Prednisolone and rapamycin reduce the plasma cell gene signature and may improve AAV gene therapy in cynomolgus macaques.

Adeno-associated virus (AAV) vector gene therapy is a promising approach to treat rare genetic diseases; however, an ongoing challenge is how to best modulate host immunity to improve transduction efficiency and therapeutic outcomes. This report presents two studies characterizing multiple prophylactic immunosuppression regimens in male cynomolgus macaques receiving an AAVrh10 gene therapy vector expressing human coagulation factor VIII (hFVIII). In study 1, no immunosuppression was compared with prednisolone, rapamycin (or sirolimus), rapamycin and cyclosporin A in combination, and cyclosporin A and azathioprine in combination. Prednisolone alone demonstrated higher mean peripheral blood hFVIII expression; however, this was not sustained upon taper. Anti-capsid and anti-hFVIII antibody responses were robust, and vector genomes and transgene mRNA levels were similar to no immunosuppression at necropsy. Study 2 compared no immunosuppression with prednisolone alone or in combination with rapamycin or methotrexate. The prednisolone/rapamycin group demonstrated an increase in mean hFVIII expression and a mean delay in anti-capsid IgG development until after rapamycin taper. Additionally, a significant reduction in the plasma cell gene signature was observed with prednisolone/rapamycin, suggesting that rapamycin's tolerogenic effects may include plasma cell differentiation blockade. Immunosuppression with prednisolone and rapamycin in combination could improve therapeutic outcomes in AAV vector gene therapy.

The Psychosocial Impact of Atopic Dermatitis.

Atopic dermatitis is a chronic skin condition that has significant psychosocial and quality-of-life impact. The condition causes physical discomfort, emotional distress, embarrassment, social stigma, and daily activity limitation. In an effort to assess these aspects of disease burden, quality-of-life measurement tools were developed. Through use of these tools, we have expanded our knowledge of the psychosocial and quality-of-life burden of this condition. A variety of quality of assessment tools exist, yet there is no consensus on which tool is best suited to assess the quality-of-life impact of atopic dermatitis. Research studies assessing quality-of-life in atopic dermatitis patients utilize a variety of quality-of-life measurement tools; this complicates comparisons across research studies. Though comparison across studies is difficult, the data echoes tremendous overall burden of disease, especially pertaining to psychosocial status and life quality.

Nonprescription Treatment Options.

The pathogenesis of atopic dermatitis (AD) is complex and multifactorial. However, recent advancements in the genetics and pathophysiology of AD suggest that epidermal barrier dysfunction is paramount in the development and progression of the condition (Boguniewicz M, Leung DYM, Immunol Rev 242(1):233-246, 2011). In addition to standard therapy for AD, there are a plethora of nonprescription treatment modalities which may be employed. Over-the-counter treatments for atopic dermatitis can come in the form of topical corticosteroids, moisturizers/emollients, and oral antihistamines. Though these treatments are beneficial, prescription treatments may be quicker acting and more efficacious in patients with moderate to severe disease or during flares. OTC agents are best used for maintenance between flares and to prevent progression of mild disease. Alternative and complementary treatments lack strong efficacy evidence. However, wet wraps, bleach baths, and other treatments appear to be promising when used in conjunction with conventional treatments. With the financial burden of atopic dermatitis ranging from 364 million to 3.8 billion dollars each year in the United States, we suspect this topic will gain further research attention.

Post-transplant primary cutaneous peripheral T-cell lymphoma not otherwise specified in a pediatric patient.

Solid organ and hematopoietic stem cell transplantation may be complicated by the development of post-transplant lymphoproliferative disorders (PTLDs). The World Health Organization categorizes PTLDs into four entities including non-destructive, monomorphic, polymorphic, and classical Hodgkin lymphoma types. The most common PTLDs are B-cell lymphomas, with T-cell lymphomas accounting for only a few cases. Cutaneous T-cell lymphomas are rarer still in post-transplant patients with primary cutaneous peripheral T-cell lymphoma being an extraordinarily rare subtype in this population. PTLDs may be aggressive and are often associated with high morbidity and mortality. Advances in medicine have led to increased awareness of PTLDs and improved diagnostic tools which assist in the diagnosis of these conditions. However, the clinical and histopathologic heterogeneity of PTLDs may make diagnosis a challenge. In the transplant patient population, the cutaneous manifestations of the lymphoproliferative disease may mimic other conditions, such as eczematous dermatitis and graft-vs-host disease. Herein, we report a case of post-transplant primary cutaneous peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in a pediatric heart transplant patient and describe the clinical presentation and diagnostic histopathologic features.

