respond, go to adalimumab if they need to, or the IL-12/23s.

I haven’t treated but 1 patient with HIV with the IL-17s [interleukin-17 inhibitors], but it’s only because they’ve responded to the others. I don’t think it should be much of an issue as long as they’re appropriately treated. And again, all of these I do in conjunction with ID or with any other specialist.

 I think there’s a lot that is different from one state to another, because in the past, we were told in New York, you had to fail the TNF blockers. And I’m not sure if it’s because I just make so much noise, I challenge everyone when they don’t let me give the drug I want. But I am never asked any more to fail a TNF blocker. They allow me to go to the IL-17s and the IL-23s, which I do view as being less immunosuppressive, and they’re very targeted.

In my patients infected with HIV, I do use an IL-23 or an IL-17. The one caveat there is moniliasis is increased if your helper T cells are down. That was one of the early findings in fact in patients infected with HIV. And of course, IL-17 makes you a little more prone. But we have used IL-17 blockers with no trouble in patients who are HIV infected.

I’m curious, James, and then Leon, do they let you go to the other drugs, or do you have to fail TNF- alpha blockers first?

 You mean only in patients with HIV, or overall?

 Well, overall usually it’s TNF-alpha inhibitors first. But it depends on the insurance. Sometimes it’s ustekinumab. They don’t have anything separate for patients with HIV, you just have to write a letter and explain the contraindication.

 It’s exactly the same situation here in Washington state. It depends on the payer, but for the most part the TNF-alpha inhibitors or ustekinumab are the 2 they prefer.

 Yes. I don’t know if it’s just me, but if they don’t give me the drug I want, I challenge it all the time. We do have the 340B drug pricing program here, and I think the federal law that protects that…the insurance companies probably are nervous about challenging those prescriptions. I find that our failure rate, when the prescription comes from our practice, which is not a 340B facility, is about 50%. When it comes from that clinic in the 340B program, it’s less than 10%. They approve almost all of those prescriptions. We have found that very beneficial for us.

HIV as a Contraindication for Treatment of Psoriasis

 The other question I have is, do you guys do any baseline depression scale? Because I really think that depression was not related to brodalumab. I think that it’s a disease that causes the depression, not the drug. And I now do this PHQ-9 [Patient Health Questionnaire, depression module]. It’s an easy thing I give them while they’re waiting in the room, to have a baseline for almost all patients with psoriasis. Then I repeat it when they come back in 3 months or 6 months.

 It’s pretty clear that depression, they did institute depression scores in the brodalumab trials; it uniformly improved. It’s a drug that works really well, because as you said, it’s the psoriasis that causes the depression. Their depression scores got much better on average. Whereas, the ones who got placebo, got worse. I think, clearly, if you look at a broad array of patients, the depression was not related to brodalumab. Having said that, I think if we had been in the shoes of the FDA at the time, we probably would have done something similar as this REMS [Risk Evaluation and Mitigation Strategy] program, which is really easy.

I put a patient on brodalumab today. To enroll in the program to be a provider takes 90 seconds, and you’re approved for life. To give it to a patient takes less than a minute. And we have it worked out, and every patient I put on brodalumab knows about the suicides. But here is the story.

There were 4 out of 4000 patients with psoriasis. There were 6 total, but of the patients with psoriasis, here were the 4. One was a guy who was going to jail, and therefore, committed suicide. One was a patient nobody would have called a suicide. It was a drug abuser, alcoholic, who mixed drugs and alcohol, didn’t leave a note, and died. But they called it a suicide because of the emerging cases that were being reported. The third was a guy whose entire income came from disability for psoriasis. He achieved a PASI [Psoriasis Area and Severity Index score of] 100 and they took away his disability, and so he had no source of income.

The fourth one was a guy who you mentioned, James, probably most trials would have excluded him. He was severely depressed. He went on brodalumab. I believe he was on it for almost 3 years. He did great, was thrilled on it. He was actually one of our patients. Then he didn’t come back, and we found out from his family…he had moved where he lived, could not adjust to his new home, and jumped off a roof.

