Wound research has typically been performed without regard for where the wounds are located on the body, despite well-known heterogeneities in physical and biological properties between different skin areas. Skin covering the palms and soles is highly specialized, and plantar ulcers are one of the most challenging and costly wound types to manage. Using primarily the porcine model, we show that plantar skin is molecularly and functionally more distinct from non-plantar skin than previously recognized, with unique gene and protein expression profiles, broad alterations in cellular functions, constitutive activation of many wound-associated phenotypes, and inherently delayed healing. This unusual physiology is likely to play a significant but underappreciated role in the pathogenesis of plantar ulcers, as well as the last 25+ years of futility in therapy development efforts. By revealing this critical yet unrecognized pitfall, we hope to contribute to the development of more effective therapies for these devastating non-healing wounds.

For patients with lower limb amputations, prostheses are immensely helpful for mobility and the ability to perform job-related or recreational activities. However, the skin covering the amputation stump is typically transposed from adjacent areas of the leg and lacks the weight-bearing capacity that is only found in the specialized skin covering the palms and soles (a.k.a. volar skin). As a result, the skin tissue in direct contact with the prosthesis frequently breaks down, leading to the development of painful sores and other complications that limit, and often preclude, the use of prostheses. Transplanting volar skin onto amputation stumps could be a solution to these problems, but traditional skin transplantation techniques cause substantial morbidity at the donor site, such as pain and scarring, which are especially problematic for volar skin given the critical functional importance of the volar skin areas. We previously developed the technology to collect and engraft full-thickness skin tissue while avoiding long-term donor site morbidity, by harvesting the skin in the form of small (~0.5 mm diameter) cores that we termed "micro skin tissue columns" (MSTCs), so that each donor wound is small enough to heal quickly and without clinically appreciable scarring or other long-term abnormalities. The goal of this study was to establish whether a similar approach could be used to confer the structural and molecular characteristics of volar skin ectopically to other skin areas. In a human-to-mouse xenograft model, we show the long-term persistence of various human plantar MSTC-derived cell types in the murine recipient. Then in an autologous porcine model, we harvested MSTCs from the bottom of the foot and transplanted them onto excision wounds on the animals' trunks. The healing processes at both the donor and graft sites were monitored over 8 weeks, and tissue samples were taken to verify volar-specific characteristics by histology and immunohistochemistry. The volar donor sites were well-tolerated, healed rapidly, and showed no signs of scarring or any other long-term defects. The graft sites were able to maintain volar-specific histologic features and expression of characteristics protein markers, up to the 8-week duration of this study. These results suggest that MSTC grafting could be a practical approach to obtain autologous donor volar skin tissue, confer volar skin characteristics ectopically to nonvolar skin areas, improve the load-bearing capacity of amputation stump skin, and ultimately enhance mobility and quality-of-life for lower limb amputees.

To the Editor: Autoimmune bullous diseases (AIBDs) have autoantibodies that correlate with disease activity. However, little is known about the duration of seropositivity before the date of diagnosis. We performed a retrospective descriptive study of disease-specific antibodies in 96 patients with dermatitis herpetiformis (DH), bullous pemphigoid (BP), mucus membrane pemphigoid (MMP), pemphigus vulgaris (PV), and pemphigus foliaceus (PF) before the date of diagnosis, defined as obtaining a diagnostic direct immunofluorescence (DIF) biopsy specimen.

INTRODUCTION Skin malignancy has increased in prevalence over the last 15 years and effective diagnosis is required for adequate treatment. Retrospective data analysis of skin biopsy data has shown correlation between various independent variables, but no studies have been shown to directly assess skin malignancy risks for military personnel. Assessing correlation could lead to more effective, targeted screening programs that could lead to decreased mortality from skin malignancies. We present a 1-year analysis of the number needed to biopsy (NNB) to detect skin cancer and analysis of military-specific risk factors in a military dermatology training program. The present study aims to (1) compare skin biopsy yields to civilian institutions and patient populations and (2) determine significance of exposure variables including age, gender, military beneficiary status, branch of service, and military rank. MATERIALS AND METHODS We performed a retrospective observational study over 1 year by identifying all skin biopsies performed in the Walter Reed National Military Medical Center dermatology clinic from August 2015 to July 2016. Utilizing the pathology reports, we manually excluded biopsies performed for the purpose of ruling out inflammatory/immunologic conditions or cosmeses and focused only on encounters performed to rule out basal cell carcinoma, squamous cell carcinoma, or melanoma. We decided to exclude malignant diagnoses that were exceedingly rare or could mimic inflammatory conditions, such as cutaneous T-cell lymphoma. For uncertain diagnoses with vague context per pathology report, previous office clinic notes and pre-biopsy differential were referenced and included only if melanoma or non-melanoma skin cancer (NMSC) diagnosis was the intended indication. RESULTS A total of 3,098 biopsies were included in the study, diagnostic for 1,084 total skin malignancy and 54 melanoma diagnoses. Melanoma comprised 4.98% of all skin malignancy diagnosed. The NNB for all skin malignancy was 2.86 (95% CI 2.76-2.96) and NNB for melanoma and NMSC was 20.93 (95% CI 19.70-22.15) and 1.91 (95% CI 1.83-2.00), respectively. Patient age, gender, and military rank significantly impacted NNB values (P < .001). CONCLUSIONS The proportion of melanoma skin cancers is notably increased in our population compared to published population statistics with comparable total biopsy yields. Skin biopsy for purpose of screening for malignancy should be performed in the military population and consideration should be made for gender, age, and rank. Our findings can further expand on military risk factors for skin cancer and aid in further multivariant modeling.