A Comparison of Alternative Medicine Users and Non-Users in Patients With Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa patients often seek non-prescription therapies. OBJECTIVE: To determine the prevalence of alternative medicine use and characterize the differences between patients who report using alternative medications versus those who do not. METHODS: We surveyed 67 patients with hidradenitis suppurativa regarding demographics, alternative medicine use, disease severity, and quality of life. RESULTS: 25 (37.2%) of the HS subjects reported alternative medicine use. Alternative medicine users tended to be younger (36.7 vs 40.8 years), have a shorter time since diagnosis (12.6 vs14.6 years), and reported worse quality of life (14.1 vs 11.0) than non-users. These differences were not statistically significant. LIMITATIONS: Limitations included a small sample size. CONCLUSION: Alternative medicine use among patients with hidradenitis is common regardless of disease severity; even mild disease may drive patients to seek alternative treatment. J Drugs Dermatol. 2021;20(10):1072-1074. doi:10.36849/JDD.6046.

Rubella Vaccine Persistence Within Cutaneous Granulomas in Common Variable Immunodeficiency Disorder.

Common variable immunodeficiency disorder is a primary immunodeficiency disorder characterized by reduced levels of serum immunoglobulins and impaired antibody response. This condition may be associated with development of noninfectious granulomatous dermatitis of the skin which may be disfiguring and destructive. There are no published guidelines for the treatment of cutaneous granulomas in this patient population. In recent studies, rubella virus-positive cells in granulomas were localized to M2 macrophages which have an important role in wound healing and the secretion of immunoregulatory cytokines. We present a case of treatment-refractory, disfiguring common variable immunodeficiency disorder-associated granulomatous dermatitis. Immunofluorescence microscopy of the biopsy specimen confirmed the presence of rubella vaccine capsid proteins in M2 macrophages within the granuloma, a newly recognized phenomenon in this patient population. This knowledge may serve to identify future therapeutic targets or preventative strategies for granulomatous dermatitis in patients with primary immunodeficiency disorder.

Cutaneous metastases of papillary renal cell carcinoma: A case report and review of the literature.

Papillary renal cell carcinoma (RCC) is an uncommon subtype of RCC that is typically encountered at early stages and has a high survival rate. Histopathology typically shows well-defined papillary architecture with tumor cells lining fibrovascular cores and can be further subdivided into type 1 and type 2 tumors based on cytology and genetic basis. Type 1 tumors have a single layer of basophilic cells and low nuclear atypia, while type 2 tumors have a pseudostratified layer of eosinophilic cells and high nuclear atypia. Some tumors have overlapping features of both types. We present a unique case of cutaneous metastases of papillary RCC with typical papillary architecture in the dermis and review the literature on this rare entity.

Validation of a Hidradenitis Suppurativa Self-Assessment Tool.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating dermatologic condition presenting with recurrent abscesses. While there are multiple scales to determine HS severity, none are designed for self-administration. A validated severity self-assessment tool may facilitate survey research and improve communication by allowing patients to objectively report their HS severity between clinic visits. OBJECTIVES: The purpose of this study was to assess a self-administered HS measure. METHODS: An HS self-assessment tool (HSSA) with 10 photographs of different Hurley stages was developed. The tool was administered to patients diagnosed with HS who visited the Wake Forest Baptist Health dermatology clinic over a span of 2 months. Physician-administered Hurley stage was recorded to determine criterion validity. To assess test-retest reliability of the measure, patients completed the HSSA again at least 30 minutes after the first completion. RESULTS: Twenty-four patients completed the measure, and 20 of these patients completed it twice. Agreement between physician-determined Hurley stage and self-determined Hurley stage was 66.7% with a weighted kappa of 0.57 (95% confidence interval [CI]: 0.30-0.84). The weighted kappa for agreement between patients' initial and second completion of the HSSA was 0.81 (95% CI: 0.64-0.99). CONCLUSIONS: The self-administered measure provides moderate agreement with physician-determined Hurley stage and good test-retest reliability.

Psoriasis and Atopic Dermatitis "Resistant" to Topical Treatment Responds Rapidly to Topical Desoximetasone Spray.