They unfortunately had bad luck with that. There has not been a suicide, I don’t even think there’s been a suicide attempt, since the drug has been on the market. It might be time to revisit that and remove the REMS program. But I think if any of us had been in the shoes of the FDA, the program they put together was actually very reasonable. Unfortunately our colleagues, 1 extra minute of work and they’re not paying attention. It is one of the most effective drugs we’ve ever had.

 I think if patients know this from the get-go. I think the REMS program is great and I agree with you, Mark, brodalumab is very fast, it works really quick. We were in the study, and I’ve used it since. People are happy on that drug. And I have people who have carried diagnoses of depression. I think as long as everybody knows from the get-go, I don’t think you see any higher incidence than you do with any of the other drugs or with any other patients with psoriasis. I do think it limits physicians’ use of it because they get nervous about it. But I think the whole thing is about awareness. If patients know the potential for depression happening, you know it, you can avoid these things and still use the drug. Because I think the drug is one of the fastest ones to work, and I use this when people fail other IL-17s [interleukin-17 inhibitors], especially those who got clear in the beginning with their IL-17, and then they start creeping back with disease. You block the receptor and it’s a home run because all the IL-17 is coming from elsewhere, you’re going to oversaturate your system, and you’ll have too much IL-17. And so, blocking the receptor I think is the way to go. I like to use that drug. I won’t say it’s a salvage drug, but I use it even when they fail other IL-17s, and you’ll get I think a very good response.

 Well, I think because it also blocks, like elbows, the IL-17C and IL-17F, at the same time because they are receptor blockers.

 It’s the only one that blocks all the other IL-17 cytokines, which is I think helpful, and that’s why we see the great results of the IL-17A and IL-17F combination that’s going to come to the market. I think blocking the IL-17F is a big issue.

But I also like the REMS program because it’s not only easy but also it sort of covers you legally because you told the patient, the patient signed it, you have proof. Versus all others, I don’t take a consent form just because I’m going to start the biologic. So, to have that paperwork it’s almost nice and easy, and it takes 2 minutes.

Managing Depression as a Psychological Effect of Psoriasis

 Let me turn to you Erin for the next question, which is, how are the available IL-23 [interleukin-23] inhibitors for the treatment of plaque psoriasis administered, and at what frequency?

 All of the IL-23s, they block the p19 subunit and so they work in a similar fashion, all of them are injectable. The first is guselkumab, which is 100 mg [subcutaneous]. It’s given at week zero, week 4, and then Q [every] 8 weeks. The other 2, tildrakizumab and risankizumab, are dosed at [every] 12-week intervals.

The dosing on tildrakizumab is 100 mg at week zero, week 4, then [every] 12 weeks. And then the risankizumab is a 150-mg loading dose at week zero, and week 4. And then [every] 12 weeks.

Generally, guselkumab is given in the office, but I will tell you, in many of my injectable-experienced patients, they inject it at home, and they have no issues with it, but that usually is administered in the office. Whereas risankizumab, I have them self-inject. And the tildrakizumab is usually self-administered as well. But that can be given as IV [intravenously].

 I believe the risankizumab comes in 75 mg.

 Correct, so it’s 2 shots, but it is 150-mg dosing.

 Leon, do you want to tell us about the long-term safety for the available agents?

 I think I’m going to concentrate on the new ones, IL-17s, IL-23s. We did talk quite a bit about the TNF [tumor necrosis factor] alpha inhibitors already. When you look at the safety and long-term safety, let’s start from the IL-17 drug, which is the first one, ustekinumab. We have 5-year long-term safety data. We do have as well with the ixekizumab, 5-year data now. I don’t believe we have 5-year data from the IL-23s yet, they come later on, but there are 4-year data. And all those when you look at them, most of the signals are very comparable to the placebo-controlled period times.

Most of the signals in psoriasis and the psoriatic arthritis population are similar and comparable. I think those are very safe drugs. As I mentioned, their package insert is 15 to 19 pages compared to 100 pages. I was looking, thinking probably the topical steroids have a bigger package insert than those new biologics. And there’s no box warning, there is no blood monitoring requirement with any of those except with the TB [tuberculosis] in the beginning, before you start you have to have a negative TB, which is the standard.

