Secukinumab for the treatment of adult-onset pityriasis rubra pilaris: a single-arm clinical trial with transcriptomic analysis.

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.

Histopathologic features of necrobiosis lipoidica.

BACKGROUND: Necrobiosis 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. METHODS: A retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM. RESULTS: Of 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). CONCLUSIONS: This 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.

Topical Ruxolitinib in the Treatment of Necrobiosis Lipoidica: A Prospective, Open-Label Study.

Necrobiosis lipoidica (NL) is a rare granulomatous disease. There are few effective treatments for NL. We sought to investigate the efficacy and safety of the Jak1/2 inhibitor, ruxolitnib, in the treatment of NL and identify the biomarkers associated with the disease and treatment response. We conducted an open-label, phase 2 study of ruxolitinib in 12 patients with NL. We performed transcriptomic analysis of tissue samples before and after treatment. At week 12, the mean NL lesion score decreased by 58.2% (SD = 28.7%, P = .003). Transcriptomic analysis demonstrated enrichment of type I and type II IFN pathways in baseline disease. Weighted gene coexpression network analysis demonstrated post-treatment changes in IFN pathways with key hub genes IFNG and signal transducer and activator of transcription 1 gene STAT1. Limitations include small sample size and a study group limited to patients with <10% body surface area. In conclusion, ruxolitinib is an effective treatment for NL and targets the key pathogenic mediators of the disease.

Oral Baricitinib in the Treatment of Cutaneous Lichen Planus.

Background: Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon (IFN)-γ, a cytokine implicated in the pathogenesis of LP. Methods: In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre-and post-treatment samples. Results: An early and sustained clinical response was seen with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrate a rapid decrease in interferon signature within 2 weeks of treatment, most prominent in the basal layer of the epidermis. Conclusion: This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. Trial Registration Number : NCT05188521.

Characteristics of ulcerated and non-ulcerated necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is complicated by ulceration in up to 35% of cases. METHODS: Retrospective study of patients with NL seen at our institution between January 1, 1992, and May 25, 2021, was conducted. Ulcerated NL (UNL, n = 83) and non-ulcerated NL (NUNL, n = 233) groups were compared. RESULTS: Twenty-six percent (83/316) of patients with NL experienced ulceration. UNL was significantly more likely to be painful (52% vs. 36%, P = 0.01), was more likely to have a lesion-associated cutaneous malignancy (7% vs. 0%, P < 0.001), and had a larger median size (7 vs. 5 cm, P = 0.004) compared to NUNL. Vascular studies were performed on a subset of patients and revealed transcutaneous oxygen pressure (TcPO2) < 40 mm Hg in 53% and venous insufficiency in 62% with no significant differences between UNL and NUNL groups. In patients with unilateral ulceration, mean TcPO2 values (39.7 vs. 46.6 mm Hg), regional perfusion index <0.6 (29% vs. 14%), and TcPO2 < 40 mm Hg (43% vs. 14%) were worse in the ulcerated leg compared to the non-ulcerated leg, but these differences were not statistically significant. CONCLUSIONS: UNL was more likely to be painful, develop lesion-associated malignancy, and be larger in size compared to NUNL. There were no statistically significant differences in venous insufficiency, arterial Doppler/ankle brachial index, or TcPO2 values between UNL and NUNL patients, however, a significant portion of the cohort demonstrated abnormal vascular studies, particularly on TcPO2 and venous insufficiency testing.