Joel M. Gelfand, MD, MSCE
University of Pennsylvania Perelman School of Medicine

Key Takeaways

  • Selective interleukin-23 (IL-23) inhibitors for the management of psoriasis are administered every 8 to 12 weeks, compared with previous treatment options that required a weekly, biweekly, or monthly injection.
  • Patient preference, underlying health issues, and shared decision-making between the clinician and patient drive treatment selection.
  • For patients with psoriasis who previously failed treatment with a phosphodiesterase-4 (PDE4) inhibitor or a tumor necrosis factor (TNF) inhibitor, IL-23 inhibitors may be an appropriate next step in care.
  • There are limited contraindications of IL-23 inhibitors that prevent its use. Selective IL-23 inhibitors have strong safety profiles.

In the management of psoriasis, the addition of selective IL-23 inhibitors has provided patients a therapeutic option that addresses difficult administration schedules and improved pharmacokinetics to increase the duration of action. Joel M. Gelfand, MD, MSCE, is the James J. Leyden Professor of Dermatology and Epidemiology, vice chair of clinical research, medical director in the Dermatology Clinical Studies Unit, and director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania Perelman School of Medicine in Philadelphia.

What is the clinical rationale for using selective IL-23 inhibitors in the management of plaque psoriasis?

Psoriasis is an autoinflammatory disease where a population of immune cells are recognizing and reacting to antigens in the skin. Cytokine IL-23 is produced in an inflammatory reaction and ultimately promotes the development and differentiation of T helper 17 cells which then releases a series of cytokines that inflame the skin and result in thick, red, scaly plaques. Targeting IL-23 is a part of a rational drug discovery where we are targeting a cytokine that is critical to the pathophysiology of psoriasis.

What are the unmet needs in the management of psoriasis? How do selective IL-23 inhibitors address these gaps in treatment?

The selective IL-23 inhibitors provide new therapeutic options to address efficacy concerns and difficult administration schedules. One way is that they are highly effective treatments so the rate of being clear or almost clear is very high with this class of medications. These agents are not dosed as frequently. Many injectable biologics we use may have to be administered every week, every 2 weeks, or every month. For the most part, the biologics targeting IL-23 are administered every 8 to 12 weeks. That is very advantageous for our patients because most people do not want to have to inject themselves regularly. It addresses the medical need of limiting the number of times the person has to inject themselves to control their disease.
The other thing that is unique to this pathway is that it tends to produce durable remissions, meaning that if the patient needs to stop the medication, it takes a significantly prolonged amount of time before their disease returns after they stop an IL-23 inhibitor. That is very advantageous because patients often lose insurance or develop other health issues that make it difficult for them to maintain their treatment. It is nice to give patients what I call a “soft landing,” where their disease gradually and slowly comes back

Can you briefly describe your approach if a patient fails both TNF and PDE-4 therapy? What is the role of selective IL-23 inhibition in this patient group who have failed first-line therapy?

All of these treatments, according to the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) treatment guidelines, are considered to be first-line because they are all effective, safe, and well-tolerated.1 What really drive the choice are patient preference, underlying health issues, and the clinician’s shared decision-making with the patient. In a situation where a patient has failed a PDE4 inhibitor such as apremilast or a TNF inhibitor, the IL-23 inhibitors are certainly a logical next step to pursue.
Most patients are going to be good candidates for the IL-23 inhibitors, including those who have significant psoriatic arthritis, although not all the IL-23 inhibitors are approved by the US Food and Drug Administration (FDA) for psoriatic arthritis. Only guselkumab is approved for the management of psoriatic arthritis while risankizumab has phase 3 data and will likely get an approval for the management of psoriatic arthritis.2,3
The general clinical impression is that the IL-23 inhibitors tend to be a little less helpful for the management of psoriatic arthritis than a biologic targeting TNF or IL-17. For most patients in a dermatology setting, an IL-23 inhibitor will be appropriate for the kind of psoriatic arthritis we tend to manage, but for patients who have much more significant psoriatic arthritis and failed multiple therapies, we tend to steer towards TNF or IL-23 inhibitors.
In terms of ustekinumab, this drug has sort of fallen out of favor from a dermatological point of view because we know that in head-to-head trials, the newer IL-23 inhibitors tend to be more effective and are more targeted.4 In addition to greater efficacy, IL-23 inhibitors have advantages of being theoretically safer because they are more specific in how they work. There is no disadvantages other than potentially the cost. If an insurance company insisted on using ustekinumab then that would be a reason to use it. However, in most cases, the clinician and patient would opt for a more specific IL-23-based biologic.

Unique to the IL-23 pathway is that it tends to produce durable remissions, meaning that if the patient needs to stop the medication, it takes a significantly prolonged amount of time before their disease returns after they stop an IL-23 inhibitor. It is nice to give patients what I call a “soft landing,” where their disease gradually and slowly comes back.

