Pittelkow, Mark R.

Objective: Even with our best practices, we are frequently unable to prevent slow and stalled wound healing—particularly in people with impaired circulation and conditions such as diabetes. As a result, greater insight into the nature of wound healing and alternative treatment approaches is needed. An avenue that may be of particular promise is increasing understanding of the role of secretory leukocyte protease inhibitor (SLPI) as there is evidence that it enhances wound healing, its expression increases in response to inflammation and infection, and it exhibits anti-protease, anti-inflammatory, antiviral antibacterial and antifungal activities. Method: The response of SLPI levels to wounding and skin injury was assessed by taking punch skin biopsies from healthy volunteers and assessing the levels of SLPI at the site of injury at the time of wounding (baseline) as well as one, two, three, four, seven, nine and 12 weeks later. Results: A total of 35 volunteers took part in the study. Significant elevations were found: levels of SLPI were greatly increased, 12 times that at baseline, and remained elevated at three weeks despite re-epithelialisation having occurred. Conclusion: These findings not only suggest that levels of SLPI rise rapidly following wounding, but that these elevations are sustained, and continue to increase even when re-epithelialisation has occurred. These results suggest that the role and potential benefits of this protease inhibitor deserve further exploration.

Abstract Background The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP. Objectives To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade. Methods Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician’s Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: ‘Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris’ – NCT03342573. Results At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab. Conclusions Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy.Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease.A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris.Secukinumab was effective in treating pityriasis rubra pilaris.Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.

AbstractBackgroundNecrobiosis lipoidica (NL) is an uncommon granulomatous dermatosis that can occur in patients with or without associated diabetes mellitus (DM). Prior studies have attempted to determine distinctive histopathologic features of NL in patients with and without DM.MethodsA retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM.ResultsOf the 97 patients, 32% (n = 31) had DM. Epidermal acanthosis was seen more commonly in diabetics than nondiabetics (32.3% vs. 12.1%; p = 0.017). Naked (sarcoidal/tuberculoid) granulomas were more frequently observed in nondiabetics than diabetics (22.7% vs. 3.2%; p = 0.016). Eosinophils were more common in nondiabetics than diabetics (38.5% vs. 9.7%; p = 0.004), while neutrophilic infiltration was more common in diabetics than nondiabetics (45.2% vs. 17.5%; p = 0.004).ConclusionsThis study corroborates well‐documented histopathologic features of NL and shows distinctive histopathologic features of NL among patients with DM‐I, DM‐II, and without DM. These results support the hypothesis that there are different underlying drivers of NL between diabetics and nondiabetics.

Abstract The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Background: Subcutaneous lymphomas are a heterogeneous group of diseases with variable clinical behavior that ranges from a lymphoproliferative disorder to an aggressive cytotoxic lymphoma. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon, often indolent cutaneous lymphoma that localizes to the subcutaneous adipose tissue. These tumors exhibit an alpha/beta phenotype (abSPTCL). Primary cutaneous gamma-delta T-cell lymphoma (PCgdTCL) is a rare, highly aggressive lymphoma that frequently involves the subcutaneous adipose tissue. The goal of this study is to identify key inflammatory and oncogenic pathways in SPTCL and PCgdTCL to determine which mutational or expression patterns differentiate abSPTCL and PCgdTCL. A comprehensive catalog of cancer gene expression profiles generated via RNA sequencing on patient samples is essential to understand tumorigenesis and to develop effective therapies. Methods: We performed transcriptomic profiling analysis using RNA sequencing in lesional skin biopsies from patients of abSPTCL (n=10), PCgdTCL (n=9), and controls (n=5). Differential analyses were performed on the entire transcriptomic profiles among the 3 groups. Results: Although the transcriptomic profiles of abSPTCL and PCgdTCL samples had similarities, there were notable differences between these groups that may elucidate unique pathways that propagate each disease. In contrast to abSPTCL, PCgdTCL samples demonstrated upregulation of cell motility and proliferation, and downregulation of pathways involving apoptosis and tumor necrosis factor production. The most significantly upregulated gene pathways in both abSPTCL and PCgdTCL samples were those involving immune and inflammatory response, viral defense, type I interferon signaling, interferon-gamma-mediated signaling, and positive regulation of T cell proliferation. The most significantly downregulated gene pathways in the two groups were those involving cell adhesion, rRNA processing and translation, and extracellular matrix organization. The top 5 upregulated immune response and downregulated cell adhesion hub genes for abSPTCL highlighted by gene interaction network analysis included: TNF, CTLA4, CD86, IL10, CCR5 & ITGB5, ITGA8, VWF, APP, CDH5, respectively. Conclusion: Our transcriptomic profiling pinpoints disease-related enrichment pathways and gene functions in abSPTCL and PCgdTCL patients, which may shed light on molecular mechanisms that drive disease activity. Hub genes in abSPTCL represent potential drug targets for further development of novel therapies. Disclosures Mangold: Kirin:Membership on an entity's Board of Directors or advisory committees;Elorac:Research Funding;Sun Pharma:Research Funding;MiRagen:Research Funding;Solagenix:Research Funding.