Psoriasis Podcast

Psoriasis Oral Agents: What to Know to Prescribe Like a Pro

Steven R. Feldman, MD, PhD; Bruce Strober, MD, PhD


July 07, 2022

This transcript has been edited for clarity.

Steven R. Feldman, MD, PhD: Welcome to Medscape InDiscussion on psoriasis. I'm your host, Dr Steve Feldman. For years we relied on older immunosuppressive drugs like methotrexate and cyclosporine to treat extensive psoriasis. Do oral agents still have a role to play in psoriasis treatment in this era of biologics? I know the perfect person to answer that question. And he's with us today, a clinical professor of dermatology at Yale University School of Medicine. He's the scientific co-director of the Core Psoriasis Registry, is the treasurer of the International Psoriasis Council, and the editor-in-chief of the Journal of Psoriasis and Psoriatic Arthritis. He's also the former chair of dermatology at the University of Connecticut Health Center. He's been instrumental in developing guidelines and standards of care for psoriasis for years now. It's my pleasure to introduce Dr Bruce Strober. Welcome, Bruce.

Bruce Strober, MD, PhD: Thanks, Steve. Happy to be here.

Feldman: You know, you and I have been doing this psoriasis thing for a long time. And when we started, patients were really suffering, and we've ridden wave after wave of new drugs. Do you have a favorite story from your experience over these years?

Strober: The best story I have is how I got into dermatology and how I got interested in psoriasis. I got into dermatology by accident. I was doing a primary care rotation in medical school and they had no place to put me, so they threw me into a psoriasis clinic in Harlem Hospital in New York City. And by accident, I fell in love with psoriasis that afternoon. When I was a resident, there was a medication that was just coming onto the scene. This was around 2001, and it was not yet approved for anything in dermatology, yet it had an approval for rheumatologic disease, and the name of that medicine was etanercept. My attending and I started a patient on etanercept, the first patient ever at NYU that received that drug. And he magically cleared up over the course of 2-3 months. I said to myself, that is a lot better than cyclosporine and I'm going to go down this pathway.

Feldman: That's great. You know, when I first started seeing patients with psoriasis on etanercept, none of them had cleared up. And that's because the only ones I saw were ones that the rheumatologists had treated for psoriatic arthritis; they didn't send me the ones that cleared up.

Strober: Right, exactly. This was one of those situations where we had a psoriasis patient in whom the disease had not yet been touched. And luckily, I worked with an attending doctor, Jerry Shupack, at NYU, who was always on the cutting edge. And he says, "Bruce, let's just try this drug that I hear works for psoriatic arthritis." The rest is history.

Feldman: That was sort of the beginning of this revolution, where we're thinking about putting psoriasis patients on these biologic drugs that are extraordinarily safe and effective. But we have these oral agents, too — non-biologics — in the 2020 American Academy of Dermatology (AAD), National Psoriasis Foundation guidelines. It mentions drugs like methotrexate, acitretin, apremilast, cyclosporine, and tofacitinib. Talk briefly about these.

Strober: Well, I don't think they should be viewed as a monolithic group. I think each drug is a different character in the armamentarium. So, for example, cyclosporine and I just wrote a prescription for cyclosporine for a person with psoriasis last week; it still has a place. It's really about a quick clearance of patients who are dramatically in need of improvement now. Cyclosporine is generic and it's something you could prescribe today, and the patient gets it tonight. And therefore, they could see improvement within a week or two. There's no prior-authorization process like we have with more modern drugs, but cyclosporine has toxicity and therefore always has sort of a half-life, a deadline at which you should pretty much switch the patient over to something safer. It's a quick-fix drug. Rarely do I add it on to another medication in a low dose to get them to another level.

Methotrexate, I think, is somewhat the opposite. It's also an old generic drug, probably less effective than cyclosporine. Yet, it works. It would be a good drug for people who, first of all, have their insurance mandate. We'd use that drug because it's so inexpensive. But if that's not the case, it might be a drug for a person who's poorly insured, who can't afford a more expensive medication, or a person who has Medicare, where a lot of the more modern medicines are not well covered. Methotrexate is a great combination drug with other biologic therapies because methotrexate adds the psoriasis effectiveness and also brings some psoriatic arthritis efficacy to the table as well.

Feldman: How about apremilast? I hear some people use it as their first-line option.