This review summarizes the history and usage of teledermatology in the US Military and potential directions in the future. Given the remote and austere environment that operational settings present, it is hard to provide specialized medical care for soldiers who are deployed. Telemedicine has been shown to improve health care in the military. It is well documented that non-life-threatening skin disease comprises the majority of specialty care requests in the deployed setting. Thus, teledermatology is a critical resource in military operational medical settings. Teledermatology continues as a critical component of military medicine to preserve the fighting forces by increasing access to specialty care. Teledermatology evaluations are more cost-effective and efficient than in-person consults at field hospitals. The US military continues to devise improved technology for teledermatology quality, including artificial intelligence. These advances may allow for autonomous teledermatology consults in the future for austere settings without bandwidth.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1–4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK–STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK–STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine. Single-cell RNA sequencing facilitates successful therapeutic treatment of a patient with a rare and severe drug-induced inflammatory skin reaction.

Anti-programmed cell death 1 (PD1) targeted immune checkpoint inhibitors such as nivolumab and pembrolizumab are increasingly used to treat advanced malignancies such as melanoma, non-small cell lung cancer, urothelial cancer, and renal cell carcinoma. A rare but increasingly reported adverse effect of anti-PD1 therapy is bullous pemphigoid (BP), an autoimmune blistering disease directed against BP antigen 1 and BP antigen 2 in the basement membrane of the epidermis. We present 3 cases of BP secondary to anti-PD1 immunotherapy in patients with melanoma and non-small cell lung cancer to highlight the diagnosis and treatment of this condition and emphasize the importance of the dermatologist in the care of patients with immunotherapy-related skin disease.

Rivard, Shayna C. MD; Kentosh, Joshua DO; Nesti, Leon J. MD, PhD; Meyerle, Jon H. MD Author Information

Epidermolysis Bullosa Acquisita (EBA) is a chronic autoimmune subepidermal blistering disease developed after damage to type VII collagen by autoantibodies. Type VII collagen is the major component of anchoring fibrils in the sub-lamina densa hemidesmosomes of the skin and squamous mucosas. The worldwide incidence is estimated between 0.2-0.5/million inhabitants per year. Two major clinical variants have been described: the mechanobullous, and the inflammatory EBA.

Unfractionated heparin (UFH) is frequently used in the treatment of venous thromboembolism and acute coronary syndrome. There are many common cutaneous adverse reactions to this medication. We present a unique case of hemorrhagic bullae limited to the oral mucosa that developed within 6 hours of a patient receiving UFH.

INTRODUCTIONSkin diseases have had a significant impact on the health of deployed military service members throughout history. Given the high prevalence historically of cutaneous disease among United States deployed servicemembers, we review the burden of skin disease on the modern military by analyzing the most common dermatologic diagnoses made in deployed settings from 2008 to 2015. Furthermore, we compare the most common dermatologic diagnoses made in the deployed setting with those made by dermatologists and nondermatologists in the civilian healthcare system to highlight the differences between the civilian and deployed military practice environment.METHODSThis study queried the Theater Medical Data Store for International Classification of Diseases, Ninth Revision (ICD-9) codes to determine the total number of dermatologic encounters as part of all medical encounters from 2008 to 2015 in a deployed setting. These data were provided by the Armed Forces Health Surveillance Branch. For all statistical tests, analyses were conducted using R statistical software, with type I error controlled at 5%.RESULTSFrom 2008 to 2015, 92 dermatology-specific ICD-9 codes accounted for 429,837 dermatologic diagnoses that were made in a deployed setting, equating to 10% of all diagnoses. The top 20 dermatologic diagnoses were identified, and the percentage of total medical diagnoses (TMD) was calculated. Once the individual diagnoses were categorized, a direct comparison was made between the top 20 most prevalent disease categories among deployed military servicemembers and those of the United States (US) population as a whole, based on claims. The most prevalent diagnoses were compared amongst four different settings: Deployed military, military teledermatology, civilian dermatologists, and civilian nondermatologists. Overall comparison of the prevalence between each of these groups showed an association between setting and diagnosis prevalence.CONCLUSIONSThe total burden of disease based on diagnostic codes from 2008 to 2015 is 429,837 diagnoses. This accounts for 10% of TMD from 2008 to 2015 in the deployed setting. Diagnoses most prevalent in the deployed military setting had more in common with those made by civilian nondermatologists compared with military teledermatology and civilian dermatologists. At 10% of diagnoses made in the deployed military setting in this timeframe, skin disease accounts for a substantial burden on deployed servicemembers. Deployed servicemembers with skin disease should be supported through use of teledermatology resources and improved dermatology education for primary care and deployed medical personnel.

