Pittelkow, Mark R.

Abstract Lichen Planopilaris (LPP) is a lymphocyte-mediated scarring alopecia characterized by progressive follicular destruction and fibrosis. In this clinical trial, patients with biopsy proven LPP were treated with deucravacitinib (an oral inhibitor of tyrosine kinase 2 (TYK2)) 6 mg BID for 24 weeks (NCT-06091956). Bulk and single-cell RNA sequencing was performed on paired pre- and post-treatment scalp biopsies from baseline and week 4. Patients (N=10) demonstrated improvements in PGA (88.9%, p=0.008), LPPAI (−2.3 points, SD 1.1, p=0.002) and Skindex-16 (−21.0 points, SD 22.1, p=0.014) scores at week 24. Bulk transcriptomic analysis of untreated LPP revealed upregulation of type I Interferon (IFN)-stimulated genes and pathways related to inflammation, immune activation, keratinization, and extracellular matrix remodelling, with downregulation of immune and inflammatory pathways following treatment. Single-cell RNA-seq of LPP was characterized by enrichment of CD8+GZMK+ T cells which showed downregulation of T-cell receptor signaling as well as antiviral pathways with treatment. Basal keratinocytes exhibited reduced cytokine and interferon signaling and decreased communication with NK cells following treatment. CCL19+ fibroblasts were prominent in untreated disease was attenuated after treatment, with downregulation of type I IFN signaling. Selective TYK2 inhibition with deucravacitinib effectively suppresses these inflammatory circuits in LPP and represents a promising therapeutic strategy.

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 IFN-γ, a cytokine implicated in the pathogenesis of LP. METHODS In this phase II trial, 12 patients with cutaneous LP received 2 mg daily baricitinib for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and posttreatment 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 + , and CXCL13 + cytotoxic T cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis. CONCLUSION This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. TRIAL REGISTRATION NCT05188521 FUNDING Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.

AbstractBackgroundCutaneous melanoma (CM) is a significant health concern because of its high metastatic potential. Gene Expression Profile (GEP) testing, particularly the 31‐GEP test (DecisionDx‐Melanoma), has been increasingly used for risk stratification in CM patients. This study aimed to evaluate the clinical utility and performance of the 31‐GEP test in a real‐world setting.MethodsPatients with CM who underwent 31‐GEP testing from August 2014 to August 2022 at our institution were identified through searches of electronic health records. The study analyzed the influence of 31‐GEP testing on clinical decision‐making related to sentinel lymph node biopsy (SLNB), medical oncology referral, and postdiagnosis surveillance. Kaplan–Meier curves and Cox proportional hazard models were used to elucidate the test's performance, focusing on relapse‐free survival (RFS) and melanoma‐specific survival (MSS).ResultsThe study included 65 CM patients. Dermatologists ordered more than 80% of 31‐GEP tests. In 81.5% of cases, 31‐GEP results did not alter standard clinical management. SLNB decisions were unaffected in 92% of patients with pre‐SLNB 31‐GEP results. Among patients with stage I‐IIA melanoma, 25% of those with high‐risk 31‐GEP results were referred to medical oncology. Contrary to expectations, the rate of nodal metastasis was higher in low‐risk than in high‐risk 31‐GEP cases. Survival analysis showed overlapping RFS and MSS curves between different 31‐GEP classes, suggesting limited prognostic value.ConclusionsThe 31‐GEP test has a limited impact on clinical management decisions and shows limited prognostic value.

