Recent advances in molecular and pathobiology have brought the field of dermatology to the cusp of reaching a goal that seemed highly improbable or impossible just a few years ago: a cure for plaque psoriasis.
"I'm quite old already, but I think it's within my lifetime. I think within my lifetime we may see curing of psoriasis," said Andrew Blauvelt, MD, of Blauvelt Consultants in Annapolis, Maryland, during a session at the recent American Academy of Dermatology (AAD) annual meeting.
Studies involving multiple aspects of plaque psoriasis evolution, persistence, and progression have produced clues and insights that, taken together, suggest treatment strategies that offer the potential to cure at least some cases of plaque psoriasis. Blauvelt referenced a recent publication on the topic as a summary of current curative-intent strategies and supportive evidence to date.
Authors of the publication concluded, "Our improved understanding of the pathomechanisms of psoriasis, coupled with anecdotal reports of long-term clearance of the disease after cell-based therapies, leads us to the hypothesis that psoriasis is curable. We propose that cure of psoriasis can be achieved by restoring immune homeostasis through a combinatorial personalized medicine approach encompassing early intervention to include biologics, advanced therapeutics, and lifestyle modification."
The authors cited eight therapeutic strategies that make a persuasive case that plaque psoriasis can be cured, most of them involving advances in fields outside of dermatology.
- Early treatment and use of high-dose biologic agents
- Hematopoietic stem cell transplantation
- Mesenchymal stromal cells
- Regulatory T cells (Tregs)
- Chimeric antigen receptor (CAR) T-cell therapy
- Bi-specific T-cell engager therapy
- Gene therapy
- MicroRNA-editing therapy
'Hit Hard, Hit Early'
The conceptual duality of "hit hard, hit early" is not new and has supporting evidence in other autoimmune inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and multiple sclerosis. The underlying hypothesis is that early intervention with aggressive treatment may prevent resident memory T cells from "setting up shop" in skin affected by psoriasis.
The hypothesis was tested in the randomized STEPIn trial comparing secukinumab (Cosentyx) and narrow-band ultraviolet B (nb-UVB) phototherapy in patients who had plaque psoriasis for less than 1 year. After 52 weeks, 91% of patients treated with the biologic agent had at least 90% improvement in the Psoriasis Area and Severity Index (PASI 90), as compared with 42.3% in the nb-UVB phototherapy arm.
"I think we're going to see more and more work in this area in the next few years, a push to hit hard, hit early," said Blauvelt. "I call this the opposite of step therapy. This is anti-step therapy. Instead of going through all of the agents to get to the best drugs, early intervention with the best drugs would be the opposite, where you have a little bit of disease. That's the window of opportunity for possible cure. If we treat aggressively those very early-onset patients, we may be able to prevent chronic disease."
Early intervention in plaque psoriasis interrupts the disease's cumulative impact on quality of life, said Richard Langley, MD, of Dalhousie University in Halifax, Nova Scotia, during the same AAD session. Early intervention also interrupts the processes, particularly systemic inflammation, involved in the development and progression of psoriasis comorbidities, in addition to the course and progression of the disease itself.
A pivotal moment in the push for earlier treatment actually occurred almost 20 years ago. An analysis of a large general practice database showed that patients with severe plaque psoriasis for 3-6 years had a 50% higher relative risk of premature mortality. On average, men and women with severe plaque psoriasis died 3.5 to 4.4 years earlier as compared with patients who did not have psoriasis.
Multiple other studies corroborated the association between plaque psoriasis and early mortality, particularly from cardiovascular disease and related disorders, said Langley. The American Heart Association now recognizes certain inflammatory diseases, including psoriasis, as a risk factor for heart attack.
Whether treatment of plaque psoriasis decreased mortality remained unclear until recently. An analysis of the PSOLAR registry, reported by Langley and colleagues, showed that systemic treatment of psoriasis reduced mortality risk, regardless of treatment duration.
Flipping the Script
"The reduction in mortality was strongest for patients on biologics, but it was found for methotrexate, as well," said Langley. "We could talk about all sorts of comorbidities, but death is probably the ultimate one that we all want to avoid. The fact of the matter is that this inflammation is associated with multiple comorbidities and improving it seems to improve overall survival."
