The anti‐inflammatory potency of biologics targeting tumour necrosis factor‐α, interleukin (IL)‐17A,IL‐12/23 andCD20 in hidradenitis suppurativa: anex vivostudy

Abstract

SummaryBackgroundBiologics targeting inflammatory mediators can achieve clinical improvements in hidradenitis suppurativa (HS). However, their clinical efficacy shows great interpatient variability in daily practice.ObjectivesTo investigate the anti‐inflammatory potency of a selection of currently available biologics and prednisolone for the treatment of HS in an ex vivo skin culture system using lesional HS biopsies.MethodsLesional skin samples from 10 patients with HS and skin samples from five healthy controls were cultured ex vivo and exposed to prednisolone or biologics targeting tumour necrosis factor (TNF)‐α, interleukin (IL)‐17A, IL‐12/23p40 or CD20 (adalimumab, infliximab, secukinumab, ustekinumab and rituximab, respectively). Real‐time quantitative polymerase chain reaction and cytokine bead arrays were used to measure the inhibitory effect of the biologics on cytokines and antimicrobial peptides (AMPs).ResultsThe relative mRNA expression of all tested cytokines and AMPs was significantly downregulated by all anti‐inflammatory agents (P < 0·001). The protein production of the proinflammatory cytokines TNF‐α, interferon γ, IL‐1β, IL‐6 and IL‐17A was significantly inhibited by adalimumab, infliximab, ustekinumab, prednisolone (all P < 0·001) and rituximab (P = 0·0071), but not by secukinumab (P = 0·0663). On both mRNA and protein levels, adalimumab, infliximab and prednisolone reduced the levels of a broader mix of individual cytokines than secukinumab, ustekinumab and rituximab. Moreover, a significant inhibitory effect on mRNA expression levels of inflammatory markers in healthy control skin was observed only for TNF‐α inhibitors (P < 0·001) and prednisolone (P = 0·0015).ConclusionsThis ex vivo study suggests that TNF‐α inhibitors and prednisolone are the most powerful inhibitors of proinflammatory cytokines and AMPs in HS lesional skin, which concurs with our clinical experience in patients with HS.

Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence

“…The inflammatory signature of established hidradenitis suppurativa has been well characterized in multiple histologic 26,41 and molecular studies. 26,[42][43][44][45] Similarities and parallels with psoriasis 26 have been observed in lesional and perilesional hidradenitis suppurativa tissue, 26,46 with lesional nodules demonstrating mixed inflammatory infiltrates comprising T cells, dendritic cells, plasma cells, neutrophils, [47][48][49][50] and monocytes. 51 Chronic long-…”

“…56 Therefore, studies that do not define the severity, treatments, sites, and lesion types of biopsies should be interpreted with caution. 41,42 The mechanisms of lesion development are unclear because perilesional inflammation is of the same character (albeit less intense) as nearby lesional inflammation 42,43,57 ; however, lesional cytokine profiles are unable to be experimentally generated from the addition of IL-1a, IL-1b, or both to perilesional tissue. 5,57 This raises the prospect that the process of inflammation in hidradenitis suppurativa is more complex than initially thought and that the inflammatory characteristics of perilesional tissue are distinct from those of lesional tissue.…”

Learning From Success and Failure: Biologics for Non-approved Skin Diseases

“…Promising early data concerning the blockage of the IL-23/IL17 pathway in HS confirm that this pathway is an important initiator of a suppurative neutrophilic inflammation (19, 20, 22, 92). The benefit of blocking IL-17 in aphthosis is in agreement with its defensive capacities against mucosal invasion of pathogens and its protective actions to maintain epithelial barrier integrity.…”

“…Case reports and a small pilot trial mention clear improvement in HS patients receiving secukinumab (17, 18). In contrast, an ex vivo study on lesional skin samples showed a more pronounced decrease in pro-inflammatory cytokine production and antimicrobial peptides with TNF-α inhibitors compared to IL-17 inhibition (19). Treatment with ustekinumab leads to moderate-marked responses in 82% of HS patients (20).…”

Effect of adalimumab on the expression profile of mRNA , and protein associated with JAK / STAT signaling pathway in fibroblast exposed to lipopolysaccharide

“…The effect of anti‐TNF therapy on the expression profile of IL‐17 is ambiguous. For example, Vossen et al determined that under the influence of using adalimumab, the expression of Il‐17 has a statistical decrease, 27 whereas Dige et al 28 indicate a lack of changes in the expression pattern of IL‐17 during adalimumab therapy. Our observations indicate that LPS to a small degree influences the activation of the Il‐17/23 axis.…”