Abstract Background We aimed to investigate the prevalence of skin disease among patients with systemic lupus erythematosus (SLE) and determine whether LE skin disease had clinical or serologic correlates with SLE. Methods We reviewed records of 335 patients with SLE (seen at Mayo Clinic, Rochester, Minnesota, USA) and abstracted skin manifestations, fulfilled mucocutaneous SLE criteria, and clinical and serologic parameters. Results Of the 231 patients with skin manifestations, 57 (24.7%) had LE‐specific conditions, 102 (44.2%) had LE‐nonspecific conditions, and 72 (31.2%) had both. LE skin disease was associated with photosensitivity, anti‐Smith antibodies, and anti‐U1RNP antibodies (all P < 0.001). Patients without LE skin disease more commonly had elevated C‐reactive protein levels ( P = 0.01). Patients meeting 2–4 mucocutaneous American College of Rheumatology criteria less commonly had cytopenia ( P = 0.004) or anti−double‐stranded DNA antibodies ( P = 0.004). No significant associations were observed for systemic involvement (renal, hematologic, neurologic, and arthritis) when comparing patients with or without LE skin involvement. LE skin involvement was not significantly associated with internal SLE disease flare, number of medications, or overall survival. Conclusions LE skin disease commonly occurs in patients with SLE. The presence of LE skin disease had no mitigating impact on the severity of SLE sequelae, disease flares, number of medications, or overall survival.

This report evaluates the use of timolol in 2 patients with long-term hydroxyurea use and lower-extremity ulcers resistant to other treatments.

AbstractBackgroundPrimary cutaneous B‐cell lymphoma (PCBCL) is a group of B‐cell lymphomas of the skin containing primary cutaneous follicle centre lymphoma (PCFCL) and marginal zone B‐cell lymphoma/lymphoproliferative disorder (PCMZL), which are indolent, and diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), which is aggressive.ObjectivesTo evaluate treatment outcomes between PCBCL subtypes after treatment with rituximab and to compare the efficacy of intralesional against systemic rituximab in indolent subtypes.MethodsA search for patients diagnosed with PCBCL and treated with rituximab (systemic or intralesional) across all Mayo Clinic sites was performed, yielding 39 patients.ResultsEight patients had PCFCL (six treated intralesionally and two systemically), 11 had PCMZL (four intralesional, eight systemic with one dual‐treated) and 20 had PCDLBCL‐LT (all systemic). The average age at diagnosis was 62.1 years (SD = 15.1), with average follow‐up of 1852.6 days (SD = 1473.2). 69.2% of all patients treated with any form of rituximab experienced a complete response (100% PCFCL, 81.8% PCMZL and 50% PCDLBCL‐LT). When comparing all three subtypes, a significant difference was seen in overall treatment response (p = 0.022), and progressive disease rates (p = 0.015), but not in retreatment with rituximab (p = 0.440), time to retreatment (p = 0.757), recurrence (p = 0.907) or survival (p = 0.093). In the indolent subtypes, no difference in overall treatment response (p = 1.000), progressive disease rates (p = 1.000), recurrence (p = 0.650), rituximab retreatment (p = 0.650) or time to retreatment (p = 0.724) was observed.ConclusionsThis study suggests that rituximab, as systemic therapy and intralesional therapy, is effective in the management of PCBCL, and that intralesional therapy should be considered before more aggressive therapy in indolent disease.

Abstract Background/Aim: Dermatitis Herpetiformis is the autoimmune skin manifestation of celiac disease, and similar to celiac disease, is tightly associated with HLA-DQ2 and HLA-DQ8. Previously we have generated a mouse model of DH using DQ8 transgenic mice on an NOD background. Herein, we describe a similar DH-like blistering disease that spontaneously develops in DQ2 transgenic mice. Methods: Transgenic mice that express DQ2 on a background deficient in endogenous MHC II (Aeo) were raised on a gluten containing (GC) chow or a gluten free chow . Results: When raised and maintained on a gluten containing chow, approximately 15% of these Aeo DQ2 mice spontaneously developed blisters on the ears and tails at about six months of age. Control Aeo mice that were also raised on a gluten containing chow did not develop this blistering disease during their lifetime. Hematoxilyn and eosin staining revealed subepidermal blisters. Immunohistochemistry revealed IgA deposits at the dermal/epidermal junction in perilesional ear tissue. However, when these mice were raised and maintained on a gluten free diet, these mice did not develop blisters. Conclusions: This blistering disease is a gluten dependent disease that has many of the elements typically associated with Dermatitis Herpetiformis, most especially the association with the DQ2 gene.

AbstractBackgroundNecrobiosis lipoidica (NL) is complicated by ulceration in up to 35% of cases.MethodsRetrospective 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.ResultsTwenty‐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.ConclusionsUNL 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.