"For dermatologists, I think it flips the script," he continued. "Instead of conversations about the risk of treating psoriasis, we should be talking about the risk of not treating patients with moderate-to-severe psoriasis."
Adding to the evidence supporting "hit hard, hit early," Blauvelt pointed to a 2023 study showing that "super response" (stable complete skin clearance) with the interleukin (IL)-23 inhibitor guselkumab (Tremfya) occurred significantly more often in patients who had plaque psoriasis for less than 2 years. In a follow-up presentation at the 2024 AAD meeting, the authors reported that patients who started guselkumab within 15 months of diagnosis were significantly more likely to have extended drug-free intervals after treatment withdrawal as compared with patients with a longer disease duration before starting treatment.
Continuing through the potential contributors to a cure, Blauvelt turned to resident memory T cells, which he described as T cells that remain in healed psoriatic skin and have the capacity to restart the disease. Upon drug withdrawal, resident memory T cells "act up again" and recruit new T cells into the same area of the healed skin.
"We know how to clear psoriasis but if we want to cure it, we should go after resident memory T cells," said Blauvelt. "We should try to get rid of the 'memory' that's responsible for the recurrences."
Given that resident memory T cell survival depends on IL-23, intervention with a high induction dose of an IL-23 inhibitor might lead to long-term remissions and possibly a cure. At the 2024 Psoriasis: From Gene to Clinic Congress, Blauvelt and colleagues reported findings from a small (N=18) randomized study that supported the concept. Adults with moderate/severe plaque psoriasis of at least 6 months' duration were randomized to two high-dose regimens of risankizumab (Skyrizi), administered three times over 16 weeks. The primary endpoint was change in number of resident memory T cells at 52 weeks.
Patients treated with either dose of the IL-23 inhibitor (300 or 600 mg, two to four times the standard dose) had similar "unprecedented" rates of PASI 90 and PASI 100 responses. Patients who received the higher dose of risankizumab had a significantly greater decrease in resident memory T cell count, but patients in both groups had persistent depletion of resident memory T cells after discontinuing treatment at 16 weeks.
Although treatment ended at 16 weeks, high-dose IL-23 inhibition achieved long-term durability. During follow-up to week 100, two patients remained completely clear and four others maintained PASI 90 responses.
"What does this mean for the future?" Blauvelt asked. "We think this 'knockout therapy' offers the possibility of once-a-year dosing ... I do think we have the possibility of cure for some patients."
Once-Yearly Treatment?
That "pie in the sky" goal of once-yearly treatment is already being put to the test in a clinical trial of the investigational IL-23 inhibitor ORKA-001. A trial in healthy volunteers is underway, and a pilot study of once-yearly dosing is expected to begin before the end of the year, involving a total of 80 patients with moderate-to-severe plaque psoriasis.
About 35 years ago, the first of multiple case reports described the disappearance of psoriasis in a patient who received a bone marrow transplant for reasons unrelated to the skin disease. The reports included one case of a patient who developed psoriasis after a bone marrow transplant involving a psoriatic donor.
A recent review article summarized the findings from the case reports and potential implications for cellular therapy for psoriasis. The authors called cell therapy "the best chance to cure psoriasis." In particular, they cited the potential for mesenchymal stem cells, which are immunomodulatory but not immunogenic.
Another strategy that might play a role in curing psoriasis involves use of therapies to expand Tregs, which inhibit several pro-inflammatory cell types. Defects in the number and/or function of Tregs are associated with several autoimmune diseases, including psoriasis, said Blauvelt. Preliminary studies of the T cell-selective IL-2 agonist rezpegaldesleukin showed good responses in patients with psoriasis and atopic dermatitis, and the activity persisted after treatment discontinuation. The clinical activity was associated with significant increases in Treg count and function.
Blauvelt closed out his presentation with a summary of evidence suggesting a potential role for gene-editing strategies to modify genetic risk or induce a protective effect against psoriasis.
Disclosures
As a long-time industry consultant, Blauvelt submitted an extensive list of financial disclosures with commercial interests.
Langley disclosed relationships with AbbVie, Amgen, Boehringer Ingelheim, Celgene, Centocor/Janssen, Eli Lilly, LEO, Merck, Novartis, Pfizer, UCB, and Union.
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