Guselkumab for hidradenitis suppurativa, a mode of action study.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease impairing
quality of life to a great extent. The pathogenesis of HS has not been
clarified yet, however, it is generally accepted that both, the innate and the
adaptive immune system have a central role in inducing an aberrant inflammatory
response. Systemic treatment of HS is therefore often aimed at suppression of
the immune response. Several studies have investigated the cytokine profile of
HS and showed that IL-23/Th17 and IL-12/Th1 pathways are overexpressed in HS
lesional skin. We demonstrated a 9-fold differential expression of IL-23 p19 in
HS lesions compared to healthy control skin (unpublished). In a recent open
label study, the IL-12/IL-23 inhibitor ustekinumab was shown to be clinically
effective in the majority of HS patients.
Guselkumab is a human monoclonal antibody directed against the IL-23 p19
subunit, recently registered for psoriasis, another auto-inflammatory skin
disease. It has been shown that IL-23 has an key role in the inflammatory
response in HS, maybe of greater significance in HS than IL-12, as this
cytokine is involved in Th17 cell regulation, which are important in a variety
of other auto-inflammatory diseases, and which is a potent inducer of
keratinocyte proliferation.

As the IL-23/Th17 pathway is central in the pathogenesis of HS, we hypothesize
that guselkumab will probably show disease modifying effect on gene expression
and cytokine levels in HS skin.

Primary objective:
To investigate changes in inflammatory pathways induced by IL-23p19 blockade
with guselkumab, in HS lesional skin at week 16 compared to baseline (t=0).
Secondary objectives:
- To determine the efficacy of 4 doses of guselkumab of 200 mg at week 0, 4, 8
and 12 in moderate to severe chronic hidradenitis suppurativa patients, by
clinical response rate at week 16
- To assess the short-term the safety and tolerability of guselkumab 200 mg in
moderate to severe chronic hidradenitis suppurativa patients at week 16.
- To assess the effect of guselkumab on patient reported outcomes measures.
- To assess effect of guselkumab on changes in levels of inflammatory cytokines
and other biomarkers in the peripheral blood.

A multicenter open-label mode of action study.

Twenty patients with moderate to severe hidradenitis suppurativa will be
treated with guselkumab 200 mg at week 0, 4, 8 and 12. The total duration of
the treatment period per subject is 16 weeks.

Eligible patients will be recruited during routine clinical consultations in
the department of Dermatology of the UMCG and Erasmus MC. There is a total of 6
site visits. The screening comprises a short medical exam, disease severity
assessment, serum test and for women also a pregnancy test. Twenty subjects
will be receiving treatment with guselkumab 200 mg. Per subject a total number
of five blood samples and seven small skin biopsies will be obtained.
Participants will be asked to fill in the following questionnaires: PGA, DLQI,
HS-QoL HSIA and NRS scores five times. Clinical photographs (optional) will be
taken at defined intervals, the vital signs (blood pressure and heart rate)
measured five times. At every visit a short medical exam will be performed and
patients will be asked about possible side effects.