Allison S. Dobry

A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin

SUMMARY The presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.

Serious infections among a large cohort of subjects with systemically treated psoriasis

Background: Biologic therapy is effective for treatment of moderate‐to‐severe psoriasis but may be associated with an increased risk for serious infection. Objective: To estimate the serious infection rate among patients with psoriasis treated with biologic as compared with nonbiologic systemic agents within a community‐based health care delivery setting. Methods: We identified 5889 adult Kaiser Permanente Northern California health plan members with psoriasis who had ever been treated with systemic therapies and calculated the incidence rates and 95% confidence intervals (CIs) for serious infections over 29,717 person‐years of follow‐up. Adjusted hazard ratios (aHRs) were calculated using Cox regression. Results: Adjusting for age, sex, race or ethnicity, and comorbidities revealed a significantly increased risk for overall serious infection among patients treated with biologics as compared with those treated with nonbiologics (aHR, 1.31; 95% CI, 1.02–1.68). More specifically, there was a significantly elevated risk for skin and soft tissue infection (aHR, 1.75; 95% CI, 1.19–2.56) and meningitis (aHR, 9.22; 95% CI, 1.77–48.10) during periods of active biologic use. Limitations: Risk associated with individual drugs was not examined. Conclusion: We found an increased rate of skin and soft tissue infections among patients with psoriasis treated with biologic agents. There also was a signal suggesting increased risk for meningitis. Clinicians should be aware of these potential adverse events when prescribing biologic agents.

Association Between Hypercoagulable Conditions and Calciphylaxis in Patients With Renal Disease: A Case-Control Study

Importance Calciphylaxis is a rare skin disease with high morbidity and mortality that frequently affects patients with renal disease. Hypercoagulable conditions are frequently observed in both patients with calciphylaxis and those with chronic kidney disease (CKD), complicating our understanding of which hypercoagulable conditions are specific to calciphylaxis. Objective To identify hypercoagulable conditions that are risk factors for developing calciphylaxis while controlling for CKD. Design, Setting, and Participants This was a case-control study, comparing the hypercoagulability status of patients with calciphylaxis and with renal disease with that of a matched control population at 2 large urban academic hospitals in Boston, Massachusetts. Retrospective medical record review of laboratory values was performed to identify patients with hypercoagulable conditions. Case and control patients were further stratified based on both severity of CKD and warfarin. Patients with a dermatologic diagnosis of calciphylaxis between 2006 and 2014 and concomitant CKD were included as cases (n = 38). Three controls (n = 114) per case patient with CKD were included, and were matched by age, sex, and race. Main Outcomes and Measures The rate of various hypercoagulable states (ie, antithrombin III [ATIII] deficiency, protein C and S deficiency, factor V Leiden mutation, prothrombin gene mutation [G20210A], elevated factor VIII level, lupus anticoagulant, anti-IgG or IgM cardiolipin antibodies, heparin-induced thrombocytopenia antibodies, and elevation of homocysteine) in patients with calciphylaxis compared with their matched controls. Results Of the calciphylaxis cohort, 28 (58%) were female and 18 (55%) were non-Hispanic white. Among all patients, lupus anticoagulant (13 [48%] positive in cases vs 1 [5%] in controls; P = .001), protein C deficiency (9 [50%] vs 1 [8%]; P = .02), and combined thrombophilias (18 [62%] vs 10 [31%]; P = .02) were found to be significantly associated with calciphylaxis. In a subanalysis of patients with stage 5 CKD, only lupus anticoagulant (12 [53%] vs 9 [0%]; P = .01) and combined thrombophilia (15 [63%] vs 1 [8%]; P = .004) remained significantly associated with calciphylaxis. In a separate subanalysis of warfarin-unexposed patients, only lupus anticoagulant (7 [50%] vs 1 [6%]; P = .01) and protein C deficiency (5 [46%] vs 10 [0%]; P = .04) remained significantly associated with calciphylaxis. Conclusions and Relevance Presence of lupus anticoagulant and combined thrombophilias are risk factors for the development of calciphylaxis in patients with late-stage renal disease. Clinicians should be aware of these associations in patients with impaired kidney function and may consider increased screening and appropriate anticoagulation treatment to reduce the risk of calciphylaxis development.

