Travis Vandergriff

Phototherapy in the management of atopic dermatitis: a systematic review.

Background/purpose: Atopic dermatitis (AD) is a common and extremely burdensome skin disorder with limited therapeutic options. Ultraviolet (UV) phototherapy is a well tolerated, efficacious treatment for AD, but its use is limited by a lack of guidelines in the optimal choice of modality and dosing. Given this deficit, we aim to develop suggestions for the treatment of AD with phototherapy by systematically reviewing the current medical literature.

Confetti-like depigmentation: A potential sign of rapidly progressing vitiligo

BACKGROUND Confetti-like depigmentation was noted in patients reporting recent worsening of vitiligo. OBJECTIVE We sought to determine if confetti-like depigmentation is a marker of rapidly progressing vitiligo. METHODS Review of patient records and images of patients from a vitiligo registry resulted in 7 patients with 12 images that fit inclusion criteria and were evaluated for percent depigmentation by 3 independent reviewers. The Vitiligo Disease Activity Score and the Koebner Phenomenon in Vitiligo Score in an additional cohort of patients with confetti-like lesions were compared with patients who had vitiligo without confetti-like lesions. RESULTS The mean percentage of depigmentation at baseline was 19.2%, which increased to 43.9% in images obtained at a mean of 16 weeks of follow-up. Vitiligo Disease Activity Score and Koebner Phenomenon in Vitiligo Score were significantly higher in the patients with confetti-like lesions compared with those without confetti-like lesions. A skin biopsy specimen of a confetti-like lesion in 1 patient revealed an inflammatory infiltrate in the papillary dermis with CD8(+) T cells localized to the dermoepidermal junction. LIMITATIONS Small, single-center retrospective review and lack of full-body photographs are limitations. CONCLUSIONS A confetti-like pattern of depigmentation may be a negative prognostic indicator for patients with rapidly progressing vitiligo. Further, prospective studies to evaluate this physical finding should be performed.

Antibiotic Use in Sexually Transmissible Diseases

Sexually transmissible diseases (STDs) remain a major health issue worldwide, with approximately 300 million new cases annually. STDs caused by bacteria can be treated with antibiotics, although the susceptibility pattern of many etiologic microbes has changed over the past few decades. Syphilis remains best managed with single-dose benzathine penicillin G. Other single-dose antibiotic regimens for lues are either associated with clinical failure or of uncertain dosage. However, single-dose azithromycin and ceftriaxone are suitable for chancroid. Lymphogranuloma venereum, reemergent as a cause of proctitis, is treated with prolonged courses of doxycycline or minocycline. Trimethoprim-sulfamethoxazole has replaced tetracycline derivatives as preferred treatment for donovanosis in many regions. Parenteral cephalosporins, such as ceftriaxone, cefotaxime, and ceftizoxime, are initial interventions for disseminated gonococcemia. Pending culture results, genital bite wounds (often consisting of deep, painful ulcerations) should be treated with high-dose amoxicillin-clavulanic acid.

