The effect of selinexor on prostaglandin synthesis in virus-positive Merkel cell carcinoma cell lines.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.

Treatment of Bullous Pemphigoid With Dupilumab: A Case Series of 30 Patients.

Bullous pemphigoid is often difficult to treat with the limited therapies available. Here, we describe clinical outcomes among 30 adults with bullous pemphigoid patients treated with dupilumab. We performed a multicenter, retrospective case series between March 2020 to August 2022. Patients received a loading dose of dupilumab 600 mg, followed by 300 mg maintenance dose with varying administration frequency tailored to individual patient response. All patients experienced at least some improvement in blister formation and pruritus, with 23 (76.7%) of patients demonstrating either complete clearance of blistering or marked response. Complete clearance of pruritus or marked response was noted in 25 (83.3%) of patients. Eight patients were effectively maintained solely on dupilumab. One (3.3%) patient reported an injection site reaction. Thirty patients represent a small sample, however, to our knowledge, this is the second largest group of BP treated with dupilumab. Furthermore, we provide an understandable framework for clinicians outside of academics to follow and assess treatment responses in their BP patients treated with dupilumab. Dupilumab should be considered as a therapeutic option in patients with bullous pemphigoid given its ability to induce sustained blistering and pruritus response in both typical and refractory cases while maintaining a favorable safety profile. J Drugs Dermatol. 2024;23(6):e144-e148. doi:10.36849/JDD.8258e.

Cedirogant in adults with psoriasis: a phase 2, randomized, placebo-controlled clinical trial.

BACKGROUND: Dysregulated interleukin (IL)-17/IL-23 signaling contributes to psoriasis pathogenesis. Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus (RORγt), a key transcription factor responsible for IL-17 synthesis and a regulator of the T helper 17 cell lineage program. OBJECTIVE: To evaluate the efficacy and safety of cedirogant to treat moderate-to-severe psoriasis. METHODS: In this phase 2b, multicenter, double-blind, 16-week study (NCT05044234), adults aged 18-65 years were randomized 1:1:1:1 to once-daily oral cedirogant 75 mg, 150 mg, 375 mg, or placebo. Assessments included ≥50%/75%/90%/100% improvement from baseline in Psoriasis Area and Severity Index (PASI 50/75/90/100), static Physician Global Assessment 0/1, Psoriasis Symptoms Scale 0, and improvements in itch, adverse events (AEs), pharmacokinetics, and IL-17A/F levels. Efficacy results based on observed cases were summarized descriptively. RESULTS: Of 156 enrolled patients, most were male (70.5%); 39 patients were randomized to each treatment. Only 47 patients completed the study; the study was terminated early due to preclinical findings. At week 16, PASI 75 achievement rates (primary endpoint) were 28.6%, 7.7%, and 41.7% in the cedirogant 75 mg, 150 mg, and 375 mg groups, respectively, and 0% in the placebo group. AE rates were similar in the cedirogant 75 mg, 150 mg, and placebo groups and higher in the cedirogant 375-mg group; most AEs were mild or moderate. CONCLUSIONS: Patients with psoriasis who received cedirogant showed PASI improvement and cedirogant was generally well tolerated. Results should be interpreted in the context of early study termination. Cedirogant development has been discontinued.

Hidradenitis Suppurativa Found Associated With Cytokine Storm.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease that generates multiple cytokines. Here, we present an example of the cytokines forming a cytokine storm and its effects on the patient. CASE PRESENTATION: We report the case of a 55-year-old man who had severe but stable HS. Serum samples were collected from the patient and extraordinarily elevated cytokine concentrations were identified in the patient's serum.  Conclusion: Cytokine storms may be a condition associated with HS posing additional risk to patient survival. J Drugs Dermatol. 2024;23(5):e134-e136.     doi:10.36849/JDD.7860R1e.

Resolution of painful trichodysplasia spinulosa with topical cidofovir: case report.

Purpose: Trichodysplasia spinulosa (TS) is a rare, disfiguring skin condition which presents with widespread asymptomatic or pruritic, skin-colored papules with white protruding keratin spiculations in immunocompromised individuals. Due to its rarity, there is little data to guide treatment decisions. The purpose of this article is to report a case of TS that completely resolved after treatment with topical cidofovir.Materials and methods: A 19-year-old immunosuppressed female presented with widespread painful, itchy bumps on the nose and face. Upon examination, there were erythematous papules with hyperkeratinized spicules affecting the central face. Biopsy of the lesions was consistent with TS which was confirmed via PCR analysis. The tenderness of this patient's eruption was highly atypical for TS. Once daily topical application of compounded 1% cidofovir cream was prescribed.Results: The patient's symptoms resolved completely after 4 weeks of therapy with topical cidofovir 1% cream, without reduction of immunosuppression.Conclusions: Topical cidofovir 1% cream may be a valuable treatment for this rare disease.