Effect of Dermatology Consultation on Outcomes for Patients With Presumed Cellulitis: A Randomized Clinical Trial

Importance Each year, cellulitis leads to 650 000 hospital admissions and is estimated to cost

Clinical Usefulness of Imaging and Blood Cultures in Cellulitis Evaluation

3.7 billion in the United States. Previous literature has demonstrated a high misdiagnosis rate for cellulitis, which results in unnecessary antibiotic use and health care cost. Objective To determine whether dermatologic consultation decreases duration of hospital stay or intravenous antibiotic treatment duration in patients with cellulitis. Design, Setting, and Participants This randomized clinical trial was conducted in a large urban tertiary care hospital between October 2012 and January 2017, with 1-month follow-up duration. Patients were randomized to the control group, which received the standard of care (ie, treatment by primary medicine team), or the intervention group, which received dermatology consultation. Medical chart review of demographic information and hospital courses was performed. Adult patients hospitalized with presumed diagnosis of cellulitis were eligible. A total of 1300 patients were screened, 1125 were excluded, and 175 were included. Statistical analysis was employed to identify significant outcome differences between the 2 groups. Interventions Dermatology consultation within 24 hours of hospitalization. Main Outcomes and Measures Length of hospital stay and duration of intravenous antibiotic treatment. Results Of 175 participants, 70 (40%) were women and 105 (60%) were men. The mean age was 58.8 years. Length of hospital stay was not statistically different between the 2 groups. The duration of intravenous antibiotic treatment (<4 days: 86.4% vs 72.5%; absolute difference, 13.9%; 95% CI, 1.9%-25.9%; P = .04) and duration of total antibiotic treatment was significantly lower in patients who had early dermatology consultation (<10 days: 50.6% vs 32.5%; absolute difference, 18.1%; 95% CI, 3.7%-32.5%; P = .01). Clinical improvement at 2 weeks was significantly higher for those in the intervention group (79 [89.3%] vs 59 [68.3%]; absolute difference, 21.0%; 95% CI, 9.3%-32.7%; P < .001). There was no significant difference in 1-month readmission rate between the groups (4 [4.5%] vs 6 [6.9%]; absolute difference, −2.4%; 95% CI, −9.3% to 4.5%; P = .54). In the intervention group, the rate of cellulitis misdiagnosis was 30.7% (27 of 88 participants). Among the entire cohort, 101 (57.7%) patients were treated with courses of antibiotics longer than what is recommended by guidelines. Conclusions and Relevance Early dermatologic consultation can improve outcomes in patients with suspected cellulitis by identifying alternate diagnoses, treating modifiable risk factors, and decreasing length of antibiotic treatment. Trial Registration clinicaltrials.gov Identifier: NCT01706913

Fractures in calciphylaxis patients following intravenous sodium thiosulfate therapy

volve a shorter duration of antibiotic exposure.6 Our study has limitations. First, we were not able to account for underlying conditions or other indicators for longer courses of antibiotic therapy. Second, by excluding visits with a diagnosis of unspecified sinusitis from our analysis, we may have excluded some cases of acute sinusitis. However, the findings of a sensitivity analysis that included cases of both acute and unspecified sinusitis were similar (median duration of therapy, 10.0 days; 88.1% [95% CI, 85.1%-91.0%] of nonazithromycin antibiotic courses were 10 days or longer in duration). Outpatient antibiotic stewardship programs can optimize infection management by ensuring guideline-concordant treatment, including the use of minimum effective durations of antibiotic therapy. The durations of most courses of antibiotic therapy for adult outpatients with sinusitis exceed guideline recommendations, which represents an opportunity to reduce the unnecessary use of antibiotics when therapy with antibiotics is indicated.

Skin Surface Temperatures Measured by Thermal Imaging Aid in the Diagnosis of Cellulitis

Calciphylaxis is a highly fatal syndrome of small vessel calcification that results in skin ischemia and necrosis.[1] Affected patients present with extremely painful, violaceous skin lesions that progress to non-healing ulcers, and can be complicated by superimposed infections and sepsis.[2] The mortality rate from calciphylaxis is estimated at 60-80%.[2, 3] Sodium thiosulfate (STS), an increasingly popular treatment for calciphylaxis, is theorized to work through vasodilation, antioxidation, and calcium chelation. Known adverse effects include volume overload, metabolic acidosis, and hypotension.[2, 4] We report four patients who experienced unusual fractures during or following treatment with intravenous STS (IVSTS), an adverse effect that has not yet been reported in the literature. This article is protected by copyright. All rights reserved.