The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1

By keeping activation of the kinase p38α in check, the ubiquitin ligase Itch inhibits skin inflammation in mice. Itching to reduce inflammation Activation of the kinase p38 is associated with various inflammatory skin disorders. Pharmacological inhibition of p38 alleviates certain inflammatory conditions, but causes toxicity in others; thus, alternative strategies are required. Theivanthiran et al. studied the role of p38α in mice deficient in the E3 ubiquitin ligase Itch, so named because these mice have itchy skin. Compared to skin cells from wild-type mice, those from Itch−/− mice had increased amounts of the p38α-binding protein Tab1 and enhanced activation of p38α. In wild-type skin cells, Tab1 was ubiquitylated by Itch and targeted for degradation. Subcutaneous injection of Itch−/− mice with a cell-permeable peptide that blocked the Tab1-p38α interaction led to decreased skin inflammation, suggesting a potential means to therapeutically target p38α in inflammatory diseases. Deficiency in the E3 ubiquitin ligase Itch causes a skin-scratching phenotype in mice. We found that there was increased phosphorylation and activation of the mitogen-activated protein kinase p38α in spontaneous and experimentally induced skin lesions of Itch-deficient (Itch−/−) mice. Itch bound directly to the TGF-β–activated kinase 1–binding protein 1 (Tab1) through a conserved PPXY motif and inhibited the activation of p38α. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38α phosphorylation exhibited by Itch−/− cells. Similarly, reconstitution of Itch−/− cells with wild-type Itch, but not the ligase-deficient Itch-C830A mutant, inhibited the phosphorylation and activation of p38α. Compared to the skin of wild-type mice, the skin of Itch−/− mice contained increased amounts of the mRNAs of proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1β, IL-11, and IL-19. Inhibition of p38 or blocking the interaction between p38α and Tab1 with a cell-permeable peptide substantially attenuated skin inflammation in Itch−/− mice. These findings provide insight into how Itch-mediated regulatory mechanisms prevent chronic skin inflammation, which could be exploited therapeutically.

Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses

Background: Human polyomavirus (HPyV)6 and HPyV7 are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression. Objective: We determined whether biopsy specimens showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection. Methods: We screened biopsy specimens showing “peacock plumage” histology by polymerase chain reaction for HPyVs. Cases positive for HPyV6 or HPyV7 were then analyzed by immunohistochemistry, electron microscopy, immunofluorescence, quantitative polymerase chain reaction, and complete sequencing, including unbiased, next‐generation sequencing. Results: We identified 3 additional cases of HPyV6 or HPyV7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared with normal‐appearing skin and the identification of intact virions by both electron microscopy and next‐generation sequencing support a role for active viral infections in these skin diseases. Limitation: This was a small case series of archived materials. Conclusion: We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a distinctive histologic pattern and describe this entity as “HPyV6‐ and HPyV7‐associated pruritic and dyskeratotic dermatoses.”

Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma

New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na+/K+ pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically extending survival. MEK inhibitor and digitoxin do not induce cell death in human melanocytes or haematopoietic cells in NSG mice. In melanoma, MEK inhibitor reduces ERK phosphorylation, while digitoxin disrupts ion gradients, altering plasma membrane and mitochondrial membrane potentials. MEK inhibitor and digitoxin together cause intracellular acidification, mitochondrial calcium dysregulation and ATP depletion in melanoma cells but not in normal cells. The disruption of ion homoeostasis in cancer cells can thus synergize with targeted agents to promote tumour regression in vivo.

Pyoderma gangrenosum (PG) associated with levamisole-adulterated cocaine: Clinical, serologic, and histopathologic findings in a cohort of patients.

BACKGROUND Recently, isolated reports of pyoderma gangrenosum (PG) secondary to levamisole-contaminated cocaine have been described, with similar serologic findings to the vasculopathic presentation. OBJECTIVE We sought to describe clinical, histopathological, and serologic findings in 8 patients with PG associated with levamisole-contaminated cocaine. METHODS Eight consecutive patients presenting with this disease spanning the period from 2011 to 2015 were included for the cohort. Observed variables included: lesion distribution, morphology, serologic titers, and histopathologic evaluation for vasculitis and vasculopathy. RESULTS All patients reported cocaine exposure prior to the onset of lesions resembling PG. Lesions appeared primarily on the upper (6 of 8 patients) and lower (all 8 patients) extremities. Most patients demonstrated elevated titers for p-ANCA and antiphospholipid antibodies, and a diffuse dermal infiltrate dominated by neutrophils was seen in all biopsy specimens. Lesions improved or remained stable with conservative management or short courses of steroids, and recurrence was only noted on re-exposure to adulterated cocaine. LIMITATIONS The study is limited by sample size. CONCLUSIONS PG may occur after exposure to levamisole-adulterated cocaine. Clinical and histopathological findings resemble those seen in conventional forms of PG, whereas serologic findings mirror those seen in other levamisole-associated vasculopathic or vasculitic eruptions. Cocaine avoidance represents a cornerstone of management in these patients.