I feel that those new biologics, both the IL-17 and 23s, are very safe drugs. As long as we know the contraindication in the IL-17 category, right, it’s the IBD [inflammatory bowel disease]. But also, some people, they get very concerned when they see the fungal infection or the Candida. The way I look at it, it’s expected because IL-17 protects us against those. When you suppress it a little bit, you’re going to see it; actually in my mind you know that the drug is working.

Ironically, one of the IL-23s, I think tildrakizumab, has a couple of fungal infections and Candida. And in my mind, you know that it’s getting and suppressing IL-17, that’s why you’re getting it, right? It happens a little bit later, but it does happen eventually. So those are expected, and I always say, “Look, I’m a dermatologist, I know how to treat fungal infections and Candida. I’m not dealing with lymphoma.” I feel very comfortable and safe with the new biologics, both IL-23, and IL-17s.

 Yes, I will say people born deficient in IL-17 get yeast infections. They don’t get more cancers, they don’t get more heart attacks. They don’t get other bad things, they get yeast infections. And to me also, if you develop yeast infections, it shows that they’re behaving like those IL-17 deficient patients.

Interestingly also, the rate of yeast infections in the first year or so is about 5%. I think with the IL-17 blockers, maybe a little lower. The new one, which is more effective, bimekizumab, it’s approaching 15% in their larger trials. So again, to me it’s more effective because it’s creating better IL-17 blockade.

 In defense of the anti-TNFs and their safety profile, I think if we look at the data—again, the IL-17/23s, I’m not arguing, they’re faster, they [lead to] better PASIs [Psoriasis Area and Severity Index scores] in general—but there are going to be patients who need the TNFs. And if you look at the data, we have no new safety signals, no new contraindications for over 15 to 18 years. So that tells me that, yes, there is some baggage with the anti-TNFs that were known very early on. But there are patients who would benefit from it, especially like your cardiovascular patients. Patients who’ve had MIs [myocardial infarctions]. My cardiologists want me to put them back on a TNF, they don’t want me to change them.

So I can say looking at the data, there are no new safety signals for over 15, 18 years after they’ve been out. For certain populations I think this is very good drug to use when appropriately prescribed and given to the right population. I think even though there is longer PI [prescribing information], not too many of my patients read the PI, but we haven’t seen any new things come up that we have to be worried about. We know how to manage those adverse effects. I think there’s still a place for them, and they’re still very safe.

 There’s a level of comfort because we’ve been using these for 20 years.

 I would agree with that, Erin. I think the IL-17 and the IL-23 inhibitor safety looks great, but sometimes rare events, the medicine needs to be out longer before you detect something. Even with ustekinumab, how long did it take before there were reports of reversible posterior encephalopathy syndrome or noninfectious pneumonia? These take years, if not decades. So everything looks good so far, but I think we still need some more long-term data for this class.

IL-23 Inhibitors for Treatment of Plaque Psoriasis

 Let me start out with an example of a 23-year-old female patient who has several thick scaly, well defined erythematous plagues, silver in color. They cover her elbows, thighs, part of the scalp, about 15% of the body surface area total.

She mentions having rashes in the past but nothing severe. She was started on apremilast but complained of GI [gastrointestinal] symptoms: nausea and diarrhea. What’s your initial impression of the case? And what are your goals of treatment? And would you recommend biologics as first-line therapy? James, you want to take that?

 Yes, Mark. Just a couple of things that I would want to point out. First is this patient’s age. She’s 23, and I don’t want to overgeneralize here, but sometimes younger patients have a harder time being adherent to their treatment than some of my elderly patients, I would say. So maybe I would want to lean more toward a medicine that has less frequent injections or one that they come in for.

She’s a female of childbearing age. And whether she’s actively trying to get pregnant, I think if you look at the numbers, up to 50% of pregnancies are unplanned. We need to take that into consideration. Some biologics have better data than others for that.

She also had an extensive body surface area, and you can define severe however you want—15% is 15%, that’s bad. And she has scalp involvement. We have some studies showing that, especially for younger females, when you have scalp involvement, it can have a disproportionate effect on their quality of life. You could just have 1 plaque of psoriasis on their scalp and that might affect them more than 3, 4, 5 plaques on their trunk.

