‘Early treatment is the key for psoriasis, and biologics should be used sooner’

Recent advances in psoriasis drugs have significantly changed the goal of psoriasis treatment from simply improving skin symptoms to maintaining long-term disease-free status and preventing comorbidities.

Accordingly, early intervention and effective biologic agents to maintain “completely clear skin” have emerged as important goals in psoriasis treatment.

Dr. Knut Schäkel, a professor of dermatology at the University of Heidelberg in Germany, is revolutionizing psoriasis treatment by presenting results from the phase 3 GUIDE trial, which has redefined concepts, such as biomarkers that can predict treatment outcomes in patients with psoriasis and the role of tissue-resident memory (TRM) cells in relapses.

Korea Biomedical Review recently met with Dr. Knut Schäkel and Dr. Park Eun-joo, the public relations director of the Korean Society of Psoriasis and a professor of dermatology at Hallym University Sacred Heart Hospital, to learn more about the future development of psoriasis treatment in Korea, the current treatment landscape, and ways to improve it, based on the results of the GUIDE study.

KBR: Recent advances in treatment have significantly increased the goals of psoriasis treatment. What are the current objectives of psoriasis treatment?

Professor Knut Schäkel: In the past, the main goal was to achieve a good skin condition, which was possible with many medications. The goal of psoriasis treatment is now much more ambitious than just improving skin symptoms.

For example, the VOYAGE-1 study confirmed that achieving a “disease-free” state where psoriasis does not relapse is possible, even when medications are stopped temporarily. These findings opened up the possibility that if the immune and inflammatory responses are significantly reduced, the disease may not recur even when medications are temporarily discontinued. In other words, medications can fundamentally alter the immune response. If the lesions are blocked early on, they can have a fundamental disease-modifying effect. Based on this, a new goal is being set to change the treatment situation by preventing psoriasis and psoriasis-related comorbidities, such as psoriatic arthritis and cardiovascular disease.

Professor Park Eun-joo: Korea's treatment goals are similar to those of the global one. In the past, psoriasis treatment aimed to achieve PASI (Psoriasis Area Severity Index) 75, PASI 90, and PASI 100 by focusing on how many lesions were cleared. Still, the goal is to maintain “completely clear skin (PASI 100)” for longer. The critical point here is relapse. The goal of treatment is to maintain a high quality of life without relapses.

Usually, patients with psoriasis are categorized as mild, moderate, or severe, and all patients want to be free of skin lesions and have clear skin. However, in Korea, only severe psoriasis patients are eligible for reimbursement, so many patients do not benefit from using biologics. From a medical point of view, many patients would like to use effective biologics as soon as possible. Still, the cost-effectiveness of the healthcare system must also be evaluated. Therefore, the use of biologics in Korea needs to be considered from multiple perspectives.

KBR: Professor Schäkel, you led the GUIDE study, which evaluated the effectiveness of the interleukin 23 (IL-23) inhibitor Tremfya (guselkumab) according to the duration of the disease. Why did you decide to conduct this study?

Schäkel: We had seen in previous studies that some patients who had been off the drug for a while maintained a good response to treatment, and we wanted to know what made this possible. We found this was true for patients with a short disease duration (SDD) of two years or less. We wondered what the results would be if we recruited patients with a short disease duration of two years or less and studied them in detail. We set out to explore the possibility that early intervention in treating psoriasis could lead to long-term maintenance of treatment effects after drug discontinuation.

The GUIDE study was a large clinical trial that recruited 880 patients, with more than 40 percent of the population having short-lived SDD (two years or less). Blood and skin samples were collected from patients, and biopsies and flow cytometric analysis were performed at three centers in Germany. The cellular components of T-cells and macrophages were analyzed in detail, and serum samples were also collected for the study. The study was divided into Parts 1, 2, and 3.

The study's goal was to find patients with a perfect response, achieving a PASI of 100, and to examine the sustainability of the treatment effect when the drug was discontinued.

The GUIDE study allowed us to identify “super responders (SRe).” Super responders were patients who achieved 100 percent clearance of their plaque psoriasis at 20 and 28 weeks after starting treatment. Patients who met certain criteria, including PASI 100, including super-responders, moved on to Part 2, which evaluated whether the treatment effect could be maintained when the dosing period was extended from eight to 16 weeks. In Part 3, the patients were followed to see if the treatment effect was sustained when they stopped the drug.