Bullous systemic lupus erythematosus (BSLE) is a rare complication of systemic lupus erythematosus (SLE) characterized by cutaneous vesicles and bullae with a primarily neutrophilic infiltrate on histopathology. Bullous SLE is a heterogeneous disease without pathognomonic clinical features, making the diagnosis and differentiation from other blistering diseases challenging. We present the case of a single patient with SLE in whom 3 different clinical appearances of BSLE manifested over 5 years. The cutaneous eruption dramatically improved with rituximab at the initial presentation and continued to respond to rituximab during subsequent flares over the subsequent 5 years.

Amputees face many challenges associated with residual limbs. Overall, amputees have an increased risk for skin disease occurring at residual limb sites. Although prosthetists and primary care physicians often accomplish routine care, the dermatologist plays a very important role within the multidisciplinary team. Many military dermatologists have unique clinical experience treating amputees, as a portion of their practice consists of providing care to soldiers with traumatic amputations from complex and dramatic blast injuries. Although current therapies and preventative treatments are for the most part successful, future research involving advanced technology is promising.

We report the case of an 8-year-old boy who was taking amantadine off label for multiple childhood neurobehavioral disorders and subsequently developed livedo reticularis. Although this side effect is well-described in adult patients taking amantadine for Parkinson disease, it is now being seen in children as the off-label use of amantadine is expanded to this population.

Drug induced linear IgA bullous dermatosis (LABD) is a rare blistering disease that has been shown to be associated with the use of various medications. Although rarely seen together, some of the medications associated with LABD can lead to the syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which presents with fever, cutaneous eruption, and multi-organ involvement. We present a patient who developed fever and a generalized vesiculobullous eruption after recently starting amlodipine and meloxicam. Initial laboratory tests demonstrated elevated liver function tests, leukocystosis, and eosinophilia. Histopathologic examination of the punch biopsy revealed a bulla with sub-epidermal split and numerous neutrophils. Direct immunofluorescence demonstrated broad deposition of IgA along the dermal-epidermal junction. These findings were consistent with an overlap between LABD and DRESS. Drug induced LABD and DRESS are independently both rare diseases. It is even more uncommon to see the two concurrently in the same patient. In this patient, these two conditions were thought to be triggered by either amlodipine or meloxicam. Given the high mortality rate associated with DRESS, it is important to recognize the presentation and initiate the appropriate treatment plan as soon as possible.

Early detection of skin cancer is essential to reducing morbidity and mortality from both melanoma and nonmelanoma skin cancers. Total-body skin examinations (TBSEs) may improve early detection of malignant melanomas (MMs) but are controversial due to the poor quality of data available to establish a mortality benefit from skin cancer screening. Total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase patient access to dermatologic care. Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to flag concerning lesions that may require closer evaluation. On a population level, inexpensive TBP has the potential to increase access to skin cancer screening and it has several specific applications in a military population. The utility of standardized TBP is reviewed in the context of skin cancer screening and teledermatology.

Given that the majority of active duty service members are young and healthy, potentially malignant diagnoses such as skin cancer may be overlooked. Although melanoma accounts for only approximately 1% of skin cancers, it causes the greatest majority of skin cancer deaths. We present the case of a 27-year-old active duty Marine who presented with a hyperpigmented macule at his lateral neck that was a malignant melanoma in situ. This article reviews risk factors for the development of melanoma, offers guidelines for primary care providers, reviews resources for providers in a deployed or austere environment, offers recommendations for prevention and early diagnosis, and discusses follow up.

Psoriasis is a chronic immune-mediated dermatologic disorder affecting approximately 2% of the general population. Under current U.S. Army regulation, the diagnosis of psoriasis is a bar to enlistment or appointment and, if poorly controlled, is grounds for referral to a Medical Evaluation Board and potential discharge from military service, according to Army Regulation 40-501. However, between 2008 and 2015, over 3,600 soldiers sought care for psoriasis while deployed to combat theaters, indicating that psoriasis remains a significant medical concern in the U.S. military. Although mild psoriasis is treatable with topical agents, moderate to severe psoriasis may require systemic treatment. Prior to Food and Drug Administration approval of apremilast (Otezla) in 2014, the standard systemic treatment options were methotrexate and biologic agents such as anti-Tumor Necrosis Factor-alpha medications. Active use of methotrexate or biologic immunomodulatory medications automatically disqualifies soldiers from deployment due to monitoring requirements, the need for refrigeration, and the risk for immune compromise. Apremilast offers treatment efficacy similar to that of methotrexate, and it may be taken while deployed because it does not require monitoring or refrigeration. However, efficacy must be evaluated in the context of its much higher unit cost. Nonetheless, we argue that apremilast may be a useful treatment option for psoriasis in a select group of soldiers who must deploy despite suffering from moderate to severe psoriasis.