Strober: Apremilast is a modern drug and its advantages are that it doesn't require blood tests like methotrexate and cyclosporine do. There's about a 1 in 3 chance that apremilast will be effective — very effective, I should say — for a patient. And that would be the problem; it's not always effective. It's the milder modern drug. The other issue is that there are some side effects like nausea, diarrhea, and headache that can pop up in patients on apremilast. Maybe the patient who gets apremilast is your milder, less severely affected patient. Or again, a patient you can combine up with a biologic and get better efficacy. And we shouldn't forget that apremilast also can help psoriatic arthritis — so people who have cleared skin but their arthritis is not well managed. You can add apremilast to the equation.

Feldman: Does acitretin still play a role? It's a retinoid, a vitamin A derivative.

Strober: Acitretin is a very old medicine, also generic and generally accessible to most patients. The problem of acitretin is, number one, it too isn't very highly effective when used alone as a monotherapy. Secondly, women can't get acitretin, especially women of childbearing [age], because it is, like any retinoid, a teratogen. It has this unique aspect of all our retinoids; if you take one dose of acitretin and you have alcohol subsequently while the acitretin is in your body, it's what's called reverse-esterified into an even older drug that we use called etretinate. Etretinate has a very long half-life; I believe it's about 4 months. And therefore, if you give acitretin and then someone has alcohol, you kind of assume the drug is in their body for about 2 years. So we leave that off the table for women of childbearing [age]. Now for postmenopausal women too, it's a problematic drug because acitretin is associated with mucocutaneous side effects such as dry skin, dry lips. But one of the side effects is alopecia. And I think this issue occurs with a fair frequency in anyone who takes acitretin such that if you gave it to a woman who's postmenopausal, she's going to lose some amount of her hair. It has been shown that if you combine phototherapy with acitretin, you can lower the dose of both modalities or the frequency of administration of both modalities. That's nice, but you can add acitretin to anything because it's not immunosuppressive, which gives it a unique feature of all our psoriasis therapeutics. But acitretin is unique. It doesn't appear to have an immunosuppressive capacity, so we can add it on to any other drug that is immunosuppressive and we're not doubling up on the immunosuppression. Finally, acitretin might be a very good drug for palmoplantar disease, meaning hands and feet. And I have seen it work very nicely in those patients. Again, you got to monitor the dosing because the side effects basically are dose related with acitretin.

Feldman: How about one of the newer medications, the JAK inhibitor tofacitinib?

Strober: Tofacitinib is only approved for psoriatic arthritis. It is not approved for psoriasis. That said, it works pretty well in psoriasis, at least as good as methotrexate at its regular dose of 5 mg twice a day. If you give 10 mg twice a day, you get even better efficacy. But we don't have that as an approved dose. With 5 mg twice a day you get decent efficacy. The issue of JAK kinase inhibition are some rare side effects and toxicities which necessitate blood test monitoring; for example, the CBC and the liver must be monitored but it's a pretty well tolerated medication.

I would consider tofacitinib, of all the drugs we just discussed, to be pretty much as immunosuppressive as any others. It's as immunosuppressive as cyclosporine, in fact, but it doesn't have the renal toxicity that predictably cyclosporine has. So you can put someone on tofacitinib and more or less make it an indefinite therapy. Where do I use it? I don't commonly prescribed tofacitinib now for people with psoriasis except if they have palmoplantar disease. It's a very consistently effective palmoplantar psoriasis drug.

Feldman: That was a fabulous overview. Why don't we go through a couple of them in a little more detail? Of the ones we've mentioned, would apremilast be the one that's most commonly used at this point?

Strober: Without question. I think apremilast surpassed methotrexate in the past few years in terms of prescription volume, and that's because it's easier than methotrexate. I actually am skeptical that it works better. I think methotrexate, if you look at the data, works a little better than apremilast, but it's a marginal difference. It's just easier as a drug.

Feldman: Apremilast is a phosphodiesterase-4 inhibitor. I think caffeine is a phosphodiesterase inhibitor. It seems like a very safe thing. You get people past that initial nausea, diarrhea, and they tolerate it great. But who are you choosing to put on apremilast?

Strober: It's funny, Steve, because it's definitely not a drug I prescribe as frequently as the biologic therapies. It's probably a 1-to-10 ratio there. It's probably the patient who you can't manage well with topicals. And they're in this sort of a 3%-8% body surface area of involvement range. Additionally, a patient who is a little reticent about taking an injectable biologic would rather move through the oral therapy before they got to an injectable therapy. So it's that combination that brings you to apremilast. I always feel good about writing apremilast. It never really hurts patients. It's like a low-risk opportunity for patients. And in 3 months, if it's not working, you talk with the patient about the next level of therapeutics, which is biologic therapy.