Psoriasis is a serious disease. However, it's possible to achieve clear skin. Other chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD), do not have such good treatment responses. In fact, in rheumatoid arthritis, a 50 percent reduction in the number of painful joints is considered positive. So, other immunologic fields have noted how dermatology can produce such good responses and are trying to learn more from dermatology.

Dermatology is pioneering a new treatment paradigm for chronic inflammatory diseases that often last for life. Psoriasis is a lifelong disease, and because of its young onset and the development of comorbidities, including heart attacks, patients have a shorter-than-average life expectancy of six to seven years. However, with the possibility of altering the course of the disease, other specialties are now interested in dermatology's research and advances. Therefore, dermatology is a leader in researching and developing chronic inflammatory diseases.

KBR: We’re also curious if the GUIDE study found any characteristics unique to “super responders.”

Schäkel: When we analyzed the factors that cause super-responders, we found that age, disease severity, and gender were insignificant. The main factor was the duration of the disease. Patients with shorter disease duration were about 10 percent more likely to be super-responders than those with longer. For example, if the average rate of achieving super-responders was 34 percent in patients with a long duration of illness, this increased to 44 percent in patients with a short duration of illness.

When a patient first comes in, it is difficult to tell if they will likely be a super-responder simply by looking at their skin condition. However, with information about the short duration of the disease, the clinician could determine that the treatment could be very effective regardless of age or severity of the disease. It's a new way of looking at patients.

KBR: The GUIDE study's implications are a bit difficult to apply to the Korean clinical setting. In Korea, effective treatments, including biologics, cannot be used early in the disease process.

Park: In Korea, we usually use drugs, such as methotrexate (MTX) or cyclosporine, for about three to six months. If the PASI score is 10 or more after six months of treatment, we can move on to biologics. Biologics are generally reserved for patients with severe psoriasis. They are sometimes used without coverage for patients with less severe psoriasis who have a personal need or can afford them financially. For these patients, the duration of biologics may be adjusted as their condition improves.

KBR: Were there any other notable findings from the GUIDE study related to treatment response?

Schäkel: In addition to disease duration, one of the key characteristics of the super-responders was prior biologic use. If you've used a biologic before, the drug is less effective the second time you use a biologic.

Another interesting finding was that biomarkers that could predict drug response were found in lesioned skin and normal skin without lesions. When inflammation occurs, anti-inflammatory cells are produced to reduce inflammation levels, and patients with a good treatment response had higher numbers of anti-inflammatory cells in their normal skin from the start of treatment. This is significant because it could be considered a characteristic of patients who may benefit more from treatment with biologics. In addition, epidemiologic studies have shown that patients who smoke, who are physically inactive or obese may have a poorer response to treatment. In the future, biomarkers that can predict treatment response in patients could be used to identify patients with good inflammation suppression, and specific dietary or exercise programs could be used to induce a higher response.

KBR: The “TRM cells” sub-analysis of the GUIDE study was also impressive. However, the concept of TRM cells is somewhat unfamiliar. Could you explain what they are and their clinical significance?

Schäkel: The immune system is there to protect the body. The skin has a well-developed immune system, with more immune cells than in the blood. The skin's immune system is responsible for protecting the body from chickenpox, herpes, bacterial and viral infections and preventing inflammation from spreading to other parts of the body. This defense response can be weakened in immunocompromised patients.

When inflammation occurs, the skin's immune system tends to remember the inflammation to protect the body. If you have psoriasis, it keeps the memory of it. These cells that have “memories” of previous inflammation or disease are called “tissue-resident memory” (TRM) cells. TRM cells can remain in the skin for at least 10 years and are characterized by their ability to act as a police force and fight against specific inflammation or disease. TRM cells can be considered a type of T-cell associated with acquired immunity. When TRM cells with psoriasis memory remain in the skin, they retain the memory of psoriasis even after the skin clears. Therefore, TRM cells can be reactivated under the right conditions and cause psoriasis relapses.

