Andrea D. Maderal

Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment.

BACKGROUND Keloid and hypertrophic scars represent an aberrant response to the wound healing process. These scars are characterized by dysregulated growth with excessive collagen formation, and can be cosmetically and functionally disruptive to patients. OBJECTIVE Objectives are to describe the pathophysiology of keloid and hypertrophic scar, and to compare differences with the normal wound healing process. The classification of keloids and hypertrophic scars are then discussed. Finally, various treatment options including prevention, conventional therapies, surgical therapies, and adjuvant therapies are described in detail. MATERIALS AND METHODS Literature review was performed identifying relevant publications pertaining to the pathophysiology, classification, and treatment of keloid and hypertrophic scars. RESULTS Though the pathophysiology of keloid and hypertrophic scars is not completely known, various cytokines have been implicated, including interleukin (IL)-6, IL-8, and IL-10, as well as various growth factors including transforming growth factor-beta and platelet-derived growth factor. Numerous treatments have been studied for keloid and hypertrophic scars,which include conventional therapies such as occlusive dressings, compression therapy, and steroids; surgical therapies such as excision and cryosurgery; and adjuvant and emerging therapies including radiation therapy, interferon, 5-fluorouracil, imiquimod, tacrolimus, sirolimus, bleomycin, doxorubicin, transforming growth factor-beta, epidermal growth factor, verapamil, retinoic acid, tamoxifen, botulinum toxin A, onion extract, silicone-based camouflage, hydrogel scaffold, and skin tension offloading device. CONCLUSION Keloid and hypertrophic scars remain a challenging condition, with potential cosmetic and functional consequences to patients. Several therapies exist which function through different mechanisms. Better understanding into the pathogenesis will allow for development of newer and more targeted therapies in the future.

Evidence-based management of common chronic lower extremity ulcers

Chronic lower extremity ulcers are a significant burden on patients and health care systems worldwide. Although relatively common, these wounds can be difficult to treat and present a challenge to physicians. Treatment has often been based on anecdotal accounts; however, there is a growing emphasis on using evidence‐based conclusions to guide clinical decisions. In this review article, the standard of care and adjuvant therapies of venous leg ulcers and diabetic foot ulcers are presented from an evidence‐based perspective.

Neuropathy and Ankle Mobility Abnormalities in Patients With Chronic Venous Disease

IMPORTANCE How complications associated with chronic venous insufficiency (CVI) develop is not clear. The central source of the complications is likely a dysfunction of the calf muscle pump, which includes veins and their valves, the gastrocnemius and other lower leg and foot muscles as well as the nerves supplying the muscles, and ankle mobility limitations. The least well-studied source of complications is the relationship between range of ankle movement (ROAM), neuropathy, and the clinical severity of the disease. OBJECTIVE To study sensory neuropathic changes and ankle mobility in patients with CVI to help elucidate the pathophysiologic development of venous ulcers. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study took place from August 2011 to August 2012 at the outpatient wound clinic and the wound healing research clinic at the University of Miami Hospital. Sixty-four limbs from 42 individuals were evaluated and individually classified according to the clinical aspect of the clinical-etiology-anatomy-pathophysiology classification for CVI. MAIN OUTCOMES AND MEASURES Range of ankle movement was measured using goniometry, measuring active ankle combined plantarflexion and dorsiflexion and combined inversion and eversion. Peripheral neuropathy was measured subjectively through the Neuropathy Symptom Score and objectively through the Neuropathy Disability Score scales. RESULTS More patients with severe CVI had reduced plantarflexion-dorsiflexion ROAM compared with patients with mild CVI (25 [89%] vs 11 [31%]; P < .001) and reduced inversion-eversion ROAM (22 [79%] vs 4 [11%]; P < .001). Patients with worse CVI had significantly worse neuropathy with higher Neuropathy Symptom Score and Neuropathy Disability Score values compared with patients with less severe CVI. CONCLUSIONS AND RELEVANCE We found a relationship between reduced ROAM and worse neuropathy with increased severity of CVI. Management in patients with CVI should include testing for neuropathy and improving ankle mobility.