We also know that scalp involvement could increase their risk for arthritis, so I think that’s something we need to be mindful of. And she’s already been on apremilast, she’s not responding, and she’s having some tolerability issues. I would say no question, this patient is a candidate for a biologic therapy.

As far as goals of treatment, in a perfect world we could get all of our patients to PASI [Psoriasis Area and Severity Index scores of] 100, zero symptoms, zero impact on their life. Even with the highest agents, probably 50% is what we’re seeing, maybe a little bit higher with the new one that’s coming out. But if our goals are too ambitious, I feel that it’s not practical, and sometimes we could be overly aggressive if we’re trying to go for these ambitious goals.

I think it’s important that we have some set guidelines, that’s how you improve, right? You need to have quantifiable numbers. The National Psoriasis Foundation, they did put out come guidelines, which I’m sure all of you were a part of, recommending that at 3 months of treatments you want to get them to about 3% of body surface area or less. So that’s 3 palm prints. And in 6 months try to get them to 1 palm print or less.

I think those are attainable for a lot of our patients. But I would say at the end of the day it matters what affects the patient. I’ve had patients with minimal objective psoriasis, and it still bothers them a lot. You might want to escalate therapy for those patients. And conversely, you’ve had patients with maybe 3% to 5% on their trunk. It’s covered with their shirts. They don’t care, it impacts them zero. Then maybe you don’t have to escalate therapy for that patient. I think it’s really important to have an open dialogue with your patient.

As far as treatment considerations, I think we touched on this already, but comorbidities I think are the most important thing. Do they have a comorbidity where you would not want to use a certain biologic, or do to have one where you would want to use a biologic. I think psoriatic arthritis is a common example of that.

For this patient I don’t really see anything other than the fact that she is a woman of childbearing age, and so I would say that might make me consider one agent over another. But as far as how I stratify my patients for treatment, I think the 2 big groups are biologically naïve patients, so they’ve been on a biologic before, and then the biologically experienced. I would say my conversation does change a little bit depending on that.

So if a patient has been biologically experienced, they failed multiple systemic and biologic agents, I focus more on efficacy and speed because those patients have been burned, and unfortunately they’ve been disappointed so many times, I’m worried that if I don’t get this right the first time, I’m going to lose them. Maybe they’re not going to come back or they’re not going to be compliant. I focus more on efficacy. For my naïve patients, some of them are afraid of needles. And I may focus more on safety, and I also may prefer an agent with less frequent injections, and I bring them in every 12 weeks.

 I agree, nice job. The pregnancy issue for a 23-year-old I certainly would agree with. It’s interesting, females with extensive psoriasis, especially involving the scalp, I find to be quite compliant because they want to get rid of that psoriasis.

One of the things that came out of your talk was, the next thing you would do is you would ask them, “Do you have psoriatic arthritis? Do you have joint pain?” And that would probably influence the treatment we would select for them.

Case Study of a 23-Year-Old Female With Plaque Psoriasis

 Let’s go to our next patient, and that’s a 49-year-old mildly obese female with type 2 diabetes; she presents with a 4-year history of plaque psoriasis, initially started on methotrexate followed by a TNF [tumor necrosis factor] inhibitor with no relief for the last 6 months. Are comorbidities more difficult to treat with biologics? And how do they factor into the AAD [American Academy of Dermatology]/National Psoriasis Foundation guidelines for the treatment of psoriasis, Erin?

 This patient is relatively young, now I can say that, but she’s obese. She’s got diabetes. She’s going to start fitting into that category of metabolic syndrome, maybe not completely, but we have to worry about those comorbidities. She has already been treated with a TNF inhibitor. I’m going to presume it’s not one that’s weight-based; I don’t know that, but that would be my guess.

In general I do like to consider comorbidities when I pick my treatment choice. I think, like James, that’s first and foremost the most important thing to think about in making a choice. I do think it makes a difference. If you have multiple comorbid diseases, maybe the TNFs that are not weight-based are not going to be useful here. Maybe in this case I might go to infliximab, but probably not. I would look more to the IL-17s [interleukin-17 inhibitors] and maybe even more particularly to the IL-23s.