Therefore, eliminating TRM cells can alter the course of the disease and treat psoriasis as a simple acute disease rather than a chronic disease that requires lifelong treatment. In addition, after achieving clear skin, patients can expect to be free of relapses for at least two to three years after discontinuing medication.

KBR: A sub-analysis confirmed a progressive reduction in TRM cells in patients treated with Tremfya. How do these results translate clinically?

Schäkel: When inflammation is reduced, T cells, such as TRM cells in the skin, are also reduced. In mice, we have shown that IL-23 plays an important role in producing and maintaining TRM cells. As a result, blocking IL-23 can have a disease-modifying effect on the course of the disease itself. Since TRM cells can reside in the skin for a lifetime, we believe that the course of the disease can be improved by gradually reducing the number of TRM cells, especially when the prevalence of psoriasis is not long.

KBR: We are also curious if Korean doctors widely understand the concept of TRM cells and if the effect of reducing TRM cells by inhibiting IL-23 has influenced their prescription of psoriasis treatments.

Park: TRM cells continue to be a hot topic in skin diseases, such as contact dermatitis and vitiligo, as well as psoriasis. Patients often report that their skin condition has improved. Still, their psoriasis has returned in the same spot after a period. In such cases, patients are told that memory cells are left in the skin and activated by the slightest stimulus, which triggers psoriasis again. This is why many doctors are interested in TRM cells.

Both IL-23 and IL-17 inhibitors are effective in treating psoriasis. However, IL-23 is a more advanced concept than IL-17. IL-23 is an important mechanism in the survival and proliferation of TRM cells. Some clinical trials, including animal studies, have suggested that IL-23 inhibitors may reduce TRM cell numbers more than IL-17 inhibitors.

KBR: So, do IL-23 inhibitors have a superior effect over IL-17 in reducing TRM cell numbers?

Schäkel: In the phase 3 ECLIPSE study in patients with moderate to severe plaque psoriasis, we directly compared the effects of IL-23 inhibitors with IL-17 inhibitors. IL-23 is a regulatory cytokine, and IL-17 is a cytokine that occurs at the end of inflammation, so if you think of IL-17 as a fire, IL-23 is the “kindling” that starts the fire. While blocking IL-17 can quickly extinguish the fire (inflammation), blocking IL-23 has the underlying effect of removing the firewood (the cause of inflammation). Based on these properties, blocking IL-23 reduced more TRM cells than blocking IL-17.

On the other hand, T cells help control inflammation, and blocking IL-17 reduced these T cells in addition to TRM cells. On the other hand, blocking IL-23 reduced TRM cells but preserved T cells that regulate inflammation. This suggests that IL-23 inhibitors effectively reduce TRM cells and positively affect inflammation control.

KBR: Based on these findings, what is your outlook for the future of psoriasis treatment?

Schäkel: I think treating psoriasis as early and quickly as possible will be the key. It is important to treat early with drugs that have fewer side effects and are highly effective. Ease of dosing should also be considered. In terms of duration of disease, it is a good biomarker, ranking second in the ranking of biomarkers that predict psoriasis treatment outcomes. In addition, patient characteristics associated with a good response to psoriasis treatment, such as lack of previous biologic experience, may be used as biomarkers for psoriasis treatment.

KBR: Applying the changing paradigm of psoriasis treatment in Korea, including early treatment, will present many challenges. What would you like to say to the government and patients?

Park: Currently, the top priority of the Korean Society of Psoriasis is to improve the treatment of patients with specialty area psoriasis, which has a significantly lower quality of life. It is known that psoriasis of certain exposed areas, such as nails, face, scalp, and groin, significantly reduces patients' quality of life. Therefore, our society focuses on stratifying the severity of psoriasis according to the quality of life of patients with psoriasis. Patients with a PASI score of less than 10 but who have severe symptoms, including nail involvement or scalp lesions and a very low quality of life, should be categorized as severe. This should improve these patients' access to effective biologics.

I would also like to emphasize the importance of lifestyle modification for patients with psoriasis. They have recently experienced great results with biologics, which may lead them to neglect their daily care. I also emphasize the importance of maintaining a regular lifestyle. At the same time, the treatment is effective, as biologics can become ineffective or cause lesions to occur again.