The FDA and designing clinical trials for chronic cutaneous ulcers

Treatment of chronic wounds can present a challenge, with many patients remaining refractory to available advanced therapies. As such, there is a strong need for the development of new products. Unfortunately, despite this demand, few new wound-related drugs have been approved over the past decade. This is in part due to unsuccessful clinical trials and subsequent lack of Food and Drug Administration (FDA) approval. In this article, we discuss the FDA approval process, how it relates to chronic wound trials, common issues that arise, and how best to manage them. Additionally, problems encountered specific to diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are addressed. Careful construction of a clinical trial is necessary in order to achieve the best possible efficacy outcomes and thereby, gain FDA approval. How to design an optimal trial is outlined.

Quality assessment of tissue specimens for studies of diabetic foot ulcers

Diabetic foot ulcers (DFUs) represent an important clinical problem resulting in significant morbidity and mortality. Ongoing translational research studies strive to better understand molecular/cellular basis of DFU pathology that may lead to identification of novel treatment protocols. Tissue at the non‐healing wound edge has been identified as one of major contributors to the DFU pathophysiology that provides important tool for translational and clinical investigations. To evaluate quality of tissue specimens and their potential use, we obtained 81 DFU specimens from 25 patients and performed histological analyses, immunohistochemistry and RNA quality assessments. We found that depth of the collected specimen is important determinant of research utility, and only specimens containing a full‐thickness epidermis could be utilized for immunohistochemistry and RNA isolation. We showed that only two‐thirds of collected specimens could be utilized in translational studies. This attrition rate is important for designs of future studies involving tissue specimen collection from DFU.

Diabetic Foot Ulcers: Evaluation and Management

Abstract Diabetic foot ulcers (DFUs) are a common complication of diabetes and present a significant health risk to patients, as well as impose a large economic burden. Evaluation for contributory factors that may impact general health or healing, such as hyperglycemia, peripheral artery disease, neuropathy, and nutritional status, is of the utmost importance. Management of DFUs requires involvement of a multidisciplinary team and a standardized approach to patient care. Standard therapy for DFUs includes offloading and debridement. Assessment and control of infection are critical, including determining the severity of the infection, which may drive therapeutic approaches. For recalcitrant ulcers, adjuvant therapies are used to hasten the healing process, and newer therapies are under investigation.

Use of a keratin-based hydrogel in the management of recessive dystrophic epidermolysis bullosa

Abstract A new keratin-based hydrogel wound dressing was applied to the neck of a patient who was suffering from recessive dystrophic epidermolysis bullosa. A significant improvement was observed in the robustness of skin in this area: reduced propensity to blister and improved healing of blisters. The improvement allowed the cessation of use of secondary dressings for this area. The factors gave a significant improvement in quality of life for the patient.