PURPOSE:: Topical corticosteroids (TS) are a treatment for atopic dermatitis (AD) and psoriasis (Ps). We assessed whether use of a TS under conditions designed to enhance adherence would be effective in patients who "failed" TS in the outpatient setting. METHODS:: Individuals with treatment-resistant Ps or AD were recruited (AD, n = 12; Ps, n = 12). Six participants were randomized to each of 2 groups of desoximetasone 0.25% spray alone (n = 6) or desoximetasone spray plus twice-daily phone call reminders to use the medication. Disease severity was assessed. RESULTS:: In treatment-resistant Ps patients, desoximetasone spray, with reminders, resulted in statistically significant improvement in all outcome measures. In treatment-resistant AD patients, there was statistically significant improvement in some assessments. Despite the very small sample size and short evaluation time, statistically significant changes were detected in this cohort. This is evidence of the large effect size of TS for Ps and AD when the treatment is used. CONCLUSIONS:: Patients with "treatment-resistant" Ps and AD generally responded well to the use of desoximetasone spray in the trial setting. This may be due to better adherence in the study environment or patients' preference for the spray vehicle. Patient reminders contributed to improved clinical outcomes in Ps and AD patients with "treatment-resistant" disease.

Aptamer-displaying peptide amphiphile micelles as a cell-targeted delivery vehicle of peptide cargoes.

Peptide amphiphile micelles (PAMs) are attractive vehicles for the delivery of a variety of therapeutic and prophylactic peptides. However, a key limitation of PAMs is their lack of preferential targeting ability. In this paper, we describe our design of a PAM system that incorporates a DNA oligonucleotide amphiphile (antitail amphiphile-AA) to form A/PAMs. A cell-targeting DNA aptamer with a 3' extension sequence (tail) complementary to the AA is annealed to the surface to form aptamer-displaying PAMs (Aptamer~A/PAMs). Aptamer~A/PAMs are small, anionic, stable nanoparticles capable of delivering a large mass percentage peptide amphiphile (PA) compared to targeting DNA components. Aptamer~A/PAMs are stable for over 4 h in the presence of biological fluids. Additionally, the aptamer retains its cell-targeting properties when annealed to the A/PAM, thus leading to enhanced delivery to a specifically-targeted B-cell leukemia cell line. This exciting modular technology can be readily used with a library of different targeting aptamers and PAs, capable of improving the bioavailability and potency of the peptide cargo.

Treating Moderate-to-Severe Plaque Psoriasis With Guselkumab: A Review of Phase II and Phase III Trials.

OBJECTIVE: Guselkumab, an anti-interleukin-23 monoclonal antibody was recently approved for the treatment of patients with moderate-to-severe plaque psoriasis. This article will review the available phase II and phase III guselkumab clinical trial data. DATA SOURCES: A PubMed search was conducted using the terms guselkumab, interleukin-23, psoriasis, adalimumab, and ustekinumab (January 2014 to August 2017). STUDY SELECTION AND DATA EXTRACTION: Articles detailing the results of phase II and phase III clinical trials were selected for review. DATA SYNTHESIS: In 1 phase II and 2 phase III clinical trials, guselkumab was more effective than adalimumab and placebo in reducing Physician's Global Assessment and Investigator Global Assessment (IGA) scores in those with moderate-to-severe plaque psoriasis. In a separate phase III trial, transitioning to guselkumab treatment was more effective than continued ustekinumab use in reducing IGA scores in those who were minimally responsive to ustekinumab ( P = 0.001). Trial results did not reveal specific patterns in adverse event (AE) incidence; the most commonly reported AEs were nasopharyngitis, headache, and upper-respiratory-tract infections. No increased incidence of malignancy, tuberculosis, or serious infections were observed with the use of guselkumab. CONCLUSIONS: Guselkumab appears to be a safe and effective option for the treatment of moderate-to-severe plaque psoriasis in patients who have been screened for susceptibility to infection and are candidates for systemic treatment or phototherapy. However, long-term safety data are lacking.

POSH Regulates CD4+ T Cell Differentiation and Survival.

The scaffold molecule POSH is crucial for the regulation of proliferation and effector function in CD8(+) T cells. However, its role in CD4(+) T cells is not known. In this study, we found that disruption of the POSH scaffold complex established a transcriptional profile that strongly skewed differentiation toward Th2, led to decreased survival, and had no effect on cell cycle entry. This is in stark contrast to CD8(+) T cells in which POSH regulates cell cycle and does not affect survival. Disruption of POSH in CD4(+) T cells resulted in the loss of Tak1-dependent activation of JNK1/2 and Tak1-mediated survival. However, in CD8(+) T cells, POSH regulates only JNK1. Remarkably, each type of T cell had a unique composition of the POSH scaffold complex and distinct posttranslational modifications of POSH. These data indicate that the mechanism that regulates POSH function in CD4(+) T cells is different from CD8(+) T cells. All together, these data strongly suggest that POSH is essential for the integration of cell-type-specific signals that regulate the differentiation, survival, and function of T cells.

