## 4 Therapeutic Targeting of IL-1 Family Cytokines  
### IL-1  
Several IL-1 blocking agents have been developed to treat different diseases; the corresponding indications have been approved in some cases, and there are several ongoing clinical trials, with variable results.  
Anakinra is a recombinant IL-1 receptor antagonist that competitively inhibits the interaction of both IL-1\(\alpha\) and IL-1\(\beta\) with their receptor. It is currently approved for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndromes. Anakinra has shown efficacy in deficiency of interleukin-1 receptor antagonist (DIRA) and variable responses have been obtained in PP patients [84; 85]. The results of the APRICOT trial--a double-blind, multicenter, 8-week placebo-controlled trial to determine the efficacy of anakinra for the treatment of adults with palmoplantar pustulosis (PPP)--have shown futility of anakinra in 64 patients [86]. However, poor adherence due to the daily injection schedule, short duration of the intervention, and a different pathogenesis in PPP could be confounding factors influencing the poor response to anakinra in this trial [86]. Anakinra has been used in HS with controversial results. Case reports and small series have shown variable degrees of efficacy, with an open-label study of five patients finding reductions in disease activity [87]. A double-blind, randomized, placebo-controlled trial had promising results (78% of treated patients achieved at least a 50% reduction in the inflammatory lesions vs. 30% in the placebo group) [88]. However, long-term results from a more recent small study showed eventual relapse and class switching from anakinra to other therapeutic strategies [89]. Anakinra was assessed in a phase II clinical trial in inflammatory pustular skin diseases including Sneddon-Wilkinson disease, acroderatitis continua of Hallopeau, PP, and PPP. Fifty percent of participants achieved 50% disease improvement by the end of week 12 [90].  
Bermekimab, an inhibitor of IL1\(\alpha\), has yielded good results in phase II open-label studies in HS patients--even after failure to anti-TNF therapy--with significant reductions in inflammatory lesions and no significant drug-related adverse events [91; 92; 93]. Currently, there is one ongoing trial with bermekimab (NCT04988308) in HS [94]. Furthermore, it was used in 11 patients with acne vulgaris, with rapid improvements and no severe adverse events [95]. In an open-label trial, bermekimab also showed encouraging results in psoriasis [96]. Two phase 2 studies of bermekimab for the treatment of adult patients with moderate-to-severe AD were terminated due to lack of efficacy [97; 98].  
Canakinumab is a human monoclonal antibody targeting IL-1\(\beta\) and has shown contradictory efficacy results in case reports in HS [99; 100]. In psoriasis, canakinumab has been reported to be efficacious in a patient with a severe form of PP [101], but not in two patients with severe PPP [102]. In an open-label prospective study of steroid-refractory PG, canakinumab provided complete remission in 3/5 patients [82].  
Gevokizumab is a novel IL-\(\beta\) inhibitor that has shown efficacy in PP patients without prior history of plaque psoriasis [91].