Hertl, Michael

Abstract Background Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden, representing a population with a clear unmet need for new treatments. Objectives To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP) that is inadequately controlled by topical corticosteroids. Methods PRELUDE was a randomized double-blind placebo-controlled phase II proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomized to either secukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W) or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator’s Global Assessment (IGA) score ≤ 2 at week 16. Results Overall, 111 patients were randomized (n = 37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the three cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤ 2 response at week 16 with SECQ4W vs. placebo in the MLP {37.5% [95% credibility interval (Crl) 20.3–57.2] vs. 23.1% (95% Crl 6.5–49.2)} and LPP cohorts [37.5% (95% Crl 20.2–57.3) vs. 30.8% (95% Crl 10.8–57.6)]. In the LPP cohort, a sustained response for IGA ≤ 2 from week 16 to week 32 was achieved with SECQ4W (week 16, 37.5%; week 32, 45.8%), and a substantial improvement was observed in IGA ≤ 2 response in patients from this cohort who switched from placebo (week 16, 30.8%) to SECQ2W after week 16 (week 32, 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals. Conclusions PRELUDE is the first randomized controlled basket trial evaluating interleukin (IL)-17A inhibition with secukinumab across three subtypes of LP. Secukinumab was well tolerated and safe, showing different response rates across the three subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of IL-17A across LP subtypes. The novel IGA score showed significant correlation with both patient- and physician-reported outcome measurements.

AbstractThis viewpoint highlights major, partly controversial concepts about the pathogenesis of pemphigus. The monopathogenic theory explains intra‐epidermal blistering through the “desmoglein (Dsg) compensation” hypothesis, according to which an antibody‐dependent disabling of Dsg 1‐ and/or Dsg 3‐mediated cell–cell attachments of keratinocytes (KCs) is sufficient to disrupt epidermal integrity and cause blistering. The multipathogenic theory explains intra‐epidermal blistering through the “multiple hit” hypothesis stating that a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. The major premise for a multipathogenic theory is that a single type of autoantibody induces only reversible changes, so that affected KCs can recover due to a self‐repair. The damage, however, becomes irreversible when the salvage pathway and/or other cell functions are altered by a partnering autoantibody and/or other pathogenic factors. Future studies are needed to (i) corroborate these findings, (ii) characterize in detail patient populations with non‐Dsg‐specific autoantibodies, and (iii) determine the extent of the contribution of non‐Dsg antibodies in disease pathophysiology.