Reliability assessment and validation of the postacne hyperpigmentation index (PAHPI), a new instrument to measure postinflammatory hyperpigmentation from acne vulgaris

BACKGROUND There are no validated outcome measures for postinflammatory hyperpigmentation (PIH). OBJECTIVE We sought to determine the reliability and validity of an outcome measure for PIH after acne in patients with skin of color. METHODS A postacne hyperpigmentation index (PAHPI) was developed. Six raters scored 21 patients with PIH twice. Reliability was determined within and between raters, whereas validity was evaluated by comparing scores with severity ranking by an independent dermatologist. The pigment intensity scores were compared with the melanin index of each patient using a narrowband reflectance spectrophotometer. A quality-of-life score (Skindex-29) was also compared with PAHPI scores. RESULTS Total PAHPI scores showed good reliability within and between raters and were valid when compared with clinical severity and melanin indices. Good correlation was achieved between the total PAHPI score and the emotion subscale of the Skindex-29. LIMITATIONS Generalizability of results is limited to African American females. CONCLUSION The PAHPI shows good reliability and validity when scored on patients with PIH from acne vulgaris. The PAHPI also correlates well with the emotional impact of PIH as measured by the Skindex-29. Future studies should assess the ability of the PAHPI to change with improvement of PIH from acne after treatment.

Prevention of scar spread on trunk excisions: A rater-blinded randomized controlled trial

IMPORTANCE Wounds that heal under tension lead to wider and more conspicuous scars and result in decreased long-term patient satisfaction. We hypothesized that prolonged intradermal suture lifetime can decrease scar spread in wounds under tension. OBJECTIVE To determine whether prolonged intradermal support would help decrease scar spread. DESIGN Prospective, randomized, controlled, rater-blinded, split-scar trial. SETTING Outpatient dermatology clinic at Dallas Veterans Affairs Hospital, Dallas, Texas. PATIENTS Patients presenting with skin cancer on the trunk were considered for the trial. We included 25 distinct surgical sites on a total of 22 patients. INTERVENTION After excision, the wounds were closed with polyglactin 910 and poly-4 hydroxybutyrate (P4HB) sutures in opposite halves of the same wound. MAIN OUTCOME MEASURES Quantitative scar spread at 12 months and qualitative assessment using a visual analog scale and Hollander Wound Evaluation Scale. RESULTS We found a statistically significant difference in scar width between the 2 suture materials, with a mean difference of 2.3 (95% CI, 1.0-3.6) mm (P < .001) favoring P4HB. A clinically significant difference on the visual analog and Hollander Wound Evaluation scales was not identified. Suture reactions were more common with P4HB. CONCLUSIONS AND RELEVANCE Prolonged intradermal suture support leads to significantly decreased scar spread. However, the use of a longer-acting absorbable suture increases the rate of suture reaction noted at 3 months. Further studies into less reactive, longer-acting biomaterials are needed. In clinical practice, excisions in high-tension areas that are classically known to spread over time can benefit from longer-acting intradermal sutures. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00938691.

Increased plasma d-2-hydroxyglutarate in isocitrate dehydrogenase 2–mutated blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm is an exceedingly rare hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 genes have been discovered in a range of neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, and intrahepatic cholangiocarcinoma. Mutant IDH acquires neomorphic enzymatic activity to generate the oncometabolite d-2-hydroxyglutarate (d-2HG). Here, we describe the first case of an IDH2 R140Q-mutated blastic plasmacytoid dendritic cell neoplasm in a patient with markedly elevated plasma d-2HG. This finding expands the spectrum of neoplasms with increased d-2HG in association with IDH mutation. The roles of IDH mutation and d-2HG in disease pathogenesis and assessment of clinical response are discussed.