Feldman: Okay. I get the sense that the second most common one that would be used would be sort of the opposite extreme from apremilast. This would be methotrexate, a drug that you can kill people with if you're not careful with it.

Strober: Exactly. And methotrexate — and I prescribe a lot of that too — just needs good patient selection. Obviously don't want someone who has liver risk, and that would obviously be a drinker, or someone who has other reasons to have liver toxicity. People with poor renal function are at risk for bone marrow suppression when getting methotrexate. People on other medications that interact with methotrexate create risk particularly bone marrow toxicity. And then you have to follow the blood tests. Methotrexate is commonly used because it's so inexpensive and you never get blockade. I shouldn't say never, but pretty much 99% time you don't get blockade from a pharmacy or prescription plan regarding its prescription. And there's this adherent group of dermatologists out there, probably older dermatologists, who are trained more extensively on methotrexate, who like it because it does beat a placebo in clinical trials pretty handily. And I would say that 40%-45% of patients, if you dose the drug appropriately, get significant improvement. Patients can like that and stay on the drug indefinitely as long as you're monitoring them correctly over time.

Feldman: Yeah. Are you starting with a test dose of methotrexate and working up or are you just starting with a full-blown dose of this stuff?

Strober: I never did test dosing. I wasn't trained on it. Dr Shupack, my mentor, told me to never do them. In 20 years I've never done them and I never had a problem. So I start almost everyone on 15 mg. Unless it's an older person who may have compromised renal function, I might drop them to 10 to 12.5 mg, but generally it's oral 15 mg, six pills all at once on the same evening every week. And I have them come back in 4 weeks and repeat their labs and just compare them to the baseline. Thousands of patients later, I've never seen the need for a test dose.

Feldman: Outstanding. In the old days, liver biopsies were recommended in these patients at intervals to monitor for cirrhosis. Are you doing that anymore?

Strober: I haven't done a liver biopsy in 15 years on methotrexate. I think it's really gone the way of the dodo. I mean, the liver biopsy has its own risks, of course, which are not insignificant; it has to be done by a trained professional. And usually it's a liver specialist. The liver biopsy also has a problem in that it only samples a portion, and then a very small portion, of the liver — like maybe 1% of it.

Feldman: A lot less.

Strober: The pathology may rest outside of the area of a biopsy, so I even think the results are unreliable from a liver biopsy. In that regard, I think liver biopsies are antiquated and not very helpful and carry their own risk. And therefore, we rely on other means by which to measure toxicity to methotrexate. And there are quite a few now being developed, both laboratory and noninvasive imaging studies.

Feldman: You mentioned drug interactions with methotrexate, and I know a high percentage of patients with psoriasis have joint issues and might be given a nonsteroidal, which I guess at least in theory could affect renal function. Is that an issue with use of methotrexate?

Strober: It really isn't. And how do I know this? Once I ran a rheum-derm clinic. It was a clinic at NYU where we saw patients with psoriasis and had a dermatologist present and a rheumatologist present. I've worked with many rheumatologists over the years, and rheumatologists probably write as many NSAID prescriptions as any other specialty out there, probably because they deal with pain and joint pain in particular. They always said that is a really erroneous drug interaction. In fact, you can give NSAIDs in moderation to people on methotrexate. The key is that NSAIDs in and of themselves have their own toxicities and that needs to be respected, and therefore you have to prescribe them judiciously and make sure patients are not abusing them.

Feldman: Then the big drug interaction for methotrexate would be what? A sulfamethoxazole-trimethoprim combination drug?

Strober: Exactly. That particular drug is not uncommonly on board in patients, and therefore that one in particular has to be looked out for. There are a few others in the textbooks and I always just use my handheld device. I have a program that checks interactions and I make sure I view them as relevant or not relevant. That's a big one: Make sure they're not on trimethoprim-sulfamethoxazole. If you give them methotrexate you can really ablate the bone marrow quickly.

Feldman: Do you think there's much role for methotrexate used in combination with biologics?