Benefit of Topical Combination Therapy for Acne: Analyzing Effect Size Using Number Needed to Treat.

BACKGROUND: Topical acne trials often are confounded by high vehicle response rates and differing outcome measures, making it difficult to compare treatments. Number needed to treat (NNT) can be a simple, clinically meaningful way to indirectly compare treatment options without head-to-head data. NNT is the number of patients who need to be treated with an intervention to observe one additional patient successfully achieving a desired outcome versus vehicle/placebo. While treatment attributes such as adverse events may not be captured, lower NNT is a good indicator of a more effective treatment. METHODS: Following a search of combination topical treatments for acne vulgaris, all treatments that reported pivotal trial efficacy data consistent with the 2018 FDA definition of success were included in NNT analyses.  Results: Of 13 treatments, 7 reported 12-week treatment success rates in 11 phase 3 trials, with similar baseline demographics/disease severity. Treatment success ranged from 26.8% with tretinoin 0.1%/benzoyl peroxide (BPO) 3% cream to 50% with triple-combination clindamycin phosphate 1.2%/adapalene 0.15%/BPO 3.1% gel. NNTs for the triple-combination gel were 4 and 5 (from 2 pivotal trials). Adapalene 0.3%/BPO 2.5% gel had an NNT of 5. Tretinoin/BPO had the largest range between trials, with NNTs of 4 and 9. The other 4 treatments had NNTs ranging from 6 to 8. CONCLUSION: A comparison of combination topical acne treatment trial data, using the same treatment outcome and similar patient populations, resulted in triple-combination clindamycin phosphate/adapalene/BPO gel and adapalene/BPO gel having the most favorable NNTs.J Drugs Dermatol. 2024;23(2):42-49.  doi:10.36849/JDD.7927.

Buffalopox: An emerging cutaneous disease in humans.

BACKGROUND: Buffalopox virus (BPXV) infection is an under-recognized zoonotic disease associated with recently reported outbreaks in humans in South Asia. It is frequently isolated from skin lesions in cattle and buffalos, and can be transmitted to humans by direct contact with the skin of infected animals and fomites. Very little data exist to inform treatment guidelines. CASE REPORT: We present a case report of a 50-year-old male with this rare but emerging disease. CONCLUSION: As outbreaks of viral skin disease such as buffalopox become more common, it is essential for dermatologists to be familiar with their cutaneous manifestations.

Leukemia Cutis in Skin of Color.

The various presentations of many dermatologic conditions among various skin types are slowly being elucidated throughout the recent years. These differences present as an issue as it leads to delayed diagnosis, treatment, and poorer quality of life. Herein, we present the characteristics of leukemia cutis in a skin of color patient with diagnosed chronic myelomonocytic leukemia. Adjei S, Temiz LA, Miller AC, et al. Leukemia cutis in skin of color. J Drugs Dermatol. 2023;22(7):687-689. doi:10.36849/JDD.7020.

Comparison of risankizumab and apremilast for the treatment of adults with moderate plaque psoriasis eligible for systemic therapy: results from a randomized, open-label, assessor-blinded phase IV study (IMMpulse).