Frontal Fibrosing Alopecia and Concomitant Lichen Planus Pigmentosus: A Case Series of Seven African American Women.

The association of frontal fibrosing alopecia (FFA) and lichen planus pigmentosus (LPPigm) is rare. Prior reports suggest that FFA and LPPigm are on the same spectrum of disease, and a diagnosis of LPPigm may predict the future development of FFA. We aim to further characterize the association between FFA and LPPigm by reviewing the clinical cases of seven African American women. Seven patients with FFA were diagnosed clinically by recession of frontotemporal hairline and confirmed by histopathologic examination showing lymphocyte-mediated cicatricial alopecia. LPPigm was diagnosed by clinical evaluation alone based on the characteristic morphology, color, and distribution of the lesions. It is difficult to distinguish whether halted progression of FFA was due to the success of the treatment regimen or spontaneous stabilization of disease over time. Our case series supports the theory that FFA and LPPigm likely exist on the same spectrum of disease. Our observations demonstrate a likely positive correlation between FFA and LPPigm.

J Drugs Dermatol. 2018;17(4):397-400.

A Pilot Study Characterizing Factors in Adherence to Cutaneous Lupus Treatment.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease that manifests as scarring, dyspigmentation, erythema, and pain. Topical corticosteroids are a mainstay of treatment. Irritation, messiness, and tediousness may deter use. Thus, nonadherence, rather than nonresponse, can result in treatment failure. Prior adherence studies were limited to systemic lupus erythematosus. We performed a single-center, open-label pilot study to assess adherence to topical medication in patients with CLE. CLE adherence to topical medications is suboptimal and declines over time. Shorter treatment duration and greater patient perception of disease severity may contribute to higher adherence. Improving adherence to existing treatments could be as or more valuable than new therapies for the disease.

Psoriasis therapy and aortic inflammation - translating statistical to clinical significance.

Psoriasis patients are known to have comorbid aortic vascular inflammation, which is one of the leading causes of cardiovascular morbidity and mortality in this population. Many studies report statistically significant improvements in aortic vascular inflammation after use of tumor necrosis factor inhibitors or interleukin-12/23 antagonists. However, the clinical significance in reduction of adverse cardiovascular events in psoriatic patients owing to biologic therapy has not been examined. Regardless of clinically significant cardiovascular benefits, dermatologists should continue to treat psoriasis patients optimally to mitigate the unfavorable effect this disease has on quality of life.

The Psychosocial Impact of Atopic Dermatitis.

Atopic dermatitis is a chronic skin condition which has significant psychosocial and quality of life impact. The condition causes physical discomfort, emotional distress, embarrassment, social stigma and daily activity limitation. In an effort to assess these aspects of disease burden, quality of life measurement tools were developed. Through use of these tools, we have expanded our knowledge of the psychosocial and quality of life burden of this condition. A variety of quality of life assessment tools exist, yet there is no consensus on which tool is best suited to assess the quality of life impact of atopic dermatitis. Research studies assessing quality of life in atopic dermatitis patients utilize a variety of quality of life measurement tools; this complicates comparisons across research studies. Though comparison across studies is difficult, the data echoes tremendous overall burden of disease, especially pertaining to psychosocial status and life quality.

Non-Prescription Treatment Options.

The pathogenesis of atopic dermatitis (AD) is complex and multifactorial. However, recent advancements in the genetics and pathophysiology of AD suggest that epidermal barrier dysfunction is paramount in the development and progression of the condition (Boguniewicz and Leung, Immunol Rev 242(1):233-246, 2011). In addition to standard therapy for AD, there are a plethora of non-prescription treatment modalities which may be employed. Over-the-counter treatments for atopic dermatitis can come in the form of topical corticosteroids, moisturizers/emollients, and oral anti-histamines. Though these treatments are beneficial, prescription treatments may be quicker acting and more efficacious in patients with moderate to severe disease or during flares. OTC agents are best used for maintenance between flares and to prevent progression of mild disease. Alternative and complementary treatments lack strong efficacy evidence. However, wet wraps, bleach baths, and other treatments appear to be promising when used in conjunction with conventional treatments. With the financial burden of atopic dermatitis ranging from 364 million to 3.8 billion dollars each year in the United States, we suspect this topic will gain further research attention.