Designing clinical trials to bring wound products to market

Few novel products supported by rigorous research have reached the wound healing market in the last decade. This has been in part because of a number of failed or inconclusive studies resulting in low-level evidence (1,2). Many of these products have failed to progress from a phase II trial to a phase III trial, where the likelihood of success would be expected to be greater, based on better data on which to design an appropriate trial. A variety of reasons might account for trial failure ranging from ineffectiveness of study product to financial costs of drug or device development. However, one key element may be study design. Although it might appear possible that a single wound healing product is a panacea for all wounds at all times, it is more logical to assume that a product alters or enhances the biology of certain wounds at certain times. Certain products might be better for stimulating refractory wounds, while others improving healing of less difficult wounds (3,4). Therefore one would suppose that no single product is appropriate for the management of all wounds and that a logical course would be to study those wounds that have the highest likelihood of healing with any given product. The need for new products exists. For example, for patients with venous leg ulcerations, from 30% to 75% of patients respond to standard care including multi-layered compression bandages over a 6-month time period (5) but due to a refractory subset, venous ulcers cost the health care system billions of dollars annually (6). Clinical predictors of leg ulcer healing have been described for those with a low likelihood of healing (7). Several studies have showed that using wound size and wound duration can predict the likelihood of healing of venous leg ulcers (8,9). Among those Margolis et al. developed a simple predictive model to stratify patients on the likelihood of healing with standard of care using compression bandages (5,10). They found that wounds of small size (<5 cm2) and of short duration (<6 months) (Margolis score 0) healed quite well with standard care (93% of the time with compression therapy by 24 weeks), those possessing one of those factors (large size or long duration but not both) (Margolis score 1) healed 65% of the time, and those of long duration and large size (Margolis score 2) healed infrequently, only 13% of the time. This information can be used as a historical control to determine the potential benefit of novel therapies under development and have the potential to be used to help future clinical trial design. Thus this model can help determine whether a product has its relative effect on easy (perhaps speeding healing), relatively difficult (increasing healing or time to healing) or exceedingly difficult (increasing healing) to heal venous ulcers. As an example, recent technological developments have led to the creation of intact keratin (non hydrolysed) products suitable for topical application, for example, a keratinbased hydrogel (11,12). After Institutional Review Board approval, an open-label study to determine the effect of topical keratin dressings (Keratec International, Christchurch, New Zealand), either a keratin-based hydrogel or keratin-based foam (depending on the amount of exudate) plus compression therapy was performed for the treatment of venous ulcers. Patients were stratified by Margolis score, as described above, and seven patients with refractory venous ulcers with a Margolis score 2 were enrolled. Baseline planimetry and photography were performed at baseline, weekly and at the end of this study. Dressings were changed at least weekly and more often if required. By 12 weeks, five of the seven (71·4%) patients healed, greater than the 13% predicted to heal by 24 weeks. This would imply for future larger trials, instead of allowing all patients with venous ulcers to be enrolled, limiting patients with refractory venous ulcers based on size and duration, would lend the best chance to optimise success. Using pilot data and intelligent trial design to propose larger and more expensive trials would allow for more efficient and costefficient trials. Most importantly, this would allow for design of more rational larger studies and provide a better chance for new treatments for success.

Preservative Sensitization—Safety With and Safety Without

Opinion statementPreservatives serve the necessary purpose of preventing microbial contamination and maintaining cosmetic product integrity and safety; however, there are limitations to their use. Preservatives, including formaldehyde (FA) and formaldehyde releasers (FRPs), isothiazolinones, iodopropynyl butylcarbamate (IPBC), methyldibromoglutaronitrile (MDBGN), parabens, thimerosal, and triclosan, are a leading cause of allergic and irritant contact dermatitis, and there is increasing evidence that some may even cause toxic effects including endocrinological effects. One approach to minimizing these effects is the use of self-preserving or preservative-free cosmetic formulations. This article will outline these preservatives, their role in cosmetics, scientific evidence for allergy and toxic effects, and potential alternatives.

Anti-IgE Therapy

Omalizumab is an anti-immunoglobulin E (IgE) therapy indicated for moderate to severe persistent asthma and chronic spontaneous or idiopathic urticaria, with several other potential uses in dermatology. It is a recombinant, 95% humanized monoclonal antibody that selectively binds circulating human IgE, thereby reducing circulating IgE levels and inhibiting mast cell response to antigenic stimuli. It is approved for use in dermatology as a third-line and fourth-line treatment for chronic spontaneous urticaria in Europe and the United States, respectively. It has also demonstrated benefit off-label for several other dermatologic conditions, including physical urticarias, urticarial vasculitis, angioedema, atopic dermatitis, bullous pemphigoid, and mastocytosis. Adverse events associated with omalizumab are overall mild, with the most common reactions including nausea, nasopharyngitis, sinusitis, upper respiratory infection, arthralgia, headache, and cough. Anaphylaxis was reported during clinical trials for asthma, with an incidence of 0.1–0.2%, and, therefore, a black box warning for anaphylaxis from omalizumab exists. In the dermatology literature, only two patients have been reported to have anaphylaxis during treatment with omalizumab. Omalizumab is contraindicated in patients with severe hypersensitivity reaction to omalizumab or any of its ingredients and is pregnancy category B.