The effectiveness of guselkumab in the treatment of psoriasis makes it a promising option for inflammatory skin disease management. While long-term guselkumab treatment is frequently required for psoriasis, tailored treatment approaches and strategies for therapy de-escalation have yet to be fully explored.
Recent studies have demonstrated survival rates above 90% after 2 years of treatment with guselkumab, 85.5% after 3 years, and 82.4% after 4 years.1 Further, the GUIDE clinical trial suggests disease activity in patients who achieve early complete skin clearance after 20 to 28 weeks of treatment — dubbed super-responders (SRs) — may be adequately controlled with an extended guselkumab dosing interval, highlighting its potential for individualized treatment approaches.2
The success of guselkumab brings even more hope to those struggling with the disease, according to John Barbieri, MD, MBA, an assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital.
Mechanisms of Action
Guselkumab is an immunoglobulin gamma 1 lambda monoclonal antibody that selectively inhibits the p19 subunit of interleukin (IL)-23 cytokine. The development of psoriasis and psoriatic arthritis is mediated by IL-23 via the activation of Th17 helper T cells, which contribute to tissue damage. Treatment with guselkumab blocks IL-23-induced Th17 cells and inhibits the production of IL-17, a cytokine detected in abundance in the blood of patients with psoriasis and psoriatic arthritis. The inflammatory properties of IL-23 and IL-17 play a significant role in the progression of both conditions.
Can we do it in a more individualized protocol that might help improve the patient experience or reduce the cost on the health care system?
Guselkumab is administered by subcutaneous injection and has an approved dosing schedule of 100 mg at baseline, followed by another 100 mg given at week 4 and in 8-week intervals thereafter for the duration of treatment. Pharmacokinetic models indicate it has a half-life of 18.1 days, providing insight into its lengthy dosing regimen.3
Long-Term Maintenance
In a novel real-world study, researchers in Italy estimated the drug survival, effectiveness, and safety of guselkumab over a period of 4 years.1
The researchers included 202 patients with psoriasis or psoriatic arthritis who received at least 1 dose of guselkumab. Effectiveness was defined as the achievement of endpoints based on Psoriasis Area Severity Index (PASI) scores: PASI 100, PASI 90, and absolute PASI 3 or lower.
The researchers found that the treatment response was rapid. Overall, 67.06% of patients attained absolute PASI scores of 3 or lower, 37.5% achieved PASI 90, and 30% achieved PASI 100 at 16 weeks. The response rate improved at 28 weeks before reaching a plateau. At 4 years, 64.71% of patients achieved PASI 100, 76.47% achieved PASI 90, and 94.12% achieved absolute PASI scores of 3 or lower (ie, near complete remission).
The estimated rate of survival after 4 years of guselkumab was 68.5%. Further, SR status and a history of cardiac comorbidities decreased the incidence of drug interruption. Safety risks were minimal, with only 2 patients discontinuing treatment due to adverse effects, the most common of which was rhinitis.1
Extending Guselkumab Dosing Intervals
In the GUIDE randomized clinical trial, international researchers hypothesized that patients with psoriasis who achieve early and complete skin clearance in response to guselkumab, along with rapid reduction in skin tissue-resident memory (TRM) T cells, signify a special population. These SRs may benefit from a dosing schedule that permits for long-term disease control with an extended dosing interval.2
In the first part of the study (weeks 0-28), patients received guselkumab at the approved dosing schedule. Patients with a PASI score of 0 at both weeks 20 and 28 were identified as SRs. In the second part of the study (weeks 28-68), patients with SR status were randomly assigned to receive guselkumab 100 mg in either 8- or 16-week intervals and those without SR status continued open-label guselkumab every 8 weeks.
At 68 weeks, the researchers found that guselkumab dosing every 16 weeks was noninferior to standard dosing for disease control in patients with SR status.
Super-Responders and Beyond
The identification patients with SR status may be the next clinical hurdle in the use of extended guselkumab dosing for psoriasis management. In the real-world study of guselkumab’s effectiveness, the researchers defined SR status according to both the GUIDE trial criteria (P <.001) and by the achievement of PASI 100 at 20 weeks with the score maintained through 28 weeks (P =.005). The use of multiple SR definitions was due to disagreement over SR status parameters and clinical characteristics established in the GUIDE trial.1-2 Overall, the researchers of the real-world study indicated their stricter definition of SR status was more clinically appropriate.1
Questions also remain regarding the use of extended guselkumab dosing among patients who meet neither of these SR definitions.