How did the approval of selective IL-23 inhibitors such as guselkumab and tildrakizumab change the treatment landscape and outcomes, including disease improvement and quality of life, of patients with plaque psoriasis?

The approval changed the landscape in a substantial way. First of all, one of the biggest benefits of IL-23 inhibitors is that there really are not many contraindications to using them. Other therapeutic options such as TNF inhibitors have warnings for increased risks of serious infection and lymphoma.5 Also, IL-17 inhibitors have warnings for exacerbating inflammatory bowel disease.6,7 The IL-23 inhibitors do not have any of those types of warnings, which has been a big advantage of the drug class. The clinician and patient do not have to worry about underlying comorbidities that are common in people with psoriasis being a contraindication to use of the IL-23 inhibitors.

Tildrakizumab adverse effects
Adverse effects commonly reported with tildrakizumab are upper respiratory infections, injection site reactions, and diarrhea.
Guselkumab adverse effects
Adverse effects commonly reported with guselkumab include upper respiratory infections, headache, injection site reactions, arthralgia, bronchitis, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections.

What endpoints, outcomes, or adverse events should clinicians monitor during follow-ups with patients with plaque psoriasis who are receiving selective IL-23p19 inhibitors?

In clinical practice, we are trying to understand the patient’s overall response. How much of their body’s surface area is not affected? How thick, red, and scaly are the remaining patches? In a perfect world, we’re trying to get patients to be completely clear or almost clear with less than 1% of their body affected. We want the patient to be satisfied and there to be no impact on their health-related quality of life. We would like for them to feel they could go about their work, have social relationships, have no physical symptoms, and feel confident that their diagnosis will not impact how they lead their life. That is what we are trying to achieve.
The other thing I encourage clinicians to think about is whether the patient is having any recurrence of their symptoms when that patient is due for another dose. This is because the pharmacokinetics of these drugs are pretty variable. In general, the dosing regimen is every 8 to 12 weeks depending on which IL-23 inhibitor we’re discussing. Patients are variable, meaning that some patients need these therapies every 4 weeks and some patients need them every 6 months. When the patient is due for their next dose, it is helpful to ask if there are any signs of recurring psoriasis. Ask them if they are having any symptoms that are coming back or if the skin is starting to itch. Those are signs that the disease may not be in deep remission and they really need to continue the drug every 12 weeks or every 8 weeks based on what the label says.
For other patients who have been on a drug for at least a year, are completely clear, and have no signs of their symptoms re-emerging when they are due for their next dose, sometimes the patient and clinician may consider extending a dosing period from every 8 weeks to every 12 weeks if it’s guselkumab, or every 12 weeks to every 16 weeks if it’s risankizumab.

Can you review the safety profile of selective IL-23 inhibitors for the management of plaque psoriasis?

Selective IL-23 inhibitors have very strong safety profiles. Their main warning is related to infection, but they don’t seem to be meaningfully associated with serious infections.8 It is pretty rare to have to stop the drug because of an infection related to one of these medications. During the COVID-19 period, of course, there are concerns of whether IL-23 inhibitors could make people more prone to COVID-19. The data, however, have not really seemed to suggest that. Patients receiving IL-23 inhibitors don’t seem to be more likely to develop COVID-19 or have worse COVID-19-related outcomes.9,10 There are some questions about whether the IL-23 inhibitors would impact how well the COVID-19 vaccines work. However, from a clinical standpoint and as best we can tell from the current state of the data, IL-23 inhibitors do not seem to have any clinical impact on how well the vaccines work.11

Are you aware of any future research directions for selective IL-23 inhibition?

One of my colleagues is doing a study where he is giving a very large dose of an IL-23 inhibitor to see if a disease can be driven really deep into remission and therefore produce prolonged remissions when patients are taken off medications. Certainly, the drugs are being studied for psoriatic arthritis and inflammatory bowel disease. There’s a critical need to understand what those drugs do to cardiovascular disease (CVD). Do they improve aortic vascular inflammation? Do they improve dyslipidemia and its resistance? Do they improve CVD and ultimately lower cardiovascular events? That’s a key issue in people with psoriatic disease and we just don’t have a lot of information yet on how the IL-23s impact CVD.

This Q&A was edited for clarity and length.


Dr Gelfand, MD, MSCE reported affiliations with Abcentra LLC, AbbVie Inc.; Bristol-Myers Squibb Company; Boehringer Ingelheim Pharmaceuticals, Inc.; Cara Therapeutics Inc; GlaxoSmithKline PLC; Eli Lilly and Company; Janssen Biologics; Novartis Pharmaceuticals Corporation; and UCB S.A.


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Reviewed May 2022