Because she does have obesity, she’s got insulin resistance, and there have been a number of studies that have shown that the TNFs improve diabetes, or insulin resistance, but they make obesity worse. I would tend not to use a TNF inhibitor in this person. I would like to go to an IL-23 or IL-17.

There are recent data looking at IL-23s and how they may affect cardiovascular disease and other things. I think those would be the ones that I would go for. They’re not necessarily tied to weight either, so I think it gives you a better option and a better chance for response.

But one thing to remember here is what many derms [dermatologists] do, and I think is not good, is as soon as a patient starts to flare, you start thinking about switching. You want to be able to determine flare versus failure before you switch out of the class completely. This lady had a partial response to a TNF, but not great. Certolizumab does pretty well in people who are obese, so you could go to that in terms of helping with the insulin resistance. I think there are a number of options for this person, but I would tend to go toward the IL-23s or the IL-17s and get out of the class for this particular patient.

 What if I told you she had a positive test for TB [tuberculosis]? How would that affect what you give her? And having said that, how do you maintain the latency of TB? Let’s say you’re going to treat her, when could you start the biologic? James or Leon, want to take that?

 Sure. I think I briefly mentioned this before, but with some of the newer MOAs [mechanisms of action] it seems that IL-17/23 inhibition probably doesn’t play that much of a role in tuberculosis defense. I think I’d feel more comfortable, not to say you can’t use a TNF alpha inhibitor, I would just want to make sure that those patients were properly treated for latent TB. I usually wait a month after starting latent TB treatments before starting the biologic agents. And I think the tricky thing is in the past, 6 to 9 months of isoniazid [INH], that’s tough to finish for a lot of our patients.

What if they only finished 5 months, were they adequately treated? It’s hard to say. I think the CDC [Centers for Disease Control] recently had some changes in their guidelines of how to treat latent TB. It’s just once weekly now for 3 months, and it’s much easier to finish that course. I would say that whether TNF, IL-17, or IL-23, I would be OK with all of those classes, but IL-17 or 23 probably would be my preferred ones.

 I actually would put her in the light box to begin with. I usually send them to the infectious disease [ID] doctors, start them on the TB treatment, and most of them say about 3 months, but it may change now. When we do clinical trials and you have a TB-positive test, they say treat them for 3 months, and then you can put them in the study. Or they say, it’s local criteria, right? Most of them, whatever your state says. So here I find out that usually it’s about 3 months of treatment and then you can put them on a biologic. Most of the ID doctors go with that. Meanwhile I’ll put them in the light box, or try to do something else, but probably light box would be the easiest.

 I’ll say the 3-month regimen, I looked at this closely because we actually have a lot of patients who are QuantiFERON [test]-positive. And there are several different regimens for treating TB. One of them is that once-a-week regimen for 12 doses, that’s 12 weeks, the 3 months that Leon’s mentioning. And it is high doses of isoniazid, pyridoxine, and rifapentine, I believe it’s called.

Anyway, it’s high doses. The problem is that the [adverse] effects of that high dosage is substantially more. The traditional regimen, which is INHand rifampin, are for 6 months. And then patients who can’t tolerate INH alone, often they’ll give rifampin for 9 months. But that doesn’t mean you have to wait that whole time to start your patients. There are no data that tell us how to handle these patients. There’s a lot written about it, and it seems that the consensus; the first time I read about this was when 

 had a letter from the CDC. And the consensus was, once they’re on treatment for a month, you can start your biologic.

Now, when you treat patients fully for latent TB, you don’t completely eradicate the risk. There is still a risk. And unfortunately, QuantiFERON [tests] remain positive, as do PPDs [purified protein derivative skin tests], and so we get an annual chest x-ray. Be aware that in patients on TNF blockers where we know there’s an increased risk of TB, 40% of TB is extrapulmonary. A chest x-ray is not quite adequate. And that’s why I agree with something you said early on James, go to an IL-17 or 23. Because the data so far, which are limited, suggest that they do not cause reactivation of latent TB. TNF blockade clearly does.