“Whether non-SRes are capable of maintaining long-term disease control with an extended dosing interval was not studied in the GUIDE clinical trial. Achievement of early and complete skin clearance at 2 consecutive visits, representing a high level of stability of response to treatment, may be a critical indicator for effective control of disease activity with an extended dosing interval,” the researchers of the GUIDE trial added.2
Immunologic Effects of Guselkumab
Additional biomarker substudies conducted during the GUIDE trial also raised further questions on the immunologic effects of guselkumab. The authors suggest that early skin clearance with guselkumab is accompanied by rapid and sustained suppression of TRM cells in lesional skin. After this, an extended dosing interval effectively controlled disease activity in SRs.2
“Importantly, the 16-week dosing interval evaluated in the GUIDE clinical trial corresponds to a duration far greater than 5 half-lives of guselkumab.Although it is currently unknown whether some SRs had higher blood levels of guselkumab throughout the dosing randomization period, our data suggest a link between TRM cells and maintenance of clinical response,” the authors wrote.2
Further research is needed to better understand the pathogenic mechanisms at play, especially considering these mechanisms differ between biologic therapies and therefore may not be generalizable. One issue to consider when extending intervals of any biologic therapy is drug antibodies, says Dr Barbieri. For instance, in a study examining extended intervals of a biologic therapy among patients with atopic dermatitis, dupilumab given less frequently than once every 1 or 2 weeks yielded diminished response.4 The authors noted that treatment-emergent antidrug antibodies in this study were slightly higher among patients receiving the extended dosing regimen.
“Psoriasis studies suggest that intermittent administration of biologics can reduce their efficacy and increase risk of antidrug antibodies (ADAs) or of safety issues,” the authors wrote.4
Nonetheless, Dr Barbieri is less concerned about this possibility when treating psoriasis with biologics.
“If you lose effectiveness from 1 biologic for psoriasis, there’s often another you can switch to. To me that is not as huge a concern, as it is for other skin conditions that have fewer treatment options,” he said.
The array of other biologics used to treat psoriasis includes risankizumab, brodalumab, secukinumab, ixekizumab, and bimekizumab.
Personalized Approach
As this research on biologic therapies progresses, patients with inflammatory or immunologic disorders have more hope for personalized treatment strategies. Tailored therapy with guselkumab remains a promising option for patients with psoriasis, despite the questions raised regarding guselkumab de-escalation in recent research.
This personalized approach to dosing guselkumab is of interest to Dr Barbieri in his clinical practice. Indeed, clearance rates vary by patient race, weight, or diabetic status. For example, clearance is higher in patients with diabetes and lower in those who weigh in the first quintile.3
He would like to see data on whether interval dosing can be extended further to 24 or 32 weeks in some patients and what factors predict who will respond best.
“Of course, figuring out what dose could be administered to transform interval dosing to remission would be the brass ring,” Dr Barbieri concluded. “Can we do it in a more individualized protocol that might help improve the patient experience or reduce the cost on the health care system?” he ponders. “There are less shots. Patients like that, too.”
References:
- Mastorino L, Dapavo P, Ortoncelli M, et al. Drug survival, effectiveness, and safety of guselkumab for moderate-to-severe psoriasis for up to 4 years. Clin Exp Dermatol. Published online January 8, 2025. doi:10.1093/ced/llaf010
- Eyerich K, Asahullah K, Pinter A, et al. Noninferiority of 16-week vs 8-week guselkumab dosing in super responders for maintaining control of psoriasis: the GUIDE randomized clinical trial. JAMA Dermatol. 2024;160(9):953-963. doi:10.1001/jamadermatol.2024.2463
- Kerut CK, Wagner MJ, Daniel CP, et al. Guselkumab, a novel monoclonal antibody inhibitor of the p19 subunit of IL-23, for psoriatic arthritis and plaque psoriasis: a review of its mechanism, use, and clinical effectiveness. 2023;15(12):e51405. doi:10.7759/cureus.51405
- Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial. 2020;156(2):131-143. doi:10.1001/jamadermatol.2019.3617
