Dose De-escalation in Psoriasis Treatment: A Commentary on Outcomes from the GUIDE Study on Guselkumab Dose Spacing Regimens

The ECLIPSE study provided evidence that interleukin (IL)-23 blockade could reduce CD8-positive tissue-resident memory T cells (TRM cells), altering the inflammatory microenvironment of psoriasis lesions.² However, whether these changes in resident cell populations could impact clinical outcomes remained unclear. The GUIDE study was developed with this objective and demonstrated this relationship.

Based on the idea that the skin’s adaptive immunity has a topographical distribution and that TRM cells play a central role in the recurrence and chronicity of psoriasis, the hypothesis was that patients who achieved early and complete clearance of lesions in response to guselkumab, along with a rapid reduction in TRM cells, would represent a distinct population. Their disease activity could be suppressed to achieve long-term control with extended dosing intervals.

Thus, the GUIDE study was divided into three phases, and this article describes the results of phase 2. Phase 1, up to week 28, aimed to identify “super-responders” (SRes) and to verify if patients with shorter disease duration were more likely to belong to this group. SRes were defined as those who achieved PASI 0 at week 20 and maintained this status until week 28. The study included patients with a ratio of 40:60 between short-duration disease (SDD; ≤2 years) and long-duration disease (LDD; >2 years). The results showed that patients with SDD were more likely to become SRes (43.7% SDD vs. 28.1% LDD).

Overall, compared to non-SRes, SRes had a shorter median disease duration (2.0 [1.3-16.0] vs. 10.0 [1.7-22.0] years), were younger (37.0 vs. 44.0 years), had lower body mass index (BMI) (26.5 vs. 28.3), and were less likely to have received prior biologic therapy (7.1% vs. 17.7%).

Phase 2, between week 28 and week 68, aimed to evaluate whether dose spacing was non-inferior to standard administration in terms of maintaining PASI <3. SRes were randomized to continue receiving guselkumab, 100 mg, every 8 or 16 weeks, while non-SRes continued guselkumab every eight weeks. The primary outcome, the proportion of SRes with PASI <3, was assessed at week 68.

Phase 3, not yet published, will monitor participants between week 68 and week 220 to assess whether SRes remain stable after guselkumab discontinuation and whether disease duration (SDD or LDD) affects these outcomes.

Phase 2 results demonstrate that the primary outcome of noninferiority for guselkumab administered every 16 weeks compared to every eight weeks in maintaining disease control was met: PASI <3 by week 68 was achieved by 137 of 149 patients treated with guselkumab every 16 weeks (91.9%; 90% CI, 87.3%-95.3%) and 137 of 148 patients treated with guselkumab every eight weeks (92.6%; 90% CI, 88.0%-95.8%); OR 0.92; 90% CI, 0.45-1.87; P = 0.001 for noninferiority.

Exploratory sub-studies also evaluated cytokine levels and T-cell subsets in the skin. Findings showed that treatment with guselkumab significantly reduced IL-17A, IL-17F, IL-22, and beta-defensin (BD)-2 levels between baseline and week 28, with sustained suppression through week 68, regardless of the dosing interval. No significant differences were found between groups, except for BD-2 levels.

CD8-positive TRM cell counts in skin lesions decreased over time with treatment. Among SRes, the count continued to be suppressed from week 28 to week 68, regardless of the dosing interval. Moreover, CD8-positive TRM cell counts were normalized as early as week 28 in SRes but not until week 68 in non-SRes.

CD8-positive TRM cells play a pivotal role in the reactivation of psoriasis lesions, and IL-23 appears to be responsible for their activation and subsequent release of IL-17, IL-22.^{2, 3} Therefore, the IL-23 blockade by guselkumab may account for the maintenance of response in SRes with dose spacing in the GUIDE study.

Previous studies on treatment de-escalation have yielded varying outcomes across different mechanisms of action, with some treatments successfully achieving dose spacing while others have not. ^4-7

This clinical trial was effective in identifying candidates for dose de-escalation (those who achieved PASI 100 at two consecutive visits, at weeks 20 and 28) and in identifying factors associated with super-response, such as shorter disease duration, lower BMI and absence of prior biologic treatment.

The study also meets the disease modification criteria established by an international DELPHI¹, showing that early intervention can alter the clinical response, reduce treatment need, and link this response to potential pathophysiological changes, such as reducing inflammatory biomarkers.

Early intervention thus emerges as a new frontier in psoriasis treatment, with evidence indicating benefits in reducing disease burden comorbidities and improving therapeutic response in both the short and long term.^{8, 9} However, this reality is still distant for many patients worldwide, as access to specialized care occurs late in the course of the disease since the availability of specialists and newer, more expensive treatments remains limited.

The ideal cutoff to identify patients with short disease duration remains uncertain in this context. The GUIDE study adopted a 2-year cutoff, while the Step-In study, investigating disease modification with secukinumab, used a 1-year cutoff.

Another critical point is that for stricter response metrics in the GUIDE study (PASI <1 and PASI = 0), the differences between the two populations (SRes with dosing every 8 or 16 weeks) were statistically significant, suggesting that, in the very long term (>68 weeks), this difference may increase.

Therefore, more research on dose reduction is necessary, highlighting the importance of randomized clinical trials, including a standard treatment arm, as in the GUIDE trial. Additionally, studies should explore other medications with the same or different mechanisms of action, including IL-23 and IL-17 inhibitors.

We know from clinical practice that some patients can maintain disease control even with dose spacing (SRes), although we still lack clarity on the characteristics of these patients. The results of this study may help us identify them and propose evidence-based dose-reduction protocols.

Finally, the study is essential for understanding new strategies in psoriasis treatment, suggesting that early intervention may be crucial for maximizing therapeutic benefits and personalizing long-term disease management.