Strober: Well, I've been doing that for years and the primary role I found was in combining methotrexate with TNF inhibitors, particularly adalimumab and infliximab, because in particular, methotrexate reduces immunogenicity. By some unknown mechanism, it reduces the patient's ability to make antidrug antibodies, and that's been shown very convincingly. And in so doing, it raises the serum levels of both adalimumab and infliximab to higher levels in the patient's body, so you get better efficacy.

Now the question is, do you need to combine methotrexate with the newer biologics? The data aren't clear on that; they suggest you don't. I don't tend to use methotrexate in combination with the current modern IL-23, IL-17 inhibitors. Only if I feel that there's residual joint disease that could benefit from a low dose of methotrexate do I combine methotrexate with a biologic; this is for patients who are not getting a full response from their biologic. You can also add on methotrexate to accelerate the skin response. Now again, we have so many drugs to choose from. You might ask, why don't you switch them to another biologic instead of adding a methotrexate? Well, these would be patients on end-of-the-line biologics, patients who've been through eight or nine of them already and are kind of running out of options. So then you start combining up therapies with methotrexate.

Feldman: As physicians are following patients on these drugs, do you think you could do it by teledermatology, especially in a primary care setting.

Strober: Teledermatology is a challenge. That said, if a patient is in follow-up, clear, well managed on any drug you're using, even methotrexate, you just need bloodwork done. But especially biologic therapy is entirely feasible to follow them by telederm, and I do. Once a week I'll have a telederm visit with a biologic follow-up and I think that's great. Why would you want a patient to come in, drive 20 miles, even longer distances, just to say, "Hello. How are you doing?" And "I'm clear, right?" And "Have a nice 6 months ahead of you." So we do this commonly for patients with well-managed psoriasis. If you're having a flaring patient, I tend to feel more comfortable bringing them in in person, examining the skin, getting a sense of the severity, how it's affecting them. And clearly, when you have a flaring patient, you often have to switch therapies; that's a discussion that's best done in person. With teledermatology, stable patients who are doing well are very appropriate.

Feldman: These oral agents have so many more issues than biologics do. It's critical to educate patients in writing about what to be looking out for and what to expect, and I've relied heavily on National Psoriasis Foundation materials for doing that. Is that something you do as well?

Strober: Typically I don't, Steve, which may be my own failing. I think it's a good idea to hand literature to patients, so I advocate for that. In my practice we write out critical features of the drug experience for the patient, very critical features of the drug experience, like dosing. How do you take the drug? But more importantly, we have a phone number they can call. If there is any confusion, they reach out to us, and truth be told there is a lot of confusion that comes on, even if you're very clear during the visit. Patients often don't fully understand the instructions or don't listen to your admonitions of certain things you don't want to do while receiving a given medicine. But I do believe handouts work and I think they're smart. Whether patients read them is another question. And if a patient asks for a handout on a medication, we do give it to them.

Feldman: Excellent. We've covered so much. Are there any other things you want to pass on to listeners before we wrap up?

Strober: The most important thing is to expand your options. Unfortunately, there are about 14 different choices, maybe 15 when we treat psoriasis and maybe they're 16 now; soon there will be 17 or 18. You still have a long laundry list. So what I would say to any provider is get to know a lot of these different choices in different classes, because invariably there are patients who don't respond to one class or type of drug that need to have another class brought to bear. And it could be a patient who does respond to apremilast but not to one of the biologics, or a patient who responds to methotrexate but not to the biologics. It's crazy, but it happens. And that's why you need to have a full list in your head and be very competent on it so that you can explain and feel confident going into the room. I have this menu of options for patients, all of which are great. And therefore, I can bring to bear a tailored approach to each patient based on their needs, their demographics, their place in life, the severity, what have they been on in the past, etc. I think it gives you a greater modern approach to psoriasis, which is very treatable these days. It should be one of your easier diagnoses to manage, and in that regard, you're really helping patients in need. It's a common disease, probably one of the more common ones we treat, so you can help people who come into your practice on a very regular basis.

Feldman: We're going to cover biologics in our next episode of this podcast, but I think today we've learned that apremilast might be a perfectly good first-line option for patients who want an oral agent. Methotrexate still has a big role to play, especially in patients who don't have good insurance, or where the insurer requires methotrexate first. Acitretin may be useful for making phototherapy more effective, especially when used in low doses to avoid side effects. And even cyclosporine may still have a role for emergent treatments, like right before a wedding and you've got to clear the psoriasis up fast. Bruce, I want to thank you so much for your time today. I'm Dr Steve Feldman, and this has been Medscape InDiscussion on psoriasis.


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