BACKGROUND: Treatment of psoriasis with risankizumab has demonstrated superior efficacy to other treatments, such as adalimumab, ustekinumab and secukinumab. OBJECTIVES: This study compared the efficacy and safety of risankizumab and apremilast in adults with moderate plaque psoriasis eligible for systemic therapy. It also evaluated the efficacy and safety of switching to risankizumab vs. continuing apremilast in patients who did not achieve ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75 nonresponders) after 16 weeks of treatment with apremilast. METHODS: This 52-week, phase IV, multicentre, randomized, open-label, efficacy assessor-blinded study (NCT04908475) enrolled patients (aged ≥ 18 years) with a diagnosis of moderate chronic plaque psoriasis (≥ 6 months) and who were candidates for systemic therapy. The enrolled patients (randomized 1 : 2) received subcutaneous risankizumab (150 mg at weeks 0 and 4) or oral apremilast (30 mg twice daily). At week 16, all patients treated with apremilast were re-randomized (1 : 1) to risankizumab or apremilast, stratified by week-16 PASI 75 response. The co-primary outcomes in period A at week 16 were the achievement of ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) and static Physician's Global Assessment (sPGA) 0/1 with a two-grade or better improvement from baseline. At week 52, the primary endpoint in period B was the achievement of PASI 90 in PASI 75 nonresponders with apremilast at week 16. Safety was monitored throughout the study. All patients who received one dose of treatment were included in the efficacy and safety analysis. RESULTS: At baseline, 118 and 234 patients were assigned to receive risankizumab and apremilast, respectively. At week 16, PASI 90 was achieved by 55.9% [95% confidence interval (CI) 47.0-64.9] and 5.1% (95% CI 2.3-8.0), and sPGA 0/1 by 75.4% (95% CI 67.7-83.2) and 18.4% (95% CI 13.4-23.3), respectively. In period B, among PASI 75 nonresponders with apremilast at week 16, 83 switched to risankizumab and 78 continued apremilast. At week 52, 72.3% (95% CI 62.7-81.9) who switched to risankizumab achieved PASI 90 vs. 2.6% (95% CI 0.0-6.1) who continued apremilast. The most frequent adverse events (reported in ≥ 5%) in risankizumab-treated patients were COVID-19 infection and nasopharyngitis. Diarrhoea, nausea and headache were most frequent among apremilast-treated patients. CONCLUSIONS: For patients with moderate psoriasis, treatment with risankizumab demonstrated superior efficacy to those treated with apremilast, including those who did not benefit from prior treatment with apremilast. The safety profile of risankizumab was similar to prior studies, and no new safety signals were identified. These results show that, compared with apremilast, risankizumab treatment can significantly improve clinical outcomes in systemic-eligible patients with moderate psoriasis.

Effect of selinexor on lipogenesis in virus-positive Merkel cell carcinoma cell lines.

BACKGROUND: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine cutaneous carcinoma aetiologically linked to the Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors are currently the first-line therapy for metastatic MCC; however, the treatment is effective in only about half of patients, highlighting the need for alternative therapies. Selinexor (KPT-330) is a selective inhibitor of nuclear exportin 1 (XPO1) and has been shown to inhibit MCC cell growth in vitro, but the pathogenesis has not been established. Decades of research have established that cancer cells significantly upregulate lipogenesis to meet an increased demand for fatty acids and cholesterol. Treatments that inhibit lipogenic pathways may halt cancer cell proliferation. AIM: To determine the effect of increasing doses of selinexor on fatty acid and cholesterol synthesis in MCPyV-positive MCC (MCCP) cell lines and aid in elucidating the mechanism by which selinexor prevents and reduces MCC growth. METHODS: MKL-1 and MS-1 cell lines were treated with increasing doses of selinexor for 72 h. Protein expression quantification was determined using chemiluminescent Western immunoblotting and densitometric analysis. Fatty acids and cholesterol were quantified using free fatty acid assay and cholesterol ester detection kits. RESULTS: Selinexor causes statistically significant reductions of the lipogenic transcription factors sterol regulatory element-binding proteins 1 and 2, and lipogenic enzymes acetyl-CoA carboxylase, fatty acid synthase, squalene synthase and 3ß-hydroxysterol Δ-24-reductase in a dose-dependent manner in two MCCP cell lines. Although inhibiting the fatty acid synthesis pathway results in meaningful decreases in fatty acids, the cellular cholesterol levels did not demonstrate such reductions. CONCLUSION: For patients with metastatic MCC refractory to immune checkpoint inhibitors, selinexor may provide clinical benefit through the inhibition of the lipogenesis pathway; however, further research and clinical trials are needed to evaluate these findings.

Antibiotic Resistance in Dermatology Part 2: Combating Resistance.

Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand how dermatologists can combat this issue.

Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor ß antibody, in moderate-to-severe prurigo nodularis: a randomised, double-blind, placebo-controlled, phase 2a study.

Background: Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis. Methods: This double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n = 40). Patient eligibility criteria included age 18-75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5-2 cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch-Numeric Rating Scale (WI-NRS) score ≥7 at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch-Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891. Findings: Of 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score, -50.6% versus -29.4% (LS-mean difference [95% CI], -21.2% [-40.82, -1.60]; p = 0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p = 0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p = 0.03); LS-mean PCFB in pruritus VAS score, -54.4% versus -32.6% (p = 0.03); and LS-mean PCFB sleep loss reduction (improvement), -56.3% versus -30.0% (p = 0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]). Interpretation: Vixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-third of the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis. Funding: Kiniksa Pharmaceuticals, Ltd.