 The QuantiFERON-TB Gold [test] commonly will have false positives, depending on if patients have viral infections or other things going. We routinely will get T-Spot TB tests if the patients have a QuantiFERON Gold test that’s positive. And I can tell you that probably 30% to 40% of my QuantiFERON Gold positives are T-Spot TB negative. We do nothing more if they’re T-Spot negative. If they tend to be positive on a T-Spot test, then ID for us say, yes, you do get a chest x-ray, but you go ahead and treat, and presume it to be latent TB.

We do not, at least our ID people in the New Orleans area, do not follow with yearly chest x-rays. And I think that’s in part because of what you said, they don’t really tell you much and you get exposure to radiation needlessly. We follow signs and symptoms, and I’ve never had reactivation yet, knock on wood. I do tend to switch them off of the TNFs if they are truly TB positive with a T-Spot test. But we don’t follow with chest x-rays at all because they said the yield is so low that it’s not useful. But I think the pearl here is the T-Spot TB test. If you can get that, you can eliminate a lot of needless 6-month courses of INH, which is very difficult to tolerate.

49-Year-Old Female With Psoriasis and Latent Tuberculosis

 OK, let’s go to the third case, which is a 68-year-old man who has a severe case of plaque psoriasis. He has several risk factors for heart disease. First of all, age, and being male. And hypertension, hyperlipidemia, and insulin resistance. He noticed patches 2 weeks earlier, and they’ve worsened since then. His skin feels itchy and hot. The lesions first appeared in areas of low visibility, but before you knew it, it was on his arms and could be seen, and his trunk was covered.

So, first of all, what are your impressions of the patient? How would you select treatment options based on the comorbidities that were published in the AAD/NPF [American Academy of Dermatology/National Psoriasis Foundation] guidelines in 2020? Alan Menter, MD, was the first author. And it reviewed frontline and subsequent options. Leon, you want to take that one?

 Sure. I think this is your typical Medicare patient, right, a 68-year-old. He does have metabolic syndrome: obesity, hypertension, hyperlipidemia, insulin resistance—you name it, he’s got it all.

Now I don’t know if he’s got psoriatic arthritis or not. But let’s assume he doesn’t right now. I’m in private practice, I’m not in a university, so I have to be practical. And one of the things we always are thinking about is the insurance. One of the things that they want from us, even before we go to a TNF [tumor necrosis factor] alpha inhibitor, we have to show failure with either light [therapy] or methotrexate. I never do methotrexate. I put almost everybody in the light box for the first couple of weeks so that I can show that I did the light [therapy] and it didn’t work.

I would start with the light, and then I’m assuming that this person has a large body surface area, so it’s going to be; actually when I walk into a room, I don’t even think about mild, moderate severe disease. In my mind, I think this is either a topical patient or a systemic patient. That’s how I look at it.

I’m assuming this is going to be a systemic patient. So first he goes to the light box, and then a couple of weeks later I know it’s not going to work unless—and most Medicare patients, by the way, they like the light box because they are retired, they have nothing else to do. They come 2, 3 times a week. They hang out in my office. They talk to the girls; they have a cup of coffee. They don’t have to pay a co-pay. It’s actually almost like a social thing for them and they like it. And sometimes we get lucky, it works; sometimes it doesn’t. Most of the time it doesn’t.

Then this would be the ideal patient for, we talked about tildrakizumab, because he’s got medical benefit on the Medicare side, so I don’t have to deal with the pharmacy benefits. He does have metabolic syndrome, which we have proof that tildrakizumab, from the poster, patients with metabolic syndrome did as well as the ones without metabolic syndrome. I think that would be my first choice.

 Obese patients don’t do as well with most drugs. The poster with tildrakizumab makes the point that people with metabolic syndrome who are obese—which is part of metabolic syndrome—do just as well whether or not they have metabolic syndrome. And the point is that the IL-23 [interleukin-23] blockers, and in the case of that poster specifically, tildrakizumab is highly effective even in obese patients.

 Now, let’s assume that he has psoriatic arthritis. [Tildrakizumab] is not going to be my first choice. Probably I would go to an IL-17 drug, where I can kill two birds with one stone if I can get it approved. Most likely he’s not going to be approved because I have to go to a TNF alpha inhibitor.

And if I would go to a TNF-alpha inhibitor, probably I would pick certolizumab. And the reason that I would pick that, if you look at the long-term data for certolizumab, they [TNF-alpha inhibitors] have the best efficacy maintenance rate. They do have quite a bit of PASI [Psoriasis Area and Severity Index] 75 and 90 maintenance rates that the older TNF-alpha inhibitors don’t have. So that would be my choice.

 OK. James, would you handle that in a similar way, and Erin?

 I agree absolutely with Leon. I think with the TNF inhibitors we have data that it may potentially help with cardiovascular morbidity and mortality, and one could question whether, these are claims-based studies, so maybe it’s not truly an effect and these are more of a healthy user effect, we call it. But still we have those data. And methotrexate too, at least for our patients with rheumatoid arthritis, it’s the same thing. It does seem to help with cardiovascular morbidity and mortality. So I would be OK with those. Certainly for some of my more obese patients, I prefer IL-17 or IL-23 if I have that choice, but I would agree with everything Leon said.

 When you look at this patient, he’s obese, he does have metabolic syndrome; I’m in total agreement with that, and insulin resistance. If you look at the long-term data for the anti-TNFs, you’ll see, again, infliximab is weight-based; you’re going to help him in that regard and he’ll get an active drug.

We know from data that the TNF drugs do improve insulin resistance, so you would improve possibly his diabetes. We know that the anti-TNFs are very effective in cardiovascular disease. If you look at the rheumatologic data, they show that patients who’ve had MIs [myocardial infarctions], if you put them on a TNF, you decrease the mortality, you decrease the incidence of second MIs with it. And the same thing is true in psoriatic patients on the TNF, that the anti-TNFs do decrease the risks of subsequent MIs. I think in this case the fact that he’s 68 [years old], he is probably on Medicare, at least in my state I have great difficulties getting any IL-17s or anything even in the office.

I think this patient would be a good candidate for infliximab, if you’re going to pick an anti-TNF. Granted, most derms [dermatologists] don’t have access to it in their own office, but there’s probably somebody in your community who could, and I think the patient would benefit. And overall, I think his metabolic syndrome may benefit, including atherosclerotic plaque disease, which has been shown with the TNFs to improve, as do the IL-17s, especially the As and the Fs, improve the atherosclerotic plaque disease. I think in general this would be one you could use infliximab for.

Elderly Male With Plaque Psoriasis, Metabolic Syndrome

 What are some of the challenges? You mentioned the access in Louisiana, but let me have you take the lead, James. Is the cost a hurdle you have to get over, low rates of treatment adherence? Tell us about some of the challenges you face.

Practical Approaches to the Management of Plaque Psoriasis

EP 1: Pathogenesis of Plaque Psoriasis and Triggering Factors

EP 2: Clinical Manifestations and Progressive Nature of Psoriasis

EP 3: Factors That Influence Choice of Treatment for Plaque Psoriasis

EP 4: Effect of Multiple Sclerosis and Obesity on Treatment of Psoriasis

EP 5: Medical Benefit of Office Administration of Tildrakizumab

EP 6: Experience With Using Older Biologics to Treat Psoriasis

EP 7: Adverse Events of TNF Inhibitors Used to Treat Psoriasis

EP 8: Contraindications to the Conventional Treatment for Psoriasis

EP 9: HIV as a Contraindication for Treatment of Psoriasis

EP 10: Managing Depression as a Psychological Effect of Psoriasis

EP 11: IL-23 Inhibitors for Treatment of Plaque Psoriasis

EP 12: Case Study of a 23-Year-Old Female With Plaque Psoriasis

EP 13: 49-Year-Old Female With Psoriasis and Latent Tuberculosis

EP 14: Elderly Male With Plaque Psoriasis, Metabolic Syndrome

EP 15: Challenges in Treating Patients With Plaque Psoriasis

EP 16: Unmet Needs and Emerging Treatments for Psoriasis