The Biological Basis of Disease Recurrence in Psoriasis

A Historical Perspective and Current Models

Lluís Puig; Antonio Costanzo; Ernesto J. Muñoz-Elías; Maria Jazra; Sven Wegner; Carle F. Paul; Curdin Conrad

Disclosures

The British Journal of Dermatology. 2022;186(5):773-781. 

In This Article

Impact of Interleukin-17 and Interleukin-23 Antagonists on Tissue-resident Memory T Cells

A number of IL-17 and IL-23 inhibitors have demonstrated efficacy, and are currently approved, in the treatment of psoriasis,[76–78] underscoring the critical role of IL-17/IL-23 in psoriasis pathogenesis.[30] Moreover, several clinical studies have shown that clinical response has been maintained with IL-23 antagonists following treatment discontinuation. In the VOYAGE 2 Phase III trial, the median time to loss of PASI 90 response after withdrawal from the IL-23 inhibitor guselkumab was 23 weeks.[79] In a pooled analysis of data from the UNCOVER-1 and UNCOVER-2 Phase III trials, the median time to relapse after withdrawal from IL-17A inhibitor ixekizumab was approximately 20 weeks.[80] The maintenance of response with these agents was greater than might be anticipated based on their elimination half-lives of approximately 18 days[81] and 13 days[82] for guselkumab and ixekizumab, respectively. Similar results have been reported in randomized withdrawal studies of risankizumab and other IL-17/IL-23 antagonists. For the IL-23A inhibitor risankizumab, a median time of 30 weeks from withdrawal of treatment until loss of PASI 90 response was reported.[83] For the IL-23 inhibitor tildrakizumab, the median time until loss of PASI 90 response was 16 and 20 weeks for patients withdrawing from a 100-mg and 200-mg dose, respectively.[84] For the IL-17A/F inhibitor bimekizumab, the median time to loss of PASI 90 response was approximately 20 weeks after the final dose.[85] A somewhat shorter time to loss of response was reported for the anti-IL-17A receptor antibody brodalumab, with loss of response for static Physician's Global Assessment (score of ≥3) occurring after a median of 11 weeks.[86]

A subanalysis of lesional biopsy specimens taken from patients treated with guselkumab and secukinumab in the ECLIPSE study[87] described the frequencies of immune cell populations over 24 weeks of the respective treatments.[49] The frequencies of both CD4+ and CD8+ TRM cells decreased in psoriatic lesions of both treatment groups from baseline up to week 24, while the frequency of CD8+ TRM cells decreased significantly with guselkumab, but not with secukinumab. Conversely, secukinumab treatment decreased the frequency of Tregs, whereas the frequency of Tregs was maintained in biopsies of patients receiving guselkumab.[49] The authors hypothesize that the increased Treg/CD8+ TRM ratio may be related to the superior long-term control of skin inflammation with guselkumab observed in the ECLIPSE study. However, further studies with larger numbers of samples are needed to confirm these preliminary findings.

Mashiko et al.[88] investigated potential mechanisms involved in psoriasis plaque persistence (existence of residual plaques despite ongoing treatment) by comparing patients with psoriasis treated with adalimumab, ustekinumab and secukinumab with a group of untreated patients. A cytokine signature analysis showed that TNF, IL-23, IL-17 and IFN-1 were elevated in lesional vs. non-lesional skin in all patient groups. T-cell subsets and their cytokine production were also investigated. Cells were stained with CD103 (a TRM cell marker) and CD161 (an IL-17-producing T-cell marker). Percentages of CD103+ and CD103 cells were similar across groups, as were those of IL-17-producing cells. Epidermal CD103+ T cells showed no changes in cytokine staining, while dermal CD161CD103 T cells and CD161+CD103 Th17 cells showed decreased IL-17A production in treated plaques, although not significantly in all groups. Overall, their results suggest that aside from subtle differences in drug-treated plaques, underlying biological mechanisms are similar to those present in untreated lesions.[88]

Based on preliminary observations and experiences from other immune-mediated inflammatory diseases such as rheumatoid arthritis, Eyerich et al.[89] hypothesized that patients with a short disease duration (≤2 years) may show a more rapid and pronounced response to guselkumab treatment. These patients may also be able to maintain longer drug-free control of disease after guselkumab withdrawal. This hypothesis is currently a subject of research in the phase III GUIDE study, which is also investigating whether patients who demonstrate a rapid and strong initial response to guselkumab treatment can maintain disease control with less frequent dosing (every 16 weeks instead of every